Text Version
Entrez PubMed
Overview
Help |
FAQ
Tutorial
New/Noteworthy
E-Utilities
PubMed Services
Journals Database
MeSH Database
Single Citation Matcher
Batch Citation Matcher
Clinical Queries
LinkOut
Cubby
Related Resources
Order Documents
NLM Gateway
TOXNET
Consumer Health
Clinical Alerts
ClinicalTrials.gov
PubMed Central
Privacy Policy
|
|
-
[Disseminated intravascular coagulation]
[Article in Japanese]
Iba T, Kidokoro A.
Department of Surgery, Juntendo University, Urayasu Hospital.
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic formation of microthrombi and fibrin deposition in the vasculature. Cancer is one of the leading cause of DIC, which often complicates bleeding tendency and organ dysfunction. Even though DIC therapy is expectant, it is still important, since the bleeding tendency limits the quality of patients' life remarkably. Heparin, low molecular weight heparin, danaparoid, protease inhibitors for coagulation factors and antithrombin III are the choices for DIC. However, since the selection of the drugs is different depending on the basal disease, it is important to understand the pathophysiology of the individual situation. In general, protease inhibitors is recommended for 'fibrinolysis dominant DIC' like DIC associated with leukemia and terminal stage solid cancer, in contrast, danaparoid and antithrombin III are the first choice for 'coagulation dominant DIC' like sepsis. Supplement of concentrated platelets and fresh frozen should be limited for the patients whose primary disease can be controlled.
Publication Types:
PMID: 12806952 [PubMed - indexed for MEDLINE]
Effects of strenuous exercise on haemostasis.
Smith JE.
Academic Department of Sports Medicine, Royal London Hospital (Mile End), Bancroft Road, London E1, UK. jason.smith75@virgin.net
OBJECTIVES: To review the effects of exercise on haemostasis and examine the possible clinical sequelae of these changes. METHODS: The search strategy included articles from 1966 to August 2002 using Medline and SportDiscus databases, and cross referencing the bibliographies of relevant papers. RESULTS: Exercise results in activation of both the coagulation and fibrinolytic cascades, as shown by a reduction in whole blood clotting time and activated partial thromboplastin time, an increase in the activity of several components of the cascades, and an increase in fibrin degradation products. In vitro tests suggest that coagulation remains activated after fibrinolysis has returned to baseline levels. CONCLUSIONS: Both the coagulation and fibrinolytic cascades are stimulated by strenuous exercise, but the temporal relation between the two and its clinical significance remains to be clarified. Doctors and athletes should be aware of the haemostatic changes induced by exercise, and further work is needed to clarify the possible role of these changes in sudden cardiac death.
PMID: 14514536 [PubMed - in process]
Fresh frozen plasma in patients with disseminated intravascular coagulation or in patients with liver diseases.
Mueller MM, Bomke B, Seifried E.
Red Cross Blood Donor Service, Frankfurt am Main, Germany. mmueller@bsdhessen.de
Disseminated intravascular coagulation (DIC) and liver diseases are complex clinical conditions. Both disorders frequently disturb the finely tuned coagulation and fibrinolysis equilibrium. In DIC, a wide range of underlying disorders can induce a systemic activation of the coagulation system with generation of soluble fibrin, possible deposition of platelet-rich fibrin clots in the microvasculature and subsequent micro- or macroembolism, impaired organ perfusion and organ failure. Such coagulation activation depletes platelets, coagulation factors, and inhibitors and clinically can result in severe, sometimes untreatable bleeding, especially when bone marrow or liver function is diminished or invasive procedures are performed. In addition, a secondary counterbalancing activation of the fibrinolytic system to dissolve microcirculatory clots adds to the bleeding tendency. In conjunction with other options based on prompt and rigorous treatment of the underlying cause of DIC, fresh frozen plasma plays an important role in therapeutic management when overt bleeding is present or anticipated in DIC patients with disturbed coagulation or when an invasive procedure is being planned.In liver disease, factor and inhibitor synthesis in both the coagulation and fibrinolytic system is impaired, both quantitatively and qualitatively. This destabilizes the balance between the two systems. In addition, the clearance of activated coagulation factors and fibrin(ogen) degradation products (FDP) from the systemic circulation is impaired. In patients with liver diseases and acute or imminent bleeding, or before invasive procedures, fresh frozen plasma (FFP) offers advantages over clotting factor concentrates. However, hypervolemia following the required doses of FFP might pose a problem in some liver disease patients.The complex pathophysiology both in DIC and in liver disease requires early diagnosis and adequate management including plasma and platelet substitution after treatment of the underlying disease. Due to the heterogeneity of DIC and liver disease, prospective randomized trials are difficult to perform. Therefore, treatment recommendations are mostly empirical and less evidence-based. Therapy must be accompanied by close and repeated clinical and laboratory monitoring.
Publication Types:
PMID: 12379287 [PubMed - indexed for MEDLINE]
Plasmin/plasminogen system in colorectal cancer.
Berger DH.
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Pericellular proteolysis plays a crucial role in tumor cell invasion. The controlled degradation of the extracellular matrix by tumor cell-associated proteases allows tumor cells to invade surrounding tissues and gain access to the circulation. One of the main protease systems involved in tumor cell invasion and metastasis is the plasminogen/plasmin system (PPS). The components of the PPS include the urokinase plasminogen activator (uPA), its cell surface receptor urokinase plasminogen activator receptor (uPAR), and its naturally occurring inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Increases in tumor and serum levels of uPA, uPAR, and PAI-1 are associated with a worse prognosis in patients with colon cancer. Use of these proteins as either tumor or serum markers may allow more accurate determination of the prognosis in colon cancer patients. Furthermore, these proteins appear to be attractive as targets for the biologic therapy of colon cancer.
Publication Types:
PMID: 11965442 [PubMed - indexed for MEDLINE]
-
Proteases in blood clotting.
Walsh PN, Ahmad SS.
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA. pnw@astro.temple.edu
The serine proteases, cofactors and cell-receptor molecules that comprise the haemostatic mechanism are highly conserved modular proteins that have evolved to participate in biochemical reactions in blood coagulation, anticoagulation and fibrinolysis. Blood coagulation is initiated by exposure of tissue factor, which forms a complex with factor VIIa and factor X, which results in the generation of small quantities of thrombin and is rapidly shutdown by the tissue factor pathway inhibitor. The generation of these small quantities of thrombin then activates factor XI, resulting in a sequence of events that lead to the activation of factor IX, factor X and prothrombin. Sufficient thrombin is generated to effect normal haemostasis by converting fibrinogen into fibrin. The anticoagulant pathways that regulate blood coagulation include the protein C anticoagulant mechanism, the serine protease inhibitors in plasma, and the Kunitz-like inhibitors, tissue factor pathway inhibitor and protease nexin 2. Finally, the fibrinolytic mechanism that comprises the activation of plasminogen into plasmin prevents excessive fibrin accumulation by promoting local dissolution of thrombi and promoting wound healing by reestablishment of blood flow.
Publication Types:
PMID: 12463164 [PubMed - indexed for MEDLINE]
Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient.
Levi M.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
The incidence of sepsis and complications stemming from septicemia has remained constant in recent years despite improved levels of monitoring and care. Disseminated intravascular coagulation (DIC), a syndrome that occurs frequently in septic patients, is associated with increased mortality. Organ dysfunction is also a common sequela that is strongly correlated with DIC. Cytokines released early in the course of sepsis stimulate a procoagulant state that causes development of intravascular fibrin deposition. In a later stage of DIC, bleeding may occur in parallel because of consumption of clotting factors and inhibitors. Therapeutic strategies to attenuate or reverse these conditions have focused on multiple stages of the molecular cascade of events, including preventing cytokine induction, inhibiting coagulation processes, and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC associated with severe sepsis. Studies of other novel therapeutic avenues are still ongoing. Future efforts may be directed at combining 2 or more agents to achieve prompt and successful reversal of DIC. Copyright 2002 by W.B. Saunders Company
Publication Types:
PMID: 11815902 [PubMed - indexed for MEDLINE]
Fibrinolysis in disseminated intravascular coagulation.
Hack CE.
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Laboratory for Experimental and Clinical Immunology, University of Amsterdam, The Netherlands. Hack@CLB.nl
Studies in experimental models for sepsis, the most common cause of disseminated intravascular coagulation (DIC), have put forward the concept of a procoagulant state that is characterized by thrombin generation exceeding that of plasmin. Convincing evidence indicates that this imbalance between coagulation and fibrinolysis is due to increased levels of plasminogen activator inhibitor type 1 (PAI-1). Levels of this fibrinolysis inhibitor indeed correlate with outcome and severity of multiple organ failure in patients with sepsis, as well as in patients with DIC from other causes. Hence we suggest that PAI-1 constitutes an important target for therapy in patients with DIC.
Publication Types:
PMID: 11740686 [PubMed - indexed for MEDLINE]
-
Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.
Watanabe R, Wada H, Miura Y, Murata Y, Watanabe Y, Sakakura M, Okugawa Y, Nakasaki T, Mori Y, Nishikawa M, Gabazza EC, Shiku H, Nobori T.
DepartmentSecond Department of Internal Medicine, Mie University School of Medicine, Tsu-city, Japan.
In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure. The plasma levels of total PAI-1 and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-I, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.
PMID: 11441985 [PubMed - indexed for MEDLINE]
An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation.
Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Kumabashiri I, Morishita E, Yamazaki M, Aoshima K, Nakao S.
Department of Internal Medicine (III), Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa 920-8641, Japan.
OBJECTIVES: To investigate the relationship between fibrinolytic enhancement and the development of multiple organ failure (MOF) in disseminated intravascular coagulation (DIC). To detect the useful prognostic index for outcome in DIC. DESIGN: Case-control study. SETTING: A department of internal medicine in a university hospital, a clinical division for diagnosis and treatment, mainly of respiratory diseases, hematologic diseases, DIC, and other diseases requiring critical care medicine. PATIENTS: A total of 69 DIC patients, 31 with MOF. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: The DIC patients with MOF had more elevated levels of tissue plasminogen activator antigen (t-PA) and plasminogen activator inhibitor antigen (PAI), and more depressed levels of plasmin-alpha2 plasmin inhibitor complex (PIC) and fibrin/fibrinogen degradation products than those without MOF, although no significant difference in thrombin-antithrombin complex (TAT) levels was observed. A fibrinolytic enhancement (shown by PIC) was parallel to an activation of blood coagulation (shown by TAT) in DIC patients without MOF, although no such fibrinolytic enhancement was provoked even by much activation of blood coagulation in DIC patients with MOF. Whereas all the patients without MOF were restored from DIC, 14 of 31 patients with MOF were unable to be restored from DIC and died. A significant increase in plasma levels of t-PA and PAI under the condition of sustained hemostatic activation was observed in the patients who died. CONCLUSION: Enhanced fibrinolysis was considered to be the important defense mechanism in preventing the development of MOF in DIC. The increases in plasma levels of t-PA and PAI were poor prognostic markers in DIC. Further careful study may be useful to clarify whether the fibrinolytic therapy is beneficial in clinical DIC patients with MOF.
PMID: 11395595 [PubMed - indexed for MEDLINE]
Pathogenetic mechanisms of thrombosis in malignancy.
Donati MB, Falanga A.
Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Via Nazionale, I-66030 Santa Maria Imbaro, Italy. donati@cmns.mnegri.it
The interactions between components of the hemostatic system and cancer cells are multifaceted. Strong clinical evidence is accumulating on the prothrombotic tendency of cancer patients, which is enhanced by anticancer therapy, such as surgery and chemotherapy. The mechanisms of thrombus promotion in malignancy include some general responses of the host to the tumor (acute phase, inflammation, angiogenesis) and specific interactions of tumor cells with the clotting/fibrinolysis systems and with blood (leukocytes, platelets) or vascular cells. It is at present difficult to rank the relative weight of these multiple interactions on the basis of the well-recognized clinical evidence of enhanced thrombotic episodes in tumor patients. In any case, the mechanisms explored so far offer a sound experimental basis for prevention/treatment of thrombosis in tumor patients and leave open the possibility that some antithrombotic strategies may also affect the processes of tumor growth and dissemination. Copyright 2001 S. Karger AG, Basel
Publication Types:
PMID: 11549773 [PubMed - indexed for MEDLINE]
Update on tumor cell procoagulant factors.
Gale AJ, Gordon SG.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA., USA.
Tumor cells produce tissue factor, cancer procoagulant, plasminogen activators and other factors that interact with the coagulation system, the fibrinolytic system and vascular or blood cells such that they can upset the normal homeostasis and balance between activation and inhibition of the coagulation and fibrinolytic systems. These activities play a role in tumor cell growth and metastasis, vascular wall function, and hemostasis. Proteases and their inhibitors are intimately involved in all aspects of the hemostatic, cell proliferation and cellular signalling systems. This review provides a brief examination of recent observations in this complex interaction of cellular and hemostatic factors. Copyright 2001 S. Karger AG, Basel
Publication Types:
PMID: 11549774 [PubMed - indexed for MEDLINE]
The thrombophilic state in cancer patients.
Gouin-Thibault I, Achkar A, Samama MM.
Laboratoire d'Hematologie, Groupe hospitalier Charles Foix-Jean Rostand, Ivry-sur-Seine, France.
Thrombosis and disseminated intravascular coagulation are common complications of cancer. Specific conditions associated with cancer such as stasis due to immobilization or blood flow obstruction, surgery, infections, endothelium damage due to chemotherapeutic agents and abnormalities of blood coagulation contribute to the hypercoagulable and thrombophilic state of cancer patients. This procoagulant state in cancer arises mostly from the capacity of tumor cells to express and release procoagulant activities (cancer procoagulant and tissue factor). Decreased levels of inhibitors of coagulation, impaired fibrinolysis, the presence of antiphospholipid antibodies and an acquired activated protein C resistance contribute to the hypercoagulable state. The activation of coagulation is also implicated in tumor proliferation through interactions of coagulation with inflammation and increased tissue factor pathway inhibitor. Laboratory diagnosis of the thrombophilic state include (1) elevation of clotting factors, fibrinogen/fibrin degradation products, hyperfibrinogenemia and thrombocytosis and (2) elevation of specific markers of activation of coagulation: fibrinopeptide A, fragment 1 + 2, thrombin-antithrombin complexes and D-dimers. However, none of the tests has any predictive value for the occurrence of thrombotic events in one individual patient. In patients with venous thromboembolism a noninvasive screening for occult cancer is able to detect a relatively high incidence of hidden cancer and the search for thrombophilia seems important in patients without known cancer. Copyright 2001 S. Karger AG, Basel
Publication Types:
PMID: 11549775 [PubMed - indexed for MEDLINE]
-
Tumor cell prothrombotic properties.
Falanga A.
Dept. Hematology-Oncology, Ospedali Riuniti, Bergamo, Italy. annafalanga@yahoo.com
Thrombin generation and fibrin formation are constantly determined in patients with malignancy, who are at increased risk of thromboembolic complications. Most importantly, fibrin formation is also involved in the processes of tumor spread and metastasis. Activation of blood coagulation in cancer is a complex phenomenon, involving many different pathways of the hemostatic system and numerous interactions of the tumor cell with other blood cells, including platelet, monocyte and endothelial cell. Tumor cells possess the capacity to interact with all parts of the hemostatic system. They can directly activate the coagulation cascade by producing their own procoagulant factors or they can stimulate the prothrombotic properties of other blood cell components. All of the mechanisms are not entirely understood, however research studies in the last ten years have greatly improved our knowledge of tumor-promoted pro-thrombotic functions.
Publication Types:
PMID: 11990464 [PubMed - indexed for MEDLINE]
Heterogeneity in the incidence and clinical manifestations of disseminated intravascular coagulation: a study of 204 cases.
Okajima K, Sakamoto Y, Uchiba M.
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan. whynot@kaiju.medic.kumamoto-u.ac.jp
The incidence and clinical manifestations of disseminated intravascular coagulation (DIC) were examined in patients with a range of underlying disorders. Out of 1,882 patients suspected as having DIC, 204 cases were diagnosed as suffering from DIC and included in this study. The underlying disorders experienced by the patients were solid tumors (33.8%), hematologic malignancies (12.7%), aortic aneurysm (10.8%), infections (6.4%), post-operative complications (4.4%), liver disease (2.9%), obstetric disorders (2.5%), and miscellaneous diseases (26.5%). The incidence of DIC was 10.8% out of all patients suspected of having DIC, and the etiologies were 10.9% in solid tumors, 10.1% in hematological malignancies, 20.4% in aortic aneurysm, 12.7% in infections, 15.5% in post-operative complications, 15.8% in liver disease, 3.7% in obstetric disorders, and 9.8% in miscellaneous diseases. The clinical manifestations of DIC patients were varying dependent on their etiologies. Most DIC patients with aortic aneurysm (95.5%) and post-operative complications (88.9%) did not reveal any clinical manifestations. Although all of the patients with obstetric disorders had bleeding, only 20.0% of the patients had organ failure. In contrast, although only 15.4% of the patients with infections had bleeding, 76.9% of these patients had organ failure. Bleeding was observed in 31.9-50.0% of DIC patients with liver disease, hematologic malignancies, and solid tumors. Organ failure was observed in 21.7-33.3% of DIC patients with liver disease, hematological malignancies, and solid tumors. Analysis by measurement of plasma levels of antiplasmin and plasmin-antiplasmin complex suggested that excessive fibrinolysis might contribute to the development of bleeding in these DIC patients. Differences in plasma levels of thrombin-antithrombin complex and cross-linked fibrin degradation products could not account for the differences in the incidence of organ failure in the patients. These findings suggest that the clinical manifestation of DIC varies and might not only be a reflection of microthrombus formation but also a reflection of the other underlying pathomechanisms.
PMID: 11074538 [PubMed - indexed for MEDLINE]
-
[Blood coagulation changes and neoplastic pathology]
[Article in Italian]
Corsi MP, De Martinis M, Di Leonardo G, Loreto MF, Modesti M, Quaglino D.
Dipartimento di Medicina Interna e Sanita Pubblica, Universita, L'Aquila.
Cancer patients show an increased susceptibility to develop thromboembolic diseases, suggesting that disorders of coagulation are very common in this pathology. Tumor cells possess the capacity to interact with the hemostatic system, activating the coagulation cascade and stimulating the prothrombotic properties of other blood cell components; the same events while inducing a hypercoagulable state, also contribute to the processes of tumor growth, neoangiogenesis and metastatic formation. Multiple risk factors associated with malignant disease contribute to the hypercoagulability state: stasis induced by prolonged bed rest, vascular invasion by the tumor and iatrogenic complications including the use of central vein catheters and chemotherapy. Several tests have been developed to assess the hypercoagulable state, however their clinical significance still needs to be defined, especially in terms of their predictive value for thrombosis. Clinical manifestations vary from localized deep venous thrombosis (DVT) or pulmonary embolism, more generally associated with solid tumors, to disseminated intravascular coagulation, frequent in hematologic malignancies and metastatic cancer. Diagnosis of idiopathic DVT, in the absence of other risk factors, could indicate the presence of occult cancer, but the usefulness of an extensive work-up to detect malignancy in terms of cost to benefit ratio still has to be demonstrated. Patients with cancer and thromboembolism must be treated with anticoagulant therapy; a large number of studies have shown that either low molecular weight heparins or standard unfractionated heparin for the treatment of acute deep vein thrombosis in hospitalized patients are equally safe and effective; however, the first treatment has been reported to be associated with a lower mortality. After an episode of thrombosis the patients should be protected by a long term course of oral anticoagulation, remaining high the risk of recurrence for as long as the cancer is active.
Publication Types:
PMID: 11072743 [PubMed - indexed for MEDLINE]
-
Changes of the coagulation and fibrinolysis system in malignancy: their possible impact on future diagnostic and therapeutic procedures.
Korte W.
Institute for Clinical Chemistry and Haematology, Kantonsspital, St. Gallen, Switzerland. wolfgang.korte@gd-ikch.sg.ch
The interaction between malignant cell growth and the coagulation and fibrinolysis system has been a well known phenomenon for decades. During recent years, this area of research has received new attention. Experimental data suggest a role for the coagulation and fibrinolysis system in tumor development, progression and metastasis. Also, clinical research suggests that targeting the coagulation system or fibrinolysis system might influence the course of malignant disease beneficially. This paper reviews data on various hemostatic and fibrinolytic parameters in malignancy; the possible use of such parameters as risk markers in oncology patients; and possible targets of anti-neoplastic therapies using anticoagulant and/or antifibrinolytic strategies. Current evidence suggests that the tissue factor/factor VIIa pathway mediates the most abundant procoagulant stimulus in malignancy via the increase in thrombin generation. Tissue factor has been suggested to mediate pro-metastatic properties via coagulation-dependent and coagulation-independent pathways; tissue factor has also been implicated in tumor neo-angiogenesis. However, so far no model has been validated that would allow the use of tissue factor in its soluble or insoluble form as a marker for risk stratification in tumor patients. On the other hand, there is now good evidence that parts of the fibrinolytic system, such as urokinase-type plasminogen activator and its receptor ("uPAR"), can be used as strong predictors of outcome in several types of cancer, specifically breast cancer. Observation of various treatment options in patients with thromboembolic disease and cancer as well as attempts to use anticoagulants and/or therapies modulating the fibrinolytic system as anti-neoplastic treatment strategies have yielded exciting results. These data indicate that anticoagulant therapy, and specifically low molecular weight heparin therapy, is likely to have anti-neoplastic effects; and that their use in addition to chemotherapy will probably improve outcome of tumor treatment in certain types of cancer. However, the body of clinical data is still relatively small and the question whether or not we should routinely consider the coagulation and/or fibrinolysis system as therapeutic targets in cancer patients is yet to be answered.
Publication Types:
PMID: 11071061 [PubMed - indexed for MEDLINE]
No grip, no growth: the conceptual basis of excessive proteolysis in the treatment of cancer.
Reijerkerk A, Voest EE, Gebbink MF.
Laboratory of Medical Oncology, Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
The formation of new bloodvessels, called angiogenesis, is critical for a tumour to grow beyond a few mm(3) in size. A provisional matrix promotes endothelial cell adhesion, migration, proliferation and survival. Synthesis and degradation of this matrix closely resemble processes that occur during coagulation and fibrinolysis. Degradation of the matrix and fibrinolysis are tightly controlled and balanced by stimulators and inhibitors of the plasminogen activation system. Here we give an overview of these processes during tumour progression. We postulate a novel way to inhibit angiogenesis by removal of the matrix through specific and localised overstimulation of the plasminogen activation system.
Publication Types:
PMID: 10959055 [PubMed - indexed for MEDLINE]
-
[Disseminated intravascular coagulation]
[Article in Dutch]
Levi M, de Jonge E, ten Cate H.
Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Inwendige Geneeskunde en afd. Intensive Care, Amsterdam.
Disseminated intravascular coagulation is characterised by systemic activation of blood coagulation, resulting in formation of intravascular thrombi and impaired organ perfusion. Simultaneously, the ongoing consumption of platelets and coagulation factors may lead to bleeding. Disseminated intravascular coagulation is seen in septicaemic infections, trauma, malignancies, obstetrical complications, vascular diseases, toxic and immunological reactions. In summary, the systemic deposition of fibrin is caused by enhanced thrombin generation, simultaneous depression of physiological anticoagulant mechanisms and diminished fibrin degradation due to inhibition of fibrinolysis. The increased insight into the pathogenesis of disseminated intravascular coagulation provides a solid basis for development of improved management strategies for patients with this complication. Therapy may include anticoagulants, platelet and plasma transfusion, concentrates of coagulation inhibitors and antifibrinolytic agents.
Publication Types:
PMID: 10726156 [PubMed - indexed for MEDLINE]
-
The plasminogen activation system in tumor growth, invasion, and metastasis.
Andreasen PA, Egelund R, Petersen HH.
Department of Molecular and Structural Biology, Aarhus University, Denmark. pa@mbio.aau.dk
Generation of the serine proteinase plasmin from the extracellular zymogen plasminogen can be catalyzed by either of two other serine proteinases, the urokinase- and tissue-type plasminogen activators (uPA and tPA). The plasminogen activation system also includes the serpins PAI-1 and PAI-2, and the uPA receptor (uPAR). Many findings, gathered over several decades, strongly suggest an important and causal role for uPA-catalyzed plasmin generation in cancer cell invasion through the extracellular matrix. Recent evidence suggests that the uPA system is also involved in cancer cell-directed tissue remodeling. Moreover, the system also supports cell migration and invasion by plasmin-independent mechanisms, including multiple interactions between uPA, uPAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors, and growth factors. These interactions seem to allow temporal and spatial reorganizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. The increased knowledge about the plasminogen activation system may allow utilization of its components as targets for anti-invasive therapy.
Publication Types:
PMID: 10949579 [PubMed - indexed for MEDLINE]
-
The role of the plasminogen activation system in cancer.
Carroll VA, Binder BR.
Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.
Hemostatic disorders are frequently observed in patients with malignancy with a significant proportion developing thrombotic and/or hemorrhagic complications including disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT), and thrombocytopenia. Together, these abnormalities are the second most common cause of mortality in cancer patients, which has led many investigators to try to unravel the pathogenesis of thromboembolic disease, in the eventuality that this will lead to novel therapeutic treatments. The plasminogen activation system is one pathway that has been consistently implicated in cancer. Its relevance to cancer extends from being responsible for many of the hemorrhagic episodes that occur in cancer patients to being fundamental to many, if not all of the molecular mechanisms that define tumor progression. Recent developments of clinical significance shall be reviewed with respect to the role of the plasminogen activation system in tumor growth and metastasis dissemination and in the thrombophilic state in the cancer patient.
Publication Types:
PMID: 10357086 [PubMed - indexed for MEDLINE]
-
[The clinical prospects for the study of the plasminogen activation system in breast cancer]
[Article in Russian]
Gershtein ES, Kushlinskii NE.
Urokinase-type plasminogen activator (UPA) which is a serine protease may play a key role in the processes of tumor invasion and metastasis since it converts plasminogen to plasmin and initiates a cascade of proteolytic events that lead to the degradation of extracellular matrix. Experiments have demonstrated that some other components, except UPA itself, can be very important in this process, including UPA receptor (UPAR) and UPA inhibitors PAI-1 and PAI-2. All these proteins are present either in the tumor cells or in the tumor-infiltrating macrophages and stromal elements, and by acting in concert, they provide a feed-back-regulated mechanism of plasmin activation and amplification. Clinical retrospective studies using predominantly ELISA techniques have shown that the high levels of UPA, PAI-1 and UPAR in the tumor tissue are associated with poor prognosis both for overall and for disease-free survival of breast cancer patients, and the elevated level of PAI-2 may be indicative of better survival. UPA and PAI-1 are now regarded as rather potent independent predictors in breast cancer. Further clinical prospects of investigations and application of the components of the plasminogen activation system are discussed.
Publication Types:
PMID: 10487126 [PubMed - indexed for MEDLINE]
-
Venous thromboembolism and cancer.
Kakkar AK, de Lorenzo F, Pineo GF, Williamson RC.
Department of Surgery, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
The association of thrombosis with malignant disease has been recognized for well over 100 years. Evidence from experimental and clinical studies indicates that the haemostatic system is involved in the growth, invasion and metastasis of tumours. Laboratory parameters of haemostasis are frequently deranged in patients with cancer and overt thrombosis is common spontaneously where it may be the first sign of malignancy or secondary to therapy. The mechanisms by which coagulation activation facilitates the malignant process remain to be completely elucidated, but it is clear that cells and proteins of the coagulation and fibrinolytic systems are involved at many steps in the processes of tumour growth and dissemination. The low-molecular-weight heparins with their well-proven safety and efficacy profiles offer unique modalities for the prevention and treatment of cancer-associated thrombosis. They may also play a role in overall mortality reduction in patients with malignant disease.
Publication Types:
PMID: 10331099 [PubMed - indexed for MEDLINE]
-
Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.
Festuccia C, Dolo V, Guerra F, Violini S, Muzi P, Pavan A, Bologna M.
Department of Experimental Medicine, University of L'Aquila, Italy.
The malignant phenotype of prostatic tumor cells correlates with the expression of both uPA and its cell-membrane receptor (uPAR); however, there is little information concerning the role of cell-bound uPA in matrix degradation and invasion. Our results suggest that cell-associated uPA plays a key role in regulating the amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differential production of uPA corresponds with the capacity to bind and activate plasminogen. In addition, we provide direct evidence that both uPA secretion and the presence of uPA-uPAR complexes characterize the invasive phenotype of PRCA cells and suggest the existence of several pathways by which tumor cells acquire plasmin activity. LNCaP cells (which do not produce uPA but express uPAR) may activate plasmin through exogenous uPA. In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observed in several other systems. PAI-1 accumulation in the conditioned medium (CM) limits plasmin action to the pericellular microenvironment. Our results indicate that MMP-9 and MMP-2 are also activated by plasmin generated by cell-bound but not by soluble, extracellular uPA. Plasmin activation and triggering of the proteolytic cascade involved in Matrigel invasion is blocked by antibodies against uPA (especially by anti- A-chain of uPA which interacts with uPAR) and by PA inhibitors such as p-aminobenzamidine which may regulate levels of cell-bound uPA. uPA may also regulate growth in PRCA cells. Indeed, antibodies against uPA A-chain (and also p-aminobenzamidine treatment) interfere with the ATF domain and inhibit cell growth in uPA-producing PC3 and DU145 prostate cancer cell lines, whereas exogenous uPA (HMW-uPA with ATF) induces growth of LNCaP prostate tumor cell line. These data support the hypothesis that in prostatic cancer patients at risk of progression, uPA/plasmin blockade may be of therapeutic value by blocking both growth of the primary tumor and dissemination of metastatic cells.
PMID: 9872599 [PubMed - indexed for MEDLINE]
-
Current drug treatment strategies for disseminated intravascular coagulation.
de Jonge E, Levi M, Stoutenbeek CP, van Deventer SJ.
Department of Intensive Care, Academic Medical Center, University of Amsterdam, The Netherlands. E.dejonge@amc.uva.nl
Disseminated intravascular coagulation (DIC) can be caused by a variety of diseases. Experimental models of DIC have provided substantial insight into the pathogenesis of this disorder, which may ultimately result in improved treatment. Disseminated coagulation is the result of a complex imbalance of coagulation and fibrinolysis. Simultaneously occurring tissue factor-dependent activation of coagulation, depression of natural anticoagulant pathways and shutdown of endogenous fibrinolysis all contribute to the clinical picture of widespread thrombotic deposition in the microvasculature and subsequent multiple organ failure. Cornerstone for the treatment of DIC is the optimal management of the underlying disorder. At present, specific treatment of the coagulation disorders themselves is not based on firm evidence from controlled clinical trials. Plasma and platelet transfusion are used in patients with bleeding or at risk for bleeding and low levels of coagulation factors or thrombocytopenia. The role of heparin and low molecular weight heparin is controversial, but their use may be justified in patients with active DIC and clinical signs of extensive fibrin deposition such as those with meningococcal sepsis. There is some evidence to indicate that low molecular weight heparin is as effective as unfractionated heparin but may be associated with a decreased bleeding risk. Antithrombin III (AT III) replacement appears to be effective in decreasing the signs of DIC if high doses are administered, but effects on survival or other clinically significant parameters are at best uncertain. If AT III supplementation is used, the dosage should be selected to achieve normal or supranormal plasma levels of 100% or higher. Results of studies on protein C concentrate, thrombomodulin or inhibitors of tissue factor are promising, but the efficacy and safety of these novel strategies remains to be established in appropriate clinical trials.
Publication Types:
PMID: 9617592 [PubMed - indexed for MEDLINE]
-
[Disseminated intravascular coagulation and hyperfibrinolysis in dogs with metastasizing mammary carcinoma]
[Article in German]
Mischke R, Wohlsein P, Busse L, Pohlenz J.
Klinik fur kleine Haustiere, Tierarztlichen Hochschule Hannover.
The alterations of the haemostatic system (platelet count, activated partial thromboplastin time [APTT], thromboplastin time [standard test, modified test], thrombin time, fibrinogen concentration, activity of the coagulation factors II, V, VII, X, VIII:C, IX, XI, XII, of prekallikrein, high molecular weight kininogen, antithrombin III, protein C, plasminogen and alpha 2-plasmin inhibitor, concentration of soluble fibrin and fibrin(ogen) degradation products [FDP], resonance thrombogram) were described in seven dogs with haemorrhagic diathesis in consequence of an infiltrative, growing mammary carcinoma with multifocal invasion of lymphatic and blood vessels. In most of the cases metastases in different organs could be demonstrated. In every case a serious stage of disseminated intravascular coagulation and hyperfibrinolysis was existent. This was indicated by the distinctly increased concentration (p < 0.0001) of soluble fibrin (27.7 [16.0-79.2] micrograms/ml, median [minimum-maximum], reference range [RR.]: < 9.4 micrograms/ml) and FDP (340 [50-860] micrograms/ml, RR.: < 18 micrograms/ml) as well as a diminished plasma level of nearly all components of the coagulation and fibrinolytic system concerning especially the concentration of fibrinogen (0.16 [0.01-0.46] g/l, RR.: 1.17-3.09 g/l), the activity of factors V (30 [21-40]%, RR.: 75-158%) and VIII:C (9 [4-16]%, RR.: 72-136%) as well as the activity of protein C (8 [3-13]%, RR.: 68-139%) (each: p < 0.0001).
PMID: 9863356 [PubMed - indexed for MEDLINE]
-
Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock.
Vervloet MG, Thijs LG, Hack CE.
Medical Intensive Care Unit of the University Hospital VU Amsterdam, The Netherlands.
In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC). The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail. The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems. Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S. As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found. The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure. A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis.
Publication Types:
PMID: 9515778 [PubMed - indexed for MEDLINE]
-
Fibrinolysis inhibitors.
Davis GL.
Medical Technology Program, Michigan State University, East Lansing 48823, USA.
The fibrinolytic system involves a series of enzymatic reactions that results in the conversion of the proenzyme, plasminogen, into the trypsin-like lytic enzyme, plasmin. The major physiologic target of plasmin is fibrin. Free plasmin in plasma is a nonspecific lytic enzyme that will degrade other proteins such as fibrinogen and coagulation factors V and VIII. Plasmin and activators of plasminogen also play a role in ovulation, embryo implantation, tissue remodeling, and inflammation.
Publication Types:
PMID: 10169620 [PubMed - indexed for MEDLINE]
-
Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy.
Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, Ulm K, Hofler H, Janicke F, Graeff H.
Frauenklinik und Poliklinik, Technischen Universitat Munchen, Germany. manfred.schmitt@lrz.tu-muenchen.de
Extravasation and intravasation of solid malignant tumors is controlled by attachment of tumor cells to components of the basement membrane and the extracellular matrix, by local proteolysis and tumor cell migration. Strong clinical and experimental evidence has accumulated that the tumor-associated serine protease plasmin, its activator uPA (urokinase-type plasminogen activator), the receptor uPA-R (CD87), and the inhibitors PAI-1 and PAI-2 are linked to cancer invasion and metastasis. In cancer, increase of uPA, uPA-R, and/or PAI-1 is associated with tumor progression and with shortened disease-free and/or overall survival in patients afflicted with malignant solid tumors. uPA and/or its inhibitor PAI-1 appear to be one of the strongest prognostic markers so far described. Strong prognostic value to predict disease recurrence and overall survival has been documented for patients with cancer of the breast, ovary, cervix, endometrium, stomach, colon, lung, bladder, kidney, brain, and soft-tissue. Due to the strong correlation between elevated uPA and/or PAI-1 values in primary cancer tissues and the tumor invasion/ metastasis capacity of cancer cells, proteolytic factors have been selected as targets for therapy. Various very different approaches to interfere with the expression or reactivity of uPA or CD87 at the gene or protein level were successfully tested including antisense oligonucleotides, antibodies, enzyme inhibitors, and recombinant or synthetic uPA and uPA-R analogues.
Publication Types:
PMID: 9198168 [PubMed - indexed for MEDLINE]
-
[Disseminated intravascular coagulations]
[Article in French]
Amstutz P, Moyo JS.
Service de Reanimation, Hopital Saint-Antoine, Paris.
Disseminated intravascular coagulation (DIC) syndromes can be defined as the formation of fibrin deposits within the microcirculation, occurring in definite clinical situations. Their biological counterpart is a consumption coagulopathy. The clinical profiles of DIC have been well known for decades, are multiform and range from latency to overwhelming haemorrhagic diatheses, including also characteristic but rare situations, such as purpura fulminans, acral cyanosis and pictures resembling thrombotic thrombocytopenic purpura or haemolytic-uraemic syndrome. Biological tests of DIC show a consumption coagulopathy, displayed on the standard haemostasis sheet; along with signs of paracoagulation and/or of secondary fibrinolysis (FDP). New tests have recently been introduced: D-dimers are specific and sensible; Antithrombin-III, protein C and alpha 2-antiplasmin also can sometimes be useful. The knowledge of the pathophysiology of DIC has made advances with passing years. Fibrin deposits may be non-occlusive, and indeed they are swiftly removed by a secondary fibrinolysis. Except in very rare situations, such as those leading to a cortical renal necrosis, and perhaps in some ARDS, there is little evidence relating DIC to organ failure syndromes. Moreover, there is no clear relationship between the severity of the consumption coagulopathy and the prognosis. For instance, the mortality is much lower in abruptio placentae, where the coagulopathy is very severe, than in septic shock, where it is usually moderate. In septic shock, the disorders of haemostasis were related initially to a platelet activation, then to an activation of the contact system (releasing kinins and triggering complement cascade), and nowadays to the activation of the extrinsic coagulation system. The treatment of DIC is mainly the treatment of its cause. Indications for heparin therapy should be strictly limited to a few exceptional circumstances. When haemorrhagic diathesis threatens, FPC and/or platelet transfusion may be indicated. Aprotinin can be useful in rare cases of overwhelming secondary fibrinolysis. Trials with antithrombin-III or C1-esterase inhibitors are in progress.
Publication Types:
PMID: 9005011 [PubMed - indexed for MEDLINE]
-
Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications.
Pappot H, Gardsvoll H, Romer J, Pedersen AN, Grondahl-Hansen J, Pyke C, Brunner N.
Finsen Laboratory, Rigshospitalet, Copenhagen-O, Denmark.
Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
PMID: 7662168 [PubMed - indexed for MEDLINE]
-
Urokinase-type plasminogen activator (uPA) and its receptor (CD87): a new target in tumor invasion and metastasis.
Schmitt M, Wilhelm O, Janicke F, Magdolen V, Reuning U, Ohi H, Moniwa N, Kobayashi H, Weidle U, Graeff H.
Frauenklinik, Technischen Universitat, Munchen, Germany.
Extravasation and intravasation of tumor cells in solid malignant tumors is controlled by 3 steps: 1) attachment to and interaction of tumor cells with components of the basement membrane and the extracellular matrix, 2) local proteolysis, and 3) tumor cell migration. Evidence has accumulated that different types of tumor-associated proteases, their inhibitors and receptors are involved in tumor invasion and metastasis. Four different classes of proteases are known to be correlated with the malignant phenotype: 1) Matrix metalloproteases; including collagenases, gelatinases and stromelysins. 2) Cysteine proteases; including cathepsins B and L. 3) Aspartyl protease cathepsin D. 4) Serine proteases; including plasmin and tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). A strong independent prognostic value (relapse-free and/or overall survival) has especially been demonstrated for uPA and its inhibitor PAI-1 in patients with cancer of the breast, ovary, stomach, esophagus, colon, lung, and kidney thus predicting the course of the cancer disease. The strong correlation between elevated uPA and/or PAI-1 values in primary cancer tissues and the malignant phenotype of cancer cells has prompted to explore new tumor biology-oriented concepts in order to suppress uPA or uPA receptor (CD87) expression or to abrogate interaction of uPA with CD87. Various very different approaches to interfere with the expression or reactivity of uPA or CD87 at the gene or protein level were successfully tested including antisense oligonucleotides, antibodies, inhibitors and recombinant or synthetic uPA and CD87 analogues.
Publication Types:
PMID: 8556577 [PubMed - indexed for MEDLINE]
-
[Diagnosis and therapy of disseminated intravascular coagulation]
[Article in Czech]
Maly J, Pecka M, Pidrman V, Blaha M, Siroky O, Jebavy L.
2. katedra vnitrnich oboru, LF UK, Hradec Kralove.
The syndrome of disseminated intravascular coagulation (DIC) is an acquired coagulation disorder which is characterized by a significant activation of haemostasis and the formation of intravascular microthrombi, the consumption of coagulation factors and activation of fibrinolysis. DIC has similar clinical stages and a similar laboratory picture, regardless of the causal factor. The diagnosis of DIC should be based on anamnestic, clinical and laboratory data. The laboratory diagnosis of DIC is possible by using relatively simple tests, which have the character of statim examinations. DIC treatment is based on the principle of treatment of the cause, discontinued consumption of haemostatic material, substitution of lacking factors and restoration of the microcirculation. The possible development of DIC must be taken into account in a number of acute conditions, in particular the development of shock syndrome. The presented article summarizes some views on causes, diagnosis and possible treatment of DIC.
Publication Types:
PMID: 7834668 [PubMed - indexed for MEDLINE]
-
Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers.
Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E, Yamazaki M, Aoshima K, Matsuda T.
Department of Internal Medicine (III), Kanazawa University School of Medicine, Japan.
Plasma levels of thrombin-antithrombin III complex (TAT), plasmin-alpha 2-plasmin inhibitor complex (PIC) and active plasminogen activator inhibitor (PAI) were assayed in 66 cases of disseminated intravascular coagulation (DIC). Significant elevation of both TAT and PIC was observed in all cases of DIC. Most elevated levels of TAT were seen in DIC with acute promyelocytic leukaemia (APL) and sepsis. The highest levels of PIC were seen in DIC with APL but were much lower in sepsis. A significant elevation in active PAI was observed in DIC due to acute leukaemia (apart from APL), chronic myeloid leukaemia and sepsis, but not in APL, non-Hodgkin lymphoma and cancer. Active PAI was higher in patients with multiple organ failure (MOF) than in those without MOF while PIC was lower in patients with this complication. Thus, the balance of coagulation and fibrinolysis varied according to the underlying cause of DIC; APL had more dominant activation of fibrinolysis, while sepsis had greater activation of coagulation. It is suggested that the inhibition of secondary fibrinolytic activation plays an important role in the progression of MOF by the disturbance of the microcirculation.
PMID: 7865691 [PubMed - indexed for MEDLINE]
-
[Diagnosis and therapy of disseminated intravascular coagulation]
[Article in German]
Scherer R, Paar D, Stocker L, Kox WJ.
Institut fur Anasthesiologie, Universitatsklinikum der GHS Essen.
Consumptive coagulation disorders are frequently observed in critically ill patients secondary to other underlying diseases. Initial hypercoagulability leads to subsequent hypocoagulability due to consumption of procoagulant proteins, inhibitors, and platelets. This process evolves in three distinct phases: an initial increase in coagulation activity is characterised by the activation of coagulation factors and platelets without any clinical symptoms of a haemorrhagic diathesis. The ongoing process of activation and accelerated consumption of coagulation factors and inhibitors causes a critical reduction in the haemostatic potential. The time of onset of the clinical symptoms of bleeding depends on the patient's underlying disease and its pharmacological management. Coagulation processes that are restricted locally under normal conditions become disseminated when the inhibitory potential--mainly represented by antithrombin III (AT III)--is exhausted. Therefore, thrombin formation occurs, especially in the microcirculation, where fibrin clot deposition begins to cause inhomogeneities of blood flow and thus to reduce oxygen delivery to the tissues. Hypocoagulability, reactive hyperfibrinolysis, and diffuse bleeding lead to an irreversible systemic breakdown of haemostatic mechanisms (disseminated intravascular coagulation, DIC). The laboratory diagnosis of accelerated consumption is based on the course of global coagulation tests (e.g., prothrombin time, activated partial thromboplastin time, platelet count) and more sensitive ("dynamic") activation parameters such as prothrombin fragment F1 + 2, thrombin-AT III complex, fibrin monomers, or d-dimer. Measurements of plasminogen, tissue plasminogen activator, plasminogen activator inhibitor 1, and alpha 2-antiplasmin-plasmin complex provide information on fibrinolytic turnover.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
PMID: 8048768 [PubMed - indexed for MEDLINE]
-
Plasmin in pericellular proteolysis and cellular invasion.
Kramer MD, Reinartz J, Brunner G, Schirrmacher V.
Institute for Immunology and Serology, University of Heidelberg, Germany.
Invasive tumor growth or severe inflammation is accompanied by the extravasation of fibrinogen from leaky or damaged blood vessels and the formation of a fibrin clot. The clot provides a matrix for the inward migration ('invasion,' 'infiltration') of tumor cells as well as inflammatory cells. The factors that govern the cell/fibrin interaction are not known. We have explored in vitro the possible role of the cell-surface-associated pathway of plasminogen activation in the adhesion of keratinocytes to fibrin and in the invasion of melanoma cells into fibrin gels. Our experiments provided evidence that generation of plasmin at the cell surface destabilizes the adhesive interaction between keratinocytes and fibrin, most likely by cleaving fibrin into fibrinopeptides and destroying its adhesive capacity. Moreover, we found that plasmin generated at the melanoma cell surface promotes the inward migration of these cells into three-dimensional fibrin matrices. In conclusion, the generation of plasmin at the cellular surface may be an important factor in pericellular proteolysis and the dynamic interaction between cells and fibrin-containing pericellular matrix under conditions of tumor invasion and inflammation.
Publication Types:
PMID: 7657514 [PubMed - indexed for MEDLINE]
-
Thromboembolic complications associated with brain tumors.
Sawaya RE, Ligon BL.
Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Thromboembolic complications are the second most common cause of death in hospitalized cancer patients; they are caused by alterations of hemostasis and include hypercoagulable states, acute and chronic disseminated intravascular coagulation, and primary fibrinolysis. The fibrinolytic system is comprised of several serine protease enzymes and their inhibitors and is associated in various biological systems with physiological and pathological events such as tissue development, remodeling, invasiveness, and migratory potentials of both normal and malignant cells. It also plays a key role in the dissolution of fibrin strands. Defective fibrinolysis, which is often associated with the pathogenesis of venous thrombosis and other thromboembolic complications, occurs when the balance is disrupted, resulting in either inhibition or enhancement of fibrinolysis. The association between thromboembolic complications and neoplastic disease has been well-established since Trousseau in 1865 first reported a high incidence of venous thrombosis in a series of patients with gastric carcinoma. In this article, we discuss the factors that have been shown to be associated with thromboembolic complications in patients who harbor brain tumors, namely, hemostatic alterations caused by the tumors themselves or through interactions with neural tissue around the tumors, pre-operative hemostatic alterations in certain patients, and defective fibrinolysis associated with specific tumor types and/or tumor locations.
Publication Types:
PMID: 7745469 [PubMed - indexed for MEDLINE]
-
Tumor cell procoagulant and urokinase expression in carcinoma of the ovary.
Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ.
Department of Veterans Affairs Medical and Regional Office Center, White River Junction, Vt.
BACKGROUND: An association between cancer and increased blood coagulation has been observed for many years. Generally, there is an equilibrium between the coagulation system (fibrin deposition) and the fibrinolytic system (degradation of fibrin by enzymes). However, in malignant disease such as ovarian carcinoma, this equilibrium is disrupted, resulting in the abnormal activation of coagulation or hypercoagulability. Also, evidence indicates that various components of these pathways may contribute to the disorderly characteristics of malignancy, such as proliferation, invasion, and metastasis. PURPOSE: Our purpose was to define the mode of interaction of tumor cells in ovarian carcinoma with both the coagulation (procoagulant-initiated) and fibrinolysis (urokinase-type plasminogen activator-initiated) (u-PA) pathways. METHODS: Studies were performed on acetone-methylbenzoate-xylene-fixed tissue prepared from fresh resected primary tumor specimens from 15 patients with cystic epithelial ovarian carcinoma. None of the patients had received prior treatment. Antibodies were tested on control and tumor tissues in concentrations that provided maximum staining intensity with minimum background staining. Laboratory immunohistochemical techniques used purified, monospecific antibodies to detect coagulant antigens. Tests were performed utilizing antibodies to recombinant human tissue factor; factor VII; factor X; factor XIIIA; high-molecular-weight and low-molecular-weight forms of u-PA; tissue-type plasminogen activator; plasminogen; and the plasminogen activator inhibitors 1, 2, and 3. Monoclonal antibodies used for specific antigen detection included 1-8C6 (fibrinogen), T2G1 (fibrin), and EBM-11 (macrophage-specific). RESULTS: The ovarian tumor cells expressed urokinase-type plasminogen activator in a pattern that was variable in intensity and distribution. Tumor cell plasminogen was not detected. Tumor cells also expressed tissue factor and coagulation pathway intermediates that resulted in local thrombin generation as evidenced by the conversion of fibrinogen (present in tumor connective tissue) to fibrin that was found to hug the surfaces of tumor nodules and individual tumor cells. Detected fibrin could not be accounted for on the basis of necrosis or a local inflammatory cell infiltrate. CONCLUSIONS: These results are consistent with the existence of a dominant tumor cell-associated procoagulant pathway that leads to thrombin generation and hypercoagulability in carcinoma of the ovary. IMPLICATIONS: In ovarian carcinoma the procoagulant pathway may contribute to tumor progression. Clinical trials of therapeutic drugs capable of limiting local coagulability (anticoagulants, protease inhibitors) are indicated in this tumor type.
PMID: 8331683 [PubMed - indexed for MEDLINE]
-
[The fibrinolytic system and its activators]
[Article in German]
Seifried E.
Abteilung Innere Medizin III, Universitat Ulm.
The human fibrinolysis system is a proteolytic enzymatic process in the blood. Its purpose is to locally limit intravascular thrombotic processes and to reopen vessels closed by thrombosis. The main enzyme of the fibrinolysis system is the active protease plasmin produced by activation of the inactive first step plasminogen by means of plasminogen activators via limited proteolysis. Thrombolytic therapy with plasminogen mimics and enhances physiological fibrinolysis. The following substances are presently available for clinical use: the non-physiological thrombolytics streptokinase and APSAC (acylated plasminogen-streptokinase activator complex), as well as the physiological plasminogen activators urokinase and tissue plasminogen activator (t-PA). Whereas the first three systemically activate the fibrinolysis system, t-PA possesses relative fibrin selectivity. The fibrin-selective active prourokinase and a recombinant mutant of t-PA with prolonged in vivo half-life have not yet been officially approved for the treatment of thromboembolytic diseases but are being clinically tested. In the development stage are mutants, hybrid enzymes and conjugates aiming at further improvement of this therapeutic concept by means of changing the half-life, thrombus affinity and thrombolytic activity. The development of highly effective antithrombotics will help to further improve the results of thrombolytic therapy.
Publication Types:
PMID: 8333223 [PubMed - indexed for MEDLINE]
-
[Activation of coagulation and fibrinolysis in patients with abdominal true aortic aneurysm associated with disseminated intravascular coagulation]
[Article in Japanese]
Akaike M, Yokoi K, Wada M, Sebe T, Shigekiyo T, Kawai H, Saito S.
First Department of Internal Medicine, School of Medicine, University of Tokushima.
Two cases of abdominal true aortic aneurysm (AAA) associated with disseminated intravascular coagulation (DIC) were reported. Case 1 was an 81-year-old male who was admitted because of hematoma on the left leg and in whom was found by MRI an aortic aneurysm of 14 cm in diameter. Coagulation studies indicated DIC by revealing thrombocytopenia, hypofibrinogenemia and increased level of FDP. DIC was well controlled by surgical repair of the aneurysm after the administration of a small dose of heparin. Case 2 was a 60-year-old male who was admitted because of lumbago and hematoemesis and in whom was found by CT and echography an aortic aneurysm of 5.5 cm in diameter. Coagulation studies indicated DIC by revealing thrombocytopenia and an increased level of FDP. On the 2nd hospital day, he suddenly died due to the rupture of the aortic aneurysm. In most of 9 cases with AAA without DIC, plasma levels of thrombin-antithrombin III complex, plasmin-alpha 2 plasmin inhibitor complex and FDP-D dimer were also elevated. These findings indicate that the coagulation and fibrinolysis systems were generally activated in patients with AAA, and that DIC tends to occur in patients with a giant aortic aneurysm or an impending ruptured aneurysm.
Publication Types:
PMID: 8469833 [PubMed - indexed for MEDLINE]
-
Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo.
Levi M, Roem D, Kamp AM, de Boer JP, Hack CE, ten Cate JW.
Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, University of Amsterdam, The Netherlands.
It has been shown that the most important inhibitor of plasmin is alpha 2-antiplasmin, however, other protease inhibitors are able to inhibit this proteolytic enzyme as well. The contribution of the various protease inhibitors to the inhibition of plasmin in vivo has never been quantitatively assessed. To assess the relative contribution of the different protease inhibitors on the inhibition of plasmin we developed a series of sensitive immunoassays for the detection of complexes between plasmin and the protease inhibitors alpha 2-antiplasmin, alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin and C1-inhibitor, utilizing monoclonal antibodies that are specifically directed against complexed protease inhibitors and a monoclonal antibody against plasmin. It was confirmed that alpha 2-antiplasmin is the most important inhibitor of plasmin in vivo, however, complexes of plasmin with alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin- and C1-inhibitor were also detected. Particularly during activation of fibrinolysis complexes between plasmin and inhibitors other than alpha 2-antiplasmin were detected. It was observed that during different situations the inhibition profile of plasmin was not constant e.g. in patients with diffuse intravascular coagulation plasma levels of plasmin-alpha 1-antitrypsin and plasmin-C1-inhibitor were increased whereas in plasma from patients who were treated with thrombolytic agents complexes of plasmin with alpha 2-macroglobulin and with antithrombin III were significantly elevated. In conclusion, we confirmed the important role of alpha 2-antiplasmin in the inhibition of plasmin, however, in situations in which fibrinolysis is activated other protease inhibitors also account for the inhibition of plasmin in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7681223 [PubMed - indexed for MEDLINE]
-
Coagulation disorders in septic shock.
Thijs LG, de Boer JP, de Groot MC, Hack CE.
Medical Intensive Care Unit, Free University Hospital, Amsterdam, The Netherlands.
Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.
Publication Types:
PMID: 8227738 [PubMed - indexed for MEDLINE]
-
[Disseminated intravascular coagulation--pathophysiology]
[Article in Japanese]
Matsuda T.
Kanazawa University School of Medicine, Department of Internal Medicine III.
The main cause of DIC (disseminated intravascular syndrome) is contact of tissue factor with circulating blood. The main symptoms of DIC are bleeding diathesis caused by consumption coagulopathy and organ dysfunction related to circulatory disturbances due to multiple thrombi. However, the symptoms of DIC differ according to degree of fibrinolysis which is characterized by causal disease of DIC. Usually, enhanced fibrinolysis does not cause organ failure but hemorrhagic diathesis, while impaired fibrinolysis does not cause severe bleeding but organ dysfunction. In almost all cases of acute leukemia and in some cases of solid cancer with DIC, hyperfibrinolysis is common. In cases of severe infection with DIC, impaired fibrinolysis due to abnormal elevation of plasminogen activator inhibitor-1 is frequently seen.
Publication Types:
PMID: 8433509 [PubMed - indexed for MEDLINE]
-
[Progress in diagnosis of disseminated intravascular coagulation (DIC)--diagnostic criteria of DIC]
[Article in Japanese]
Koyama T, Aoki N.
First Department of Medicine, Tokyo Medical and Dental University.
DIC is an acquired disorder in which intravascular coagulation may lead to microvascular fibrin formation and a hemorrhagic diathesis. If DIC is acute and severe, fibrin formation may lead to microvascular thrombosis, and consumption of coagulation factors and platelets may result in a hemorrhagic diathesis. Secondary to or simultaneously with coagulation, the fibrinolytic system may be activated, accentuating the bleeding tendency. All the systems involved in DIC, such as coagulation, fibrinolysis, kallikrein-kinin, complement, and possibly other systems are regulated. Coagulation is the central event of DIC. The different coagulation factor derivatives may be generated that can be determined and used as markers for the degree of DIC and for effective control of therapy. Some of the procoagulant and anticoagulant factors are converted in the course of coagulation to their active forms and activation peptides. The active factor is subsequently neutralized by forming a complex with an inhibitor. Hemostatic molecular markers, D-dimer of cross-linked fibrin degradation products (D-dimer), thrombin-antithrombin III complex (TAT), and plasmin-alpha 2-plasmin inhibitor complex (PIC) have all been used for the diagnosis of DIC.
Publication Types:
PMID: 8433527 [PubMed - indexed for MEDLINE]
-
The plasminogen-plasmin system in malignancy.
Kwaan HC.
Department of Medicine, Northwestern University Medical School, Chicago, IL.
The study of the plasminogen-plasmin system has, in the past, contributed much to the understanding of fibrinolysis and thrombolysis. Attention is now focused on the role of the components of this system in many biologic functions. Findings of uPA, its receptor and its inhibitor in many tumor tissues and tumor cell lines, strongly implicate their involvement in tumor invasion, tumor cell proliferation and metastasis. The characteristics of the plasminogen activators, the uPA receptor and the plasminogen activator inhibitors as well as their expression and regulation in tumors and tumor cell lines are reviewed.
Publication Types:
PMID: 1423820 [PubMed - indexed for MEDLINE]
-
Fibrinolytic mechanisms in tumor growth and spreading.
Sudhoff T, Schneider W.
Medizinische Klinik, Heinrich-Heine-Universitat, Dusseldorf.
The high prevalence of hypercoagulative states in cancer patients has been known for more than a century. Venous thrombosis in gastric cancer was described by Trousseau in 1865 [55]. In 1878, Billroth observed intravascular thrombus formation in association with metastasis [4]. Thrombohemorrhagic complications regularly occur in patients with disseminated malignancy and are related to an increase in fibrinogen and fibrin turnover. During the past decade, clinicians have witnessed considerable advances in the understanding of fibrinolysis. Initially centered on the role as part of a dynamic, hemostatic balance, research began to unravel the pathophysiological contribution of fibrinolysis to tumor progression. The mechanisms of tumor invasion and metastasis formation in cancer are of critical importance, since metastasis is the major cause of treatment failure and death. It has been suggested that cell-associated proteolytic enzymes contribute to tumor aggressiveness [11, 22, 23]. Fibrinolytic mechanisms are involved in a number of physiological processes in which tissue degradation and remodeling occurs. These include disruption of the ovarian follicle during ovulation and blastocyst implantation. These events in part resemble the invasive growth of cancer [37, 47]. Inspired by this hypothesis, the role of fibrinolytic processes in tumor invasion is under intensive study.
Publication Types:
PMID: 1392438 [PubMed - indexed for MEDLINE]
-
Coagulation and fibrinolysis in cancer.
Heimburger N, Paques EP, Romisch J.
Research Laboratories of Behringwerke AG, Marburg, Germany.
Haemostasis is a system of finely adjusted interactions between cells, enzymatic reaction cascades and inhibitors. Disturbances of this balance occur in many disorders, especially in inflammatory processes, septicaemia and cancer. In such cases malignant cells and infectious organisms activate the plasmatic enzyme cascades, especially of the coagulation and fibrinolysis cascades. The resulting consumption and proteolytic degradation of the regulatory proteins contribute to hypercoagulability and secondarily to reactive fibrinolysis, and these may then lead to local thromboses and haemorrhages. These pathogenic events culminate in disseminated intravascular coagulation (DIC), frequently with organ failure and death. Factors of both plasmatic systems are also "misused" by malignant cells for the purposes of growth and metastasis. Prominent examples of this misuse are the formation of a protective fibrin shield against the endogenous defence mechanisms and the local degradation of tissues for tumor proliferation as well as for cell permeation and invasion. In the search for a potential therapy a number of protease inhibitors, predominantly of enzymes of coagulation and fibrinolysis, have been tested in vivo with regard to their efficacy. So far, however, it has not been possible to find a new uniform treatment principle to inhibit the growth and/or metastasis of different types of tumor. The haemorrhagic diathesis and thromboses frequently associated with tumors are generally treated by substitution with plasma components, especially concentrates of coagulation factors and inhibitors.
Publication Types:
PMID: 1388019 [PubMed - indexed for MEDLINE]
-
Changes in the coagulation-fibrinolysis balance of endothelial cells and mononuclear phagocytes: role in disseminated intravascular coagulation associated with infectious diseases.
Semeraro N, Colucci M.
Dipartimento di Scienze Biomediche e Oncologia Umana, University of Bari, Italy.
Over the last few years, evidence has accumulated that the pathogenetic mechanism of disseminated intravascular coagulation encountered in patients with infectious diseases is extraordinarily complex and involves multiple interactions between the microorganism itself and/or a number of mediators, both microorganism derived and host manufactured, and multifunctional cellular systems, namely endothelial cells and mononuclear phagocytes. In particular, infectious agents and mediators shift the coagulation-fibrinolysis equilibrium of these cells towards fibrin formation and accumulation, via enhancement of procoagulant properties and reduction of both anticoagulant and fibrinolytic capacities. New insights into the pathogenetic mechanism may have important implications for the management of infected patients with disseminated intravascular coagulation.
Publication Types:
PMID: 1591371 [PubMed - indexed for MEDLINE]
-
Pathways of coagulation/fibrinolysis activation in malignancy.
Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, Memoli VA.
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire.
Recent progress in elucidating the complex and heterogeneous interactions between malignancy and coagulation or fibrinolysis reactions in humans has clarified the pathogenesis of disseminated intravascular coagulation that occurs with malignancy and has revealed evidence for two distinct pathways of growth regulation based on production by tumor cells of initiators of thrombin formation versus plasminogen activators. We have proposed a preliminary classification of tumors (see Table 2) based on these interactions. Type I tumors are those in which the tumor cells are associated with an intact coagulation pathway that leads to thrombin formation at the tumor periphery but in which the tumor cells lack u-PA. Examples of tumors in this category include SCCL, malignant melanoma, and renal cell carcinoma. Type II tumors are those in which the tumor cells express u-PA but lack an associated coagulation pathway leading to thrombin formation. Examples of type II tumors include prostate cancer, colon cancer, breast cancer, and N-SCLC. Type III tumors are those that express neither of these pathways, or exhibit some other pattern of interaction. Obviously, this formulation must be regarded as hypothetical. However, this concept fits with the limited data available to date from clinical trials. More importantly, this hypothesis can be tested further by means of intervention aimed at interrupting pathways relevant to specific tumor types. Characterization of additional tumor types by the methods described should permit amplification of this classification of tumors and other patterns of interaction may be defined. Exploration of the coagulation-cancer interaction holds considerable promise for gaining new understanding of both the coagulation mechanism and tumor biology. Most intriguing is the prospect that imaginative approaches to cancer treatment may be devised that are not only relatively nontoxic and low cost, but also effective.
Publication Types:
PMID: 1574711 [PubMed - indexed for MEDLINE]
-
Haemostasis in oral surgery--the possible pathogenetic implications of oral fibrinolysis on bleeding. Experimental and clinical studies of the haemostatic balance in the oral cavity, with particular reference to patients with acquired and congenital defects of the coagulation system.
Sindet-Pedersen S.
Department of Clinical Chemistry, Ribe County Hospital, Esbjerg.
Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after oral surgery. Further investigations are necessary in order to clarify these aspects, and should include extensive laboratory analyses to reveal rare congenital defects such as factor XIII- and alpha 2-antiplasmin deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
PMID: 1802633 [PubMed - indexed for MEDLINE]
-
[Changes in coagulation and fibrinolysis cascades upon extracorporeal circulation]
[Article in Japanese]
Kanamori N, Koiwa F, Uda S.
Department of Nephrology, Showa University Fujigaoka Hospital.
PMID: 1839690 [PubMed - indexed for MEDLINE]
-
Immunohistochemical localization of coagulation, fibrinolytic and antifibrinolytic markers in adenocarcinoma of the lung.
Nakstad B, Lyberg T.
Department of Pathology and Surgery, Ulleval University Hospital, Oslo, Norway.
Extravascular coagulation and fibrinolysis are intimately involved in and modulate cancer cell growth, invasion and metastasis. Samples from resection specimens of patients with primary lung cancer (adenocarcinomas) were tested with monoclonal (MAb) and polyclonal (PAb) antibodies against various factors of the coagulation or fibrinolysis systems, or against antigens of inflammatory or proliferating cells. MAb Ki-67 specific to nuclear antigens of proliferating cells showed a distinct but variable staining of cell nuclei throughout the tumor tissue. Nests of tumor tissue stained with cytokeratin-specific antibodies (PKK1), whereas other parts were negative. Fibrin(ogen) and fibronectin were found throughout the tumor tissue stroma and in the alveolar lining, and the most densely stained areas were at the transition zone between normal and tumor tissue. Fibrinolytic system components like tissue plasminogen activators (t-PA), and urokinase (u-PA), and their inhibitors PAI-1 and PAI-2 were all studied. All specimens were negative for t-PA (except endothelial linings), whereas urokinase-specific antibodies stained loosely packed tumor cells and macrophages within the tumor stromal tissue and alveolar septa. Both PAI-1 and PAI-2 were most prominently expressed within interstitial and alveolar macrophages. A weaker staining of tumor tissue cells was demonstrated. Inflammatory cells like macrophages and T lymphocytes were located in aggregates or diffusely spread within tumor stromal tissue. The inflammatory reaction was most intense at the border between normal lung and tumor tissue.
PMID: 1720319 [PubMed - indexed for MEDLINE]
-
[Coagulation and fibrinolysis parameters in disseminated intravascular coagulation (DIC)]
[Article in Japanese]
Nakagawa T, Saito H, Watanabe Y, Sato M, Murakawa E.
Department of Laboratory Medicine, Niigata Cancer Center Hospital.
Eighty six plasma samples from 41 patients with suspected disseminated intravascular coagulation (DIC) were divided into 3 groups as follows: Group A, 53 samples from established DIC; Group B, 19 samples from possible DIC; and Group C, 14 samples from probable DIC. The following parameters of coagulation and fibrinolysis were evaluated: thrombin/antithrombin III complex (TAT), plasmin/alpha 2 plasmin inhibitor complex (PIC), D-dimer (D-D) and fibrin monomer (FM). In Group A, TAT and PIC were significantly elevated, being 29.5 +/- 20.7 micrograms/l and 7.2 +/- 6.1 mg/l respectively, suggesting marked hypercoagulability and accelerated fibrinolysis. There were no correlations between antithrombin III (ATIII) and TAT, between alpha 2 plasmin inhibitor (alpha 2PI) and PIC, or between TAT and PIC, showing the clinical diversity of patients with DIC. In all groups abnormal TAT, PIC and D-D findings were observed in many samples (86-100%), and FM was present in 83%, 63%, and 29% of samples in Groups A, B, and C respectively. In Groups B and C, abnormal findings for TAT, PIC, D-D, FM and alpha 2PI apparently indicated hypercoagulability and accelerated fibrinolysis, even though fibrinogen and platelet count were within normal limits.
PMID: 1828842 [PubMed - indexed for MEDLINE]
-
Haemostatic problems in acute leukaemia.
Wilde JT, Davies JM.
University Department of Haematology, Royal Liverpool Hospital, UK.
Disseminated intravascular coagulation (DIC) is a frequent complication of acute leukaemia, in particular acute promyelocytic leukaemia. Although procoagulant substances released from leukaemic blast cells may induce DIC by activating conventional coagulation pathways, there is increasing evidence to suggest that direct activation of fibrinogen by proteases released from blast cells may be the predominant mechanism by which DIC is initiated. Primary fibrinolysis has also been proposed as the cause of the haemorrhagic diathesis in some cases of acute leukaemia. Although plasminogen activators have been demonstrated in leukaemic blast cells supporting this view, cases of primary fibrinolysis would appear to be rare. A bleeding tendency attributed to primary fibrinolysis may more often be the result of an exaggerated fibrinolytic response secondary to DIC. The main strategies of treatment for leukaemia associated DIC are rapid initiation of chemotherapy and vigorous blood product support until the DIC resolves once the blast cells have been eradicated. The role of heparin in the management of leukaemia associated DIC remains controversial. There is recent evidence to suggest that heparin therapy does reduce the incidence of haemorrhagic death although it has been recommended that relatively low intravenous doses should be administered initially to reduce the risk of heparin induced haemorrhage.
Publication Types:
PMID: 2076471 [PubMed - indexed for MEDLINE]
-
[The role of proteases in the growth, invasion and spread of cancer cells]
[Article in Norwegian]
Buo L, Aasen AO, Karlsrud TS, Johansen HT, Sivertsen SM.
Institutt for kirurgisk forskning, Rikshospitalet, Oslo.
Cancer cells show a greater capability than normal cells do to break down proteins in the surrounding tissue. This tissue destruction involving proteolytic enzymes is probably essential for the invasion and metastatic spread of malignant cells. The process takes place through an interplay of proteolytic enzyme systems where plasmin-mediated proteolysis plays an important role. Plasminogen activator activity and receptors for plasminogen activators have been discovered in tumors, mainly in areas with invasive growth and tissue degradation. Patients with malignant diseases often demonstrate abnormalities in their blood coagulation, including hyperaggregability of platelets. Experimental research has shown that therapy with antiplatelet drugs, and prophylaxis with protease inhibitors, can limit spread of tumors.
Publication Types:
PMID: 2274946 [PubMed - indexed for MEDLINE]
-
[Hemostasis, fibrinolysis, proteolysis: interaction with inflammatory reactions]
[Article in German]
Romisch J, Schuler E, Paques EP, Heimburger N.
Forschungslaboratorien Behringwerke AG, Marburg, Bundesrepublik Deutschland.
Many physiological processes are based on the finely regulated interaction between cells and enzymatic reaction cascades. Mainly proteinases are involved in these processes, which are regulated by inhibitors, principally proteins. If this sensitive balance is disturbed, uncontrolled pathophysiological events can be induced, which are often associated with inflammatory reactions. Characteristic for inflammation are events like contact activation of hemostasis, increasing permeability of blood vessels caused by activation of the Kallikrein-Kinin- and the Complement-system and Plasmin-release induced by activation of fibrinolysis. The following uncontrolled proteolysis, leading to tissue destruction, is mainly associated with the degree of illness. Inflammatory cells excrete besides proteinases also mediators maintaining and increasing these processes. Only when the balance between proteinases and inhibitors is restored, inflammation subsides. Afterwards the controlled course of physiological reactions is possible again.
Publication Types:
PMID: 2252459 [PubMed - indexed for MEDLINE]
Comment in:
Hemostasis in malignancy.
Nand S, Messmore H.
Department of Medicine, Loyola University Stritch School of Medicine, Maywood, IL 60153.
Hemostatic abnormalities are present in a majority of patients with metastatic cancer. These abnormalities can be categorized as 1) increased platelet aggregation and activation, 2) abnormal activation of coagulation cascade, 3) release of plasminogen activator, and 4) decreased hepatic synthesis of anticoagulant proteins like Protein C and antithrombin III. The abnormal activation of coagulation cascade is mediated through release of Tissue Factor, Factor X activators, and other miscellaneous procoagulants from the plasma membrane vesicles of tumor cells. Macrophages of a tumor-bearing host also produce increased amounts of Tissue Factor. Production of Factor X activators and macrophage Tissue Factor is decreased by warfarin. The ability of the tumor cells to produce platelet-aggregating activity and plasminogen activator parallels their metastatic potential in animal and experimental systems. These studies also show that antiplatelet agents and antibodies against plasminogen activator can suppress the metastatic process. One or more laboratory abnormalities of hemostasis can be shown in up to 95% of patients with metastatic cancer. These abnormalities, however, are unable to predict subsequent development of thromboembolic or hemorrhagic complications. Clinical complications occur in 9-15% of the patients in the form of thrombotic or hemorrhagic disorders. The therapy of tumor-related coagulopathy should be guided by its clinical expression. Subclinical DIC should not be treated. Coumadin is generally ineffective for therapy of thrombosis in cancer patients. There is no consensus regarding the use of heparin in acute promyelocytic leukemia (APL). The defibrination in APL may be from disseminated intravascular coagulation as well as systemic fibrinolysis, as shown by decreased alpha 2 antiplasmin levels. In such cases, epsilon aminocaproic acid plus heparin therapy may be of benefit.
Publication Types:
PMID: 2202206 [PubMed - indexed for MEDLINE]
-
Fibrinolysis and cancer.
Kwaan HC, Keer HN.
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611.
Publication Types:
PMID: 2146746 [PubMed - indexed for MEDLINE]
-
Evolution of blood coagulation and fibrinolysis.
Patthy L.
Institute of Enzymology, Hungarian Academy of Sciences, Budapest.
The key steps in the evolution of blood coagulation and fibrinolysis have been reconstructed from an analysis of the molecular evolution of their constituents. The data suggest that the blood coagulation and complement cascades are descendants of an ancestral defence system that served the dual role of immobilization and destruction of invading bacteria and the prevention of loss of body fluids. The enzymes of the fibrinolytic, tissue-remodelling cascades form a distinct group, more closely related to the proteases of the digestive tract than to the components of the blood coagulation and complement cascades. Molecular evolution of these enzymes therefore suggests that they are descendants of an ancestral protease responsible for degradation of extracellular proteins. It is shown that the regulatory extensions of the proteases of the blood coagulation, fibrinolytic and complement cascades were assembled from domains borrowed from other proteins. Most non-protease components of these systems were also constructed by this evolutionary mechanism.
Publication Types:
PMID: 2130927 [PubMed - indexed for MEDLINE]
-
Biochemical and biological aspects of the plasminogen activation system.
Mayer M.
Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel.
Plasminogen activators (PAs) are specific proteolytic enzymes which convert the inactive proenzyme plasminogen to plasmin. The plasmin formed is a potent and nonspecific protease which cleaves blood fibrin clots and several other extracellular proteins. In addition to their primary role in the initiation of fibrinolysis, PAs are implicated in a variety of basic biological processes, such as, degradation of the extracellular matrix, tumor invasiveness, tissue remodelling, and cellular differentiation. This review describes recent observations on the biochemical and biophysical characteristics of the different components of the plasminogen activation system. This complex system includes: the proenzymes of tissue type PA (tPA) and urokinase type PA (uPA); the active enzymes tPA, uPA and plasmin; the substrate plasminogen; several natural inhibitors of PA and plasmin activity; and the cellular receptors that bind the proenzymes, enzymes, and inhibitor-enzyme complexes. Through the coordinated interactions of these components, the location, timing, and extent of potent proteolytic activity is controlled. Recent findings on the structure, properties, biological functions, and regulation of the different components of the plasminogen activation cascade are reviewed. Current methods for assay of the amount and activity of the enzymes, inhibitors, and receptors are described. Observations implying specific functions of the system in health and disease, and its potential utilization for diagnosis are examined. Specifically, the potential application of PAs as laboratory markers of neoplasia, as diagnostic tools in diseases of the blood clotting system, their use for monitoring of thrombolytic therapy, and their possible relevance in certain disease states are described.
Publication Types:
PMID: 2197030 [PubMed - indexed for MEDLINE]
-
The haemostatic balance in groups of thrombosis-prone patients. With particular reference to fibrinolysis in patients with myocardial infarction.
Gram J.
Department of Chemical Chemistry, Ribe County Hospital, Esbjerg.
The concept of the haemostatic balance was reviewed, and its potential role in the regulation of tissue repair and the pathogenesis of thrombotic processes was surveyed. Physiological activation of coagulation appears to be dominated by effects of degenerated and injured cells of the vascular wall causing local release of thromboplastin and exposition of activating surfaces. Inhibition of coagulation impairs its progression and the non-thrombogenic nature of the normal endothelium is chiefly caused by the binding of inhibitory components (antithrombin-III, protein C) to specific receptor sites. Physiological activation of fibrinolysis appears to be triggered by and limited to the fibrin because of a specific affinity to fibrin of plasminogen and plasminogen activators. Systemic activation of fibrinolysis is prevented by primary (alpha 2-antiplasmin) and secondary (alpha 2-macroglobulin, alpha 1-antitrypsin) plasmin inhibitors. A plasminogen binding protein (histidine-rich glycoprotein), plasmin inhibitors and activator inhibitors appear to contribute to the regulation of the initial phase of fibrinolysis. A deviation from normal of the dynamic balance, regulating fibrin formation and resolution, may lead to a haemorrhagic and/or a thrombophilic state. Described were the optimization of selected methods for assessment of variables involved in the haemostatic balance. An overestimation of plasminogen concentrations in plasma may occur in patients with elevated levels of fibrinogen or fibrin degradation products, when using assays based on the activation of plasminogen by streptokinase followed by the hydrolysis of a synthetic chromogenic substrate. This source of error could be eliminated by presence of fibrinogen in excess in the plasminogen assay, thereby securing maximum stimulation of the plasminogen-streptokinase complex. The presence of cryoglobulin in plasma interferes with the assessment in euglobulins of plasminogen activator activities. Experiments indicate that tissue-type plasminogen activator adsorb cryoglobulins and that a cold-promoted activation of the factor XII-dependent proactivator system of fibrinolysis is related to the presence of cryoglobulins. Experiments supported the existence of an as yet not characterized factor XII-dependent proactivator. Strictly optimized procedures for the preparation of euglobulins for the accurate determination of plasminogen activators were recommended. The determination of plasminogen activator inhibition in plasma was optimized and simplified. The amidolytic assay of antithrombin-III was shown to be influenced by adsorption to laboratory utensils and aggregation of thrombin. This error could be corrected by protection with additives (Tween 80, polyethyleneglycol 6,000), which also improved the solubility of the chromogenic substrates in aqueous media. The role of thrombosis in myocardial infarction was reviewed.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
PMID: 2192835 [PubMed - indexed for MEDLINE]
-
Urokinase-dependent cell surface proteolysis and cancer.
Blasi F, Verde P.
Institute of Microbiology, University of Copehagen, Denmark.
Plasmin formation is an important and complex process in vivo. It involves two enzymes, two inhibitors, the substrate and specific receptors. Plasmin formation, dependent on the urokinase-type plasminogen activator (uPA), is discussed in its biochemical, regulatory and physiological aspects and its involvement in cancer malignancy analysed. The role of cell surface plasminogen activation in the processes of extracellular matrix degradation, basement membrane dissolution and cancer invasiveness and metastasis is now established in a variety of model systems. The ability of cells to produce plasmin on their surface, due to the presence of uPA and plasminogen receptors, is at the basis of the regulation of the plasminogen activating system in vivo. Synthesis, activity and localization of each component can be individually regulated thus providing the system with an enormous flexibility.
Publication Types:
PMID: 2151734 [PubMed - indexed for MEDLINE]
-
The elastase-mediated pathway of fibrinolysis.
Machovich R, Owen WG.
Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, MN 55905.
Plasmin and elastase degrade fibrin and inhibit the blood coagulation system by degrading key proteins. Elastase can facilitate plasmin expression via an alternative pathway of plasminogen activation. Elastase modifies plasminogen to yield a zymogen that is a better substrate for activators than native plasminogen. Furthermore, elastase inactivates the inhibitor system of plasmin and plasminogen activators without affecting plasmin and plasminogen activators. While plasmin activity develops from a blood zymogen as a consequence of activators synthesized and secreted by endothelium and possibly other cells, elastase is secreted in an active form primarily by polymorphonuclear leukocytes. Plasmin and elastase may play mutual roles in thrombolysis, inflammation, and tumour invasion and metastasis.
Publication Types:
PMID: 2151710 [PubMed - indexed for MEDLINE]
-
Plasminogen activators: pharmacology and therapy.
Holden RW.
Department of Radiology, Wishard Memorial Hospital, Indiana University School of Medicine, Indianapolis 46202.
Biochemical advances are providing new insights into coagulation and fibrinolysis. Integrating this biochemical knowledge into plasminogen activator therapy improves understanding of currently available enzymes. Basic components of the fibrinolytic system are discussed and the chemical structures, pharmacokinetics, dosages, and modes of delivery of current and future plasminogen activators are reviewed.
Publication Types:
PMID: 2137641 [PubMed - indexed for MEDLINE]
-
Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung.
Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC.
Department of Medicine, Dartmouth Medical School.
Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.
PMID: 2153429 [PubMed - indexed for MEDLINE]
-
Haemostasis and cancer.
Francis JL.
Patients with cancer have an increased incidence of thromboembolic disease and haemostatic abnormalities, and there is considerable evidence that the haemostatic system is involved in the growth and spread of malignant disease. Anti-haemostatic agents have given promising results in the treatment of experimental tumours, and several clinical trials in humans have been initiated. The formation of fibrin around the tumour may be a particularly important factor in malignant dissemination. The precise mechanisms of peri-tumour fibrin deposition remain to be elucidated, but may involve alterations in local vascular permeability and the presence of tumour and/or macrophage procoagulants. In addition to their role in fibrin formation, haemostatic components may also be involved in neovascularisation and angiogenesis.
Publication Types:
PMID: 2693872 [PubMed - indexed for MEDLINE]
-
Mechanism of fibrin-specific fibrinolysis by staphylokinase: participation of alpha 2-plasmin inhibitor.
Sakai M, Watanuki M, Matsuo O.
Yakult Central Institute for Microbiological Research, Kunitachi, Japan.
When the extent of plasminogen activation by staphylokinase (SAK) or streptokinase (SK) was measured in human plasma, SAK barely induced plasminogen activation, whereas SK activated plasminogen significantly. When the plasma was clotted with thrombin, the plasminogen activation by SAK was markedly enhanced, but that of SK was little enhanced. Similarly, in a purified system composed of plasminogen, fibrinogen and alpha 2-plasmin inhibitor (alpha 2-PI, alpha 2-antiplasmin), such a fibrin clot increased the activity of SAK significantly. However, when alpha 2-PI was removed from the reaction system, enhancement of the SAK reaction was not observed. In addition, SAK as distinct from SK, showed very little interference with the action of alpha 2-PI. Plasminogen activation by SAK is thus essentially inhibited by alpha 2-PI, but this reaction is not inhibited in fibrin clots. These results suggest that SAK forms a complex with plasminogen, which binds to fibrin and induces fibrinolysis.
PMID: 2527034 [PubMed - indexed for MEDLINE]
-
[The physiology of hemostasis: plasma and tissue factors in coagulation and fibrinolysis]
[Article in French]
Francois P, Verstraeten L, Dinant JP.
Coagulation and fibrinolysis are two antagonistic phenomena, the harmonious balance of which results form a perfect regulation of their respective activators and inhibitors. Indeed, the efficacy of the response of the organism to an aggression against the blood vessel and its plasmatic and cellular contents, depends on the capacity of maintaining this balance. The mechanisms involve plasma proteins (factors) endowed with a proteolytic activity, as well as mediators released from injured tissues (endothelium). Coagulation corresponds to the process of fibrin formation (fibrin clump), which assures the consolidation of the platelet clot which was pre-formed during the activation of the platelets. Fibrinolysis consists in the gradual dissolution of this fibrin clump, aimed at re-permeabilization of the vessel at the site of the lesion, and thus at a normalization of the blood circulation at this level. Coagulation and fibrinolysis can hardly be dissociated from primary haemostasis (platelet activation), not only because of their interactions, but also because of their chronology: all these events are, indeed, triggered almost simultaneously, even though the duration varies. The mechanisms that are implicated in thrombo-embolic phenomena are comparable to those of physiological haemostasis. However, it is the imbalance between these events which constitutes the pathological aberration and thus induces the formation of a fibrin-platelet thrombus.
Publication Types:
PMID: 2691642 [PubMed - indexed for MEDLINE]
-
[Tumor metastasis and the fibrinolytic system]
[Article in Japanese]
Yamamura M, Yamamoto M.
Dept. of Surgery, Kansai Medical University.
Metastatic spread of malignant tumor appears to correlate with activation of the fibrolytic system. The role of fibrinolysis in growth and metastasis was examined in Lewis lung carcinoma of mice. The inhibition of fibrinolysis or proteases decreased the primary tumor growth and pulmonary metastasis, whereas the activation of fibrinolysis or proteases increased the number of metastatic foci in the lung. Electronmicroscopically, thrombus formation in the primary site prevented tumor invasion and metastasis formation. Plasminogen activator (PA) content of excised tumors was determined by SDS-PAGE, and major PA was found to be urokinase (UK) type. Immunohistochemical study with specific antisera was done. When tumor cells possessed a high level of UK, laminin and type IV collagen, components of the basement membrane, disappeared from tumor tissues. These findings suggest that PA through protease cascade plays a role in tumor invasion and metastasis. Clinically, patients with advanced cancer are usually in a hypercoagulable state with elevated fibrinogen, and fibrin deposition around tumor mass is a serious problem in cancer chemotherapy. UK infusion prior to 5-fluorouracil increased tissue concentration of antitumor agent. However, development of consumption coagulopathy characterized by progression from hypercoagulable state to disseminated intravascular coagulation has also been found in several cases.
PMID: 2730023 [PubMed - indexed for MEDLINE]
-
Hemostasis associated with abnormalities of fibrinolysis.
Aoki N.
First Department of Medicine, Tokyo Medical and Dental University School of Medicine, Japan.
Hemostatic plugs consist of platelet aggregates and fibrin mesh containing blood cells and plasma components. Hemostatic efficiency depends on the rate of formation of hemostatic plugs as well as the structural integrity and stability of the formed hemostatic plugs. Fibrin elements are major constituents contributing to the structural integrity and stability, but they are subject to fibrinolytic activity occurring spontaneously after fibrin formation. Fibrinolysis is usually suppressed by endogenous inhibitors. Increase of a profibrinolytic component or deficiency of an inhibitor would result in an accelerated fibrinolysis, causing a premature lysis of hemostatic plugs before restoration of injured vessels, leading to a hemorrhagic tendency. Such a state can be seen typically in patients with congenital deficiency of alpha 2-plasmin inhibitor or a hereditary increase of plasminogen activator, and it is also seen in acquired situations such as amyloidosis, liver cirrhosis, disseminated intravascular coagulation (particularly in patients with acute promyelocytic leukemia) and thrombolytic therapy. The hemorrhagic tendency can be well controlled by an administration of an antifibrinolytic agent: epsilon-aminocaproic acid or tranexamic acid. In contrast to an accelerated fibrinolysis causing a hemorrhagic tendency, retarded fibrinolysis may predispose an individual to a thrombotic tendency. Retarded fibrinolysis may be due to either an increase in plasminogen activator inhibitors or decrease of plasminogen activators. Quantitative or qualitative deficiency of plasminogen may also lead to a thrombotic tendency.
Publication Types:
PMID: 2650772 [PubMed - indexed for MEDLINE]
-
[Therapy of consumption coagulopathies]
[Article in German]
Kunzer W.
Universitats-Kinderklinik, Freiburg i.B.
The terms "consumption coagulopathy" and "disseminated intravascular coagulation" are used synonymously, though the former expression refers to the process of consuming the haemostatic potential, whereas the latter is based upon the generalized formation of microthrombi. Both terms apply to an acquired disturbance of blood clotting leading to an increased turnover of coagulation factors and platelets by which the production sites are being exhausted. Such a process is triggered off by generalized activation of the haemostatic system: after a period of hypercoagulability, haemostasis changes into hypocoagulability with subsequent haemorrhagic diathesis. Additionally, the generalized activation of the haemostatic system leads to a formation of microthrombi in the microcirculation. Since consumption coagulopathies are bound to be secondary disorders, any underlying disease prone to lead to disseminated intravascular coagulation, should be treated as early and as intensively as possible. Solely by this and by restoring circulatory functions impaired by the underlying disease, it is possible in the majority of cases to stop the consumptive coagulopathy and to repair its sequelae. The shock frequently going along with a consumption coagulopathy requires immediate therapy: correction of hypothermia, treatment of acid-base and electrolyte disorders as well as fighting against hypovalaemia, anuria, and uraemia. Dextran does not serve only as plasma expander, but also corrects hypercoagulability and improves the rheological qualities of circulating blood. If these measures fail to stop the consumptive reaction of blood coagulation and/or fail to restore microcirculation in vital organs, indication for the use of anticoagulants or fibrinolytic drugs is given.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
PMID: 3070363 [PubMed - indexed for MEDLINE]
-
Mechanisms of thrombus formation and lysis.
Stump DC, Mann KG.
Department of Medicine, University of Vermont, Burlington, Vermont 05405.
Maintenance of a patent vasculature is critical to provide nutrient blood flow to dependent tissues. This is normally facilitated by vessels composed of actively nonthrombogenic endothelium and blood that contains both nonactivated platelets and inactive coagulation proenzymes. Following vessel injury, active hemostasis results from vasoconstriction, adherence and aggregation of activated platelets, and coagulation enzyme activation. The resulting thrombus contains a mixture of blood cells and the insoluble product of coagulation, fibrin, which further stimulates the activation of another blood enzyme system known as the fibrinolytic system. This results in the conversion by plasminogen activators of the circulating plasma proenzyme plasminogen into the active fibrinolytic enzyme plasmin, which dissolves the clot into degradation products. Vascular patency ultimately is restored and healing is thus facilitated. The hemostatic system is highly regulated by a variety of processes. Derangement of regulation can lead to disease manifesting either as thrombosis or hemorrhage. Furthermore, improved understanding of the molecular interactions involved in these processes has led to design of newer therapeutic interventions targeted toward amelioration of the sequelae of thromboembolic disease.
PMID: 3142314 [PubMed - indexed for MEDLINE]
-
Plasminogen activation: biochemistry, physiology, and therapeutics.
Wun TC.
Department of Biological Sciences, Monsanto Co., Chesterfield, Missouri.
The mammalian serine protease zymogen, plasminogen, can be converted into the active enzyme plasmin by vertebrate plasminogen activators urokinase (uPA), tissue plasminogen activator (tPA), factor XII-dependent components, or by bacterial streptokinase. The biochemical properties of the major components of the system, plasminogen/plasmin, plasminogen activators, and inhibitors of the plasminogen activators, are reviewed. The plasmin system has been implicated in a variety of physiological and pathological processes such as fibrinolysis, tissue remodeling, cell migration, inflammation, and tumor invasion and metastasis. A defective plasminogen activator/inhibitor system also has been linked to some thromboembolic complications. Recent studies of the mechanism of fibrinolysis in human plasma suggest that tPA may be the primary initiator and that overall fibrinolytic activity is strongly regulated at the tPA level. A simple model for the initiation and regulation of plasma fibrinolysis based on these studies has been formulated. The plasminogen activators have been used for thrombolytic therapy. Three new thrombolytic agents--tPA, pro-uPA, and acylated streptokinase-plasminogen complex--have been found to possess better properties over their predecessors, urokinase and streptokinase. Further improvements of these molecules using genetic and protein engineering tactics are being pursued.
Publication Types:
PMID: 2976309 [PubMed - indexed for MEDLINE]
-
Antimetastatic agents. II. Summary of the interactions of tumor cells with blood coagulation factors, platelets, fibrinolytic factors, and inflammatory cells and their soluble mediators: potential for therapeutic interventions.
Rickles FR, Hancock WW.
Department of Medicine, University of Connecticut School of Medicine, Farmington 06032.
Although not reviewed during this session of the Workshop, other reactions in the hemostatic pathways are relevant to tumor-host cell interactions, are potential targets for antimetastatic agents, and are therefore included in Figure 1 and Table 1. For example, elsewhere in this issue of Seminars Loskutoff reviews the recent evidence for the importance of naturally occurring plasminogen activator inhibitors in the regulation of fibrinolysis. Since tumor cells may contain both tissue plasminogen activator and a urokinase-like plasminogen activator, the balance between tumor-mediated fibrin formation and fibrinolysis becomes an important issue in assessing antimetastatic treatment protocols. The relationship of the fibrinolytic pathways to metastasis has been reviewed recently by Dano and colleagues. Clearly, no single therapeutic approach designed to inhibit only one of these complicated interactions between tumor cells and host defense mechanisms is likely to be successful. However, each of the pathways illustrated (Fig. 1) and each of the theoretical steps in the metastatic cascade (Table 1) must be considered in the design of new strategies for the use of antimetastatic agents.
PMID: 3353730 [PubMed - indexed for MEDLINE]
-
Physiologic regulation and pathologic disorders of fibrinolysis.
Francis CW, Marder VJ.
Physiologic fibrinolysis is a reparative process that occurs in response to hemostatic plug or thrombus formation. The final enzymatic step, fibrin proteolysis, results from a coordinated interaction of enzymes and inhibitors, which produces effective action at the site of the disease and spares the proteins of the blood or uninvolved parts of the vascular system. The agent of fibrinolysis, the enzyme plasmin, is derived from its zymogen (plasminogen) through limited proteolysis effected by plasminogen activators. They can be grouped according to functional and immunologic properties into the tissue type and urokinase-like plasminogen activators. The ability of alpha 2 antiplasmin to neutralize efficiently free (nonfibrin-bound) plasmin prevents inappropriate systemic activation of fibrinolysis. This control is superseded in certain conditions, such as with the therapeutic administration of plasminogen activators to lyse pathologic thrombi, when plasmin degrades plasma fibrinogen into degradation fragments (X, Y, D, and E). Degradation of cross-linked fibrin results in distinctive products that are characterized by cross-linked (factor XIIIa-induced) derivatives such as D dimer. Disease states resulting from abnormalities in the fibrinolytic system include both hemorrhagic disorders, resulting from excessive fibrinolysis, and thrombosis, as the result of deficient fibrinolysis. Hyperfibrinolysis can result from pharmacologic administration of activators or from defective inhibition produced by alpha 2 antiplasmin deficiency. Hypofibrinolytic thrombosis can result from hereditary defects, for instance of plasminogen or fibrinogen, or from pharmacologic inhibition of fibrinolysis such as with epsilon aminocaproic acid. Laboratory evaluation of fibrinolysis is useful for monitoring fibrinolytic therapy and assessing thrombotic disorders and bleeding; it also includes the specific measurements of plasminogen activator, plasminogen, plasmin, inhibitors and circulating fibrinogen, and cross-linked fibrin degradation products.
Publication Types:
PMID: 3546075 [PubMed - indexed for MEDLINE]
-
Thrombosis and cancer.
Dvorak HF.
Abnormal hemostasis is a fundamental property of malignant disease, not merely an epiphenomenon attributable to therapy or to chronic illness. Many types of tumor cells express clotting initiators such as tissue factor and act again late in the coagulation pathway by providing a surface for prothrombinase generation. Thus, entry of tumor cells into the plasma, as during metastasis, may be expected to trigger intravascular clotting. However, and perhaps of greater importance, solid tumors growing outside of the blood vasculature regularly deposit fibrin locally in the tissues. They do so by rendering the microvasculature hyperpermeable, allowing fibrinogen and other plasma-clotting proteins to leak into the extravascular space where procoagulants associated with tumor cells or with benign stromal cells initiate clotting. Both fibrin deposition and turnover in solid tumors proceed at rapid rates. Thus, whether attributable to events in the intra- or extra-vascular space, the result is the same: abnormal clotting and fibrinolysis whose consequences may include protection from host inflammatory cells, modulation of the immune response, and induction of angiogenesis.
Publication Types:
PMID: 3546076 [PubMed - indexed for MEDLINE]
-
Coagulation and fibrinolysis.
Nilsson IM.
Dept. of Coagulation Disorders, University of Lund, General Hospital, Malmo, Sweden.
The two final phases in the haemostatic process, plasma coagulation with the formation of a fibrin clot, and fibrinolysis leading to the dissolution of fibrin clots, are reviewed. Coagulation may be initiated either by reactions occurring between components of the blood alone, the intrinsic pathway, or by reactions which also involve tissue components, termed the extrinsic pathway. In the diagnosis of coagulation disorders, it is convenient to divide the intrinsic pathway into three phases. In phase 1, resulting in the activation of factor (f) X, are involved f XII, XI, VIII and IX, platelet phospholipids, and calcium. In phase 2, prothrombin is converted to thrombin by f Xa in conjunction with f V, phospholipids, calcium. In phase 3, thrombin converts fibrinogen to fibrin, which is then stabilized by f XIII. Antithrombin III is the most important inhibitor. The key component in fibrinolysis is plasminogen, which under the influence of various activators is converted to plasmin. Plasmin is a serine protease and its main in vivo target is fibrin. Alpha 2-antiplasmin and a fast-acting inhibitor of tissue plasminogen activator are the most important inhibitors.
Publication Types:
PMID: 3321400 [PubMed - indexed for MEDLINE]
-
The significance of the fibrin/fibrinogen degradation product in serum of carcinoma patients with hematogenous metastasis.
Imaoka S, Sasaki Y, Iwanaga T, Terasawa T.
Fibrin/fibrinogen degradation product (FDP) was measured in 270 cases with various carcinomas. An elevation of FDP (5 micrograms/ml or more) was observed in 68 cases (25%). Of the 68 elevated FDP cases, 5 (82%) were inoperable or received nonradical resection. Forty of those 56 cases (71%) showed hematogenous metastasis. FDP in those cases which showed hematogenous metastasis was found to be due to fibrinolysis accompanied by consumption coagulopathy.
PMID: 3742466 [PubMed - indexed for MEDLINE]
-
[Studies on fibrinolysis and ascites accumulation associated with peritonitis carcinomatosa--effects of protease inhibitors (PI) on MM2 ascites tumor growth, ascites accumulation and fibrinolysis]
[Article in Japanese]
Shibata J.
The effects of protease inhibitors(PI), t-AMCHA, gabexate, aprotinin and heparin on the growth of mouse MM2 ascites tumor (MAT) and on several components of fibrinolysis were studied. The drugs were administered intraperitoneally one time daily for 12 days, one day after the tumor transplant. The volumes of ascites, total packed cell volume (TPCV) and fibrinolytic parameters (FDP, whole plasmin, plasminogen activator (PA)) were measured on the 8, 10 and 12th days of therapy. Fibrinolytic activity was assayed by the lysin sepharose affinity chromatography-radio caseinolytic method. Fibrinolytic activity in the ascites increased during the tumor growth. The ascites accumulation as well as levels of FDP, whole plasmin and PA in the drug treated group were significantly decreased when compared to the control group. In these drug-treated groups, MAT cells agglutinated in the abdominal cavity, but in contrast to this, no agglutination was observed in the control group. It was uncertain whether PI directly inhibited tumor growth. The fact that PI inhibited the ascites accumulation and also decreased fibrinolytic activity suggest the involvement of protease in the neoplastic process and indicates another therapeutic approach to malignant ascites tumors.
PMID: 2425022 [PubMed - indexed for MEDLINE]
-
The initiation of fibrinolysis in alpha 2-plasmin inhibitor deficient plasma. Role of fibrin.
Ichinose A, Aoki N.
Plasmin activity and fibrin degradation products (FDP) are found in alpha 2-plasmin inhibitor (alpha 2-PI) deficient plasma only when clotted, but are not found when the plasma is not clotted. To determine whether fibrin itself could initiate fibrinolysis without activating coagulation enzymes, fibrin monomers were prepared and added to alpha 2-PI deficient plasma. The addition of fibrin monomers resulted in the generation of plasmin activity, a marked increase in FDP concentration, and the release of 125I from 125I-labeled fibrin monomers. Replenishment of the deficient plasma with purified alpha 2-PI abolished the effects of fibrin monomers on the initiation of fibrinolysis. Neither development of plasmin activity, increase of FDP, nor release of 125I was observed. These findings indicate that fibrinolysis can be induced by fibrin itself without activation of coagulation cascade and the induction of fibrinolysis is efficiently blocked by alpha 2-PI.
PMID: 2939589 [PubMed - indexed for MEDLINE]
-
[Sepsis and blood coagulation]
[Article in German]
Muller-Berghaus G.
Septicemia is frequently accompanied by changes in the plasmatic as well as cellular coagulation systems and by microclot formation. The occurrence of a hemorrhagic diathesis and microthrombosis is best explained by the syndrome disseminated intravascular coagulation (= consumption coagulopathy). Disseminated intravascular coagulation can be initiated by different agents and by different pathways. The activation of coagulation by endotoxin is well studied; it is mediated by synthesis of tissue factor by monocytes and endothelial cells. The formation of microthrombi is caused by the precipitation of circulating soluble fibrin under the influence of localizing factors, and it is observed under conditions of reduced fibrinolysis activation. Furthermore, thrombocytopenia, thrombocytopathy and endothelial cell damage caused by a direct effect of the toxic agent contribute to the bleeding diathesis.
PMID: 3718402 [PubMed - indexed for MEDLINE]
Concepts of clot lysis.
Francis CW, Marder VJ.
Physiologic thrombolysis is efficient, while pathologic aberrations in the fibrinolytic system may result in either thrombotic or hemorrhagic disease. This review considers the molecular interactions involved in fibrinolysis, discusses the normal control mechanisms that provide for localized activation without systemic effects, and describes the molecular mechanism of plasmic degradation of fibrinogen and of cross-linked fibrin. The consequences of excessive or deficient fibrinolysis are discussed and specific examples cited of pathologic hemostasis directly related to abnormalities in the fibrinolytic system.
Publication Types:
PMID: 2939790 [PubMed - indexed for MEDLINE]
-
The fibrinolytic system in man.
Collen D, Lijnen HR.
The fibrinolytic system comprises a proenzyme, plasminogen, which can be activated to the active enzyme plasmin, that will degrade fibrin by different types of plasminogen activators. Inhibition of fibrinolysis may occur at the level of plasmin or at the level of the activators. Fibrinolysis in human blood seems to be regulated by specific molecular interactions between these components. In plasma, normally no systemic plasminogen activation occurs. When fibrin is formed, small amounts of plasminogen activator and plasminogen adsorb to the fibrin, and plasmin is generated in situ. The formed plasmin, which remains transiently complexed to fibrin, is only slowly inactivated by alpha 2-antiplasmin, while plasmin, which is released from digested fibrin, is rapidly and irreversibly neutralized. The fibrinolytic process, thus, seems to be triggered by and confined to fibrin. Thrombus formation may occur as the result of insufficient activation of the fibrinolytic system and (or) the presence of excess inhibitors, while excessive activation and/or deficiency of inhibitors might cause excessive plasmin formation and a bleeding tendency. Evidence obtained in animal models suggests that tissue-type plasminogen activator, obtained by recombinant DNA technology, may constitute a specific clot-selective thrombolytic agent with higher specific activity and fewer side effects than those currently in use.
Publication Types:
PMID: 2420482 [PubMed - indexed for MEDLINE]
-
Blood coagulation and fibrinolysis in heat stroke.
Mustafa KY, Omer O, Khogali M, Jamjoom A, Gumaa KA, Abu el-Nasr N, Gader MA.
Blood coagulation and fibrinolysis were assessed in 55 cases of heat stroke who presented with or without bleeding tendencies during the Makkah pilgrimage of 1983. 17 patients were identified to have evidence of disseminated intravascular coagulation (DIC). Bleeders with DIC had a higher incidence of shock and a higher mortality when compared to non-bleeders. Thrombocytopenia and liver cell damage were not limited to cases with DIC. Coagulation factors and serum enzyme studies suggested non-specific tissue damage as the trigger mechanism for DIC possibly proceeding through the extrinsic system of blood clotting. We conclude that the breakdown of haemostasis in heat stroke is multifactorial: thrombocytopenia, liver cell damage and DIC.
PMID: 4063208 [PubMed - indexed for MEDLINE]
-
[Fibrinolysis and disseminated intravascular coagulation]
[Article in Japanese]
Ikematsu S.
Publication Types:
PMID: 2931536 [PubMed - indexed for MEDLINE]
-
[Hemostatic mechanisms and malignant tumors]
[Article in German]
Kase F, Pospisil J, Hlouskova D.
The mutual relationships between malignant tumours and mechanisms of blood coagulation are presented in a brief survey. In this connection, the mechanisms of a tumour cell entering the circulation through the vessel well and its leaving into the tissues are discussed, the theory of microtrauma being used for explaining these processes. Subsequently, the alterations to be found in the count and function of thrombocytes after contact with a malignant cell and the impact on this cell by blood platelets are represented. As a third factor the activation of blood coagulation which is exercised by substances with a procoagulatory effect produced by the malignant tissue and the frequently observed thrombosis in the course of neoplastic diseases are dealt with in connection with blood level changes of some coagulation factors. In a fourth section the significance of fibrinolysis, its activation and inhibition as well as the production of fibrinolytic activators by neoplasms are discussed.
Publication Types:
PMID: 2419210 [PubMed - indexed for MEDLINE]
-
Changes in plasma levels of protease and fibrinolytic inhibitors induced by treatment in acute myeloid leukemia.
Velasco F, Torres A, Andres P, Martinez F, Gomez P.
We have studied the main protease inhibitors of leukocytes, alpha-1-protease (alpha 1-PI), alpha-1-antichymotrypsin (alpha 1-Achy) and alpha-2-macroglobulin (alpha 2-M), as well as different parameters of coagulation and fibrinolysis in 21 cases of acute nonlymphoblastic leukemia (ANLL) before, during and after therapy. Nine of the patients presented signs of DIC, 8 of whom belonged to subtype M3 and to subtype 1 M1. The initial alpha 1-PI and alpha 1-Achy levels, which were elevated, increased during the treatment period. There was no significant difference between patients with and without DIC. However, those leukemic patients with DIC showed a significant decrease in plasminogen (p less than 0.005) and fast antiplasmin (p less than 0.01) only during the treatment compared with DIC free patients. All DIC cases demonstrated circulating plasmin-antiplasmin complex (P-AP) both before and during treatment. Independent of a possible proteolytic action of leukocyte enzymes on clotting factors in the clinical course of ANLL (mainly M3 subtype), our results suggest an activation of plasmin-mediated fibrinolysis related to the activation of plasminogen by leukocytes, reactive DIC or both.
PMID: 6238445 [PubMed - indexed for MEDLINE]
-
Initial plasmin-degradation of fibrin as the basis of a positive feed-back mechanism in fibrinolysis.
Suenson E, Lutzen O, Thorsen S.
This study deals with the effect of fibrin on the transformation of Glu-plasminogen to Glu-plasmin during fibrinolysis. It focuses particularly on changes in fibrin effector function caused by plasmin-catalysed fibrin degradation. Conversion of 125I-labelled Glu-plasminogen to Glu-plasmin was catalysed by urokinase or tissue plasminogen activator, in the presence of different preparations of progressively degraded fibrin. Plasmin catalysis of Glu-plasminogen and the fibrin (derivative) effector was inhibited by aprotinin. The presence of intact fibrin enhanced the rate of Glu-plasmin formation catalysed by tissue plasminogen activator, but not by urokinase. The presence of initially plasmin-cleaved fibrin, however, increased the rates of Glu-plasmin formation with both activators, as compared to those found with intact fibrin. The rate enhancements induced by initial plasmin degradation of the fibrin effector were associated with an increase in its affinity to both Glu-plasminogen and tissue plasminogen activator, suggesting causal relationships. The weak binding of urokinase was unaffected by fibrin degradation, indicating that effector function was solely exerted on the Glu-plasminogen moiety of urokinase-activated systems. Further degradation of fibrin decreased the stimulating effect on Glu-plasmin formation. This decrease occurred at an earlier stage of degradation with tissue plasminogen activator than with urokinase, indicating that greater integrity of the fibrin effector is necessary for its optimal interaction with the tissue plasminogen activator than with Glu-plasminogen. Concentrations of tranexamic acid that saturate low-affinity lysine-binding sites nearly completely dissociated the binding of Glu-plasminogen to degraded fibrin, but not to intact fibrin. In analogy with the binding of lysine analogues to these sites, the conformation of Glu-plasminogen may be altered by binding to degraded fibrin, thus giving rise to the increased activation rate.
PMID: 6233145 [PubMed - indexed for MEDLINE]
-
Plasmin-alpha 2-antiplasmin complexes in bleeding disorders characterized by primary or secondary fibrinolysis.
Booth NA, Bennett B.
A two-dimensional immunoelectrophoresis (2DIEP) method detects plasmin complexed to its major inhibitor, alpha 2-antiplasmin, in plasma in the blood of patients during (a) thrombolytic therapy with urokinase, (b) episodes of disseminated intravascular coagulation (DIC) with active fibrinolysis, and (c) episodes of fibrinolytic haemorrhage without evidence of DIC. Clearance of the complexes from the blood is rapid and their detection thus implies active plasmin generation at the time of blood sampling or within the preceding 24 h. Abolition of the complexes using tranexamic acid therapy allowed surgery without bleeding in two previously grossly haemorrhagic patients in group (c). Antithrombin III complexed with activated procoagulants was detected using a similar 2DIEP method in only two of four patients with DIC. Abnormalities of alpha 2-macroglobulin were detected on 2DIEP of plasma in the patients studied with proteolytic disorders; these did not appear to reflect complex formation.
PMID: 6201189 [PubMed - indexed for MEDLINE]
-
[Hemostasis and tumor invasion. Therapeutic implications]
[Article in French]
Cattan A.
Plasminogen activator activity (PAA) has been detected in various tumor cells or in their excretion products. In some cell systems PAA is a symptom of cell transformation, but its amount is questionably correlated with the invasiveness of the tumor cells. Procoagulant and aggregation activities on platelets, have been demonstrated in various tumor cells. There are weakly correlated with the metastatic potential of these cells. In vivo, the treatment of animals by modifiers of the hemostasis, or of the fibrinolysis systems provides contradictory results. Some reduction of metastatic diffusion and increase of life span have been noted with Warfarin. Clinical trials are scarce and their methodology is debatable. When conclusive, a lengthening of the life span has been observed, but not a reduction of the metastatic spread as metastases were still present.
Publication Types:
PMID: 6395923 [PubMed - indexed for MEDLINE]
-
Extrinsic plasminogen activator: a new principle in fibrinolysis.
Lijnen HR.
Fibrinolysis in the blood seems to be regulated by specific molecular interactions between plasminogen activator, plasmin(ogen), fibrin and alpha 2-antiplasmin. Plasmin(ogen) contains structures, called lysine-binding sites, which mediate its interaction with fibrin and with alpha 2-antiplasmin. In plasma normally no systemic plasminogen activation by plasminogen activator occurs and plasmin, if formed, is efficiently neutralized by alpha 2-antiplasmin. When fibrin is formed in plasma a small amount of plasminogen is bound via its lysine-binding sites. Plasminogen activator present or released in the blood is strongly adsorbed to the fibrin and activates bound plasminogen in situ. The formed plasmin, which remains transiently complexed to fibrin, both by its lysine-binding site(s) and active center, is only slowly inactivated by alpha 2-antiplasmin, while plasmin which is released from digested fibrin is rapidly and irreversibly neutralized. The fibrinolytic process thus seems to be triggered by and confined to fibrin. An important consequence of this molecular model for fibrinolysis is that specific thrombolysis is only expected with the use of a specific activator, like the physiological extrinsic plasminogen activator, which confines the activation of plasminogen to the fibrin surface. Recent in vitro and in vivo studies have confirmed that the extrinsic plasminogen activator (tissue-type) might constitute a superior thrombolytic agent compared to urokinase or streptokinase.
PMID: 6236789 [PubMed - indexed for MEDLINE]
-
[The experimental study of blood coagulation and fibrinolysis in acute portal vein occlusion]
[Article in Japanese]
Nakao A.
Influence of acute portal vein occlusion on blood coagulation and fibrinolysis have not been fully clarified. In this experimental study in mongrel dogs, 1) changes of blood coagulation and fibrinolysis in portal vein and peripheral vein, 2) histological changes in small intestine and 3) activity of plasminogen activator in small intestine were investigated periodically after acute portal vein ligation with or without heparinized hydrophilic catheter-bypass between portal and femoral vein. All five dogs died 81-130 minutes (mean 105 minutes) after portal vein ligation. On the other hand, all five bypassed dogs survived in good condition for more than four hours. Acute portal venous congestion caused hypercoagulable state in portal system and apparent DIC occurred in portal system 10 minutes after portal vein ligation. Activity of tissue plasminogen activator which was observed mostly in the endothelial cells of vessels in submucosal layers of small intestine decreased rapidly and disappeared within 20 minutes after portal vein ligation. To the contrary, with the use of the catheter-bypass procedure, no significant changes of blood coagulation and fibrinolysis were observed. These results indicate clearly that portal venous congestion is the trigger of hypercoagulable state in portal system, which progresses to irreversible DIC in 20 minutes. With the use of the catheter-bypass procedure, portal vein shut-down is performed without any abnormal coagulation and fibrinolysis in portal bed and systemic circulation.
PMID: 6687131 [PubMed - indexed for MEDLINE]
-
[Development and dissemination of malignant tumors, and hemostasis]
[Article in French]
Kher A, Hilgard P.
Strong circumstantial evidence suggests that the activation of the hemostatic system is involved in the growth and spread of malignant tumors. Nevertheless, the considerable experimental and clinical data presently available cannot be interpreted in one specific direction. The presence of a fibrin and/or a platelet thrombus in the environment of tumor cells only represents the visible end product of a complex biochemical and biophysical process during which other phenomena like haemodynamic changes and the generation of many biologically active enzymes occur. In the interpretation of experimental studies and clinical trials of anticoagulants in cancer disease, a wider concept of the hemostatic process and its multiple interactions with other biological systems is needed. The complement system, adhesive glycoproteins of the cell surface, chemotaxis, growth factors and prostaglandins are some examples of factors which interact with the hemostatic system as well as with the pathology of cancer. The definite pathogenic connection between the clinically observed hypercoagulability of patients with malignant disease and the biology of tumor growth and tumor dissemination remains unclear. Agents which modify hemostatic reactions must be evaluated in specific tumor categories using carefully controlled prospective trials. The results of such studies on tumor regression and also on longevity will permit to assess the efficacy of these agents as adjuvant therapy in the treatment of cancer.
Publication Types:
PMID: 6306819 [PubMed - indexed for MEDLINE]
-
Fibrinolytic activity in human tumor tissues.
Yuen P, Kwaan HC.
The fibrinolytic activity of 156 malignant and 36 benign solid tumors from autopsy and biopsy specimens was studied by the fibrin slide technique. The inhibitory activity against fibrinolysis was graded according to the lysis time of vascular tissues within the tumor. The results show that all malignant solid tumors, with the exception of prostate carcinoma, demonstrated varying degrees of inhibition of fibrinolysis. Persistently high inhibitory activity was found in squamous cell carcinoma of the esophagus, the respiratory tract, cervix uteri, and skin; carcinoma of uterus; colorectal carcinoma; small cell anaplastic carcinoma of lung; neuroblastoma, carcinoma of bile duct, while malignant tumors of the kidney show a lesser degree of inhibition. In contrast, with the exception of the hydatidiform mole, benign solid tumors show little or no inhibition. A similar absence of fibrinolytic activity is seen in metastatic disease. Further studies of the role of the fibrinolytic system in tumors seems warranted.
PMID: 6686789 [PubMed - indexed for MEDLINE]
-
Inhibition of the arrest of hematogenously disseminated tumor cells.
Tsubura E, Yamashita T, Sone S.
Most metastases in patients occur as a result of hematogenous dissemination of tumor cells. This process of metastasis is complex and consists of several steps, foremost of which is the arrest of circulating emboli in capillary beds and the formation of a thrombus at that site. Thrombus formation in the metastasis of human cancer was described first by Billroth in 1878. It was reported that the organization of tumor cell emboli, and the subsequent penetration of tumor cells into the capillary wall, was the first stage of metastasis. Since then, many investigations and observations have been made clinically as well as experimentally to clarify the process (or mechanisms) of tumor cell arrest and how to inhibit it. Coagulative and fibrinolytic pathways were believed to have a main role in thrombus formation. However, other factors responsible for the relationship between tumor cells and the host must be also considered. Elegant and extensive studies by Fidler and Kripke demonstrated that development of metastasis is not a random process, but a selection process of specialized subpopulations of highly metastatic cells within the primary tumors. Biochemical constituents and ionic properties on cell surfaces, deformability or locomotive activities of tumor cells, as well as thrombo-plastic-fibrinolytic activities, are also important factors determining the arrest patterns of circulating tumor cells. On the other hand, host defense factors against tumor cells in the bloodstream have been attracting much attention recently in tumor immunology. Host defense factors relating the arrest of tumor cells to the establishment of metastatic foci seemed difficult to define, since many studies showed contradictory data concerning the influence of immune response on tumor cell arrest. Hemodynamic abnormality may also influence the arrest of tumor cells in the circulation. Hypercoagulability induced from host tissues is greatly associated with the arrest patterns. Platelet activities might affect thrombus formation. Nevertheless, exact explanations of the process or mechanisms inhibiting or enhancing the arrest of tumor cells after hematogenous dissemination have not been obtained. In any event, for cancer treatment, it is important to determine which substances inhibit the arrest of circulating tumor cells and how to prevent hematogenous metastasis. In this review, we will focus upon coagulative and fibrinolytic processes and then upon substances that inhibit the arrest of circulating tumor cells. Furthermore, some comments on the possible clinical applications of inhibitory substances for prevention of cancer metastasis are added.
Publication Types:
PMID: 6367967 [PubMed - indexed for MEDLINE]
-
Cell detachment and metastasis.
Weiss L, Ward PM.
Cancer cell detachment in three distinct and critical parts of the metastatic cascade is discussed. The detachment of cancer cells from their parent tumors is an initial early event in metastasis. The site of detachment with respect to proximity to blood vessels may determine the initial dissemination route. Many factors affect cell detachment; we specifically consider the effects of growth-rate, necrosis, enzyme activity, and stress on cell release in terms of metastasis-promoting mechanisms. Detachment is also discussed in relation to active cancer cell locomotion, where localized detachment from the substratum is a prerequisite for translatory movement. The importance of active cell movement in tissue invasion has only recently been assessed, and, in the case of at least some human malignant melanomas, a zone of actively moving cancer cells is believed to precede the growing body of the tumor. The secondary release of cancer cells from temporary arrest sites at the vascular endothelium consequent upon intravascular dissemination is also a major area of investigation. Circulating cancer cells arrest at vascular endothelium or are impacted in small vessels, however, most are released into the circulation and subsequently perish. The blood stream is a hostile environment, and it is probable that cancer cells are sufficiently damaged in translocation by hemodynamic trauma and humoral factors such that they easily detach or are 'sheared-off' the vascular endothelium by blood flow. Another possibility is that in some cases they are processed by 'first organ encounters' and perish before or shortly after arriving in a second organ. Animal studies have shown that, following intravenous injection, 60-100% of the injected dose of viable cancer cells are initially arrested in the lungs, but very few remain after 24 hr. As it is only those retained cells which produce tumors, the mechanisms involved in this secondary release, which occurs in all organs so far examined, are critical to any understanding of the metastatic cascade and metastatic inefficiency. The arrest of cancer cells at the vascular endothelium and their subsequent release have been associated with the presence of platelets, and the deposition of fibrin and manipulation of platelet-aggregating mechanisms and fibrinolysis are discussed in terms of their antimetastatic effects. The role of the reticuloendothelial system, natural killer cells, and polymorphs is discussed in relation to cancer cell clearance from blood vessels and also to inherent cancer cell properties which may act to inhibit their metastasis. Although detachment of cancer cells from a primary tumor may be regarded as metastasis promoting, secondary release of cancer cells may be associated with inhibition of metastasis.
Publication Types:
PMID: 6352010 [PubMed - indexed for MEDLINE]
-
Fibrin as a component of the tumor stroma: origins and biological significance.
Dvorak HF, Senger DR, Dvorak AM.
An association between cancer and the coagulation system was suggested by Trousseau more than a century ago and initial reports of fibrin deposition in the stroma of solid tumors date back some 25 years. However, the validity and generality of these observations have only quite recently been established, and their implications for an understanding of tumor biology, metastasis, and therapy are only now coming to be appreciated by investigators in the mainstream of cancer research. This article reviews the current status of fibrin's role in the biology of tumor growth, considering in turn: (1) the evidence that fibrin is present in tumors, the nature of such fibrin, and its relation to plasma fibronectin; (2) the mechanisms by which fibrin may come to be deposited in tumors; and (3) the potential biological and medical significance of tumor-associated fibrin deposition and degradation. Among the last are such important possibilities as a barrier function to the immune response and possible roles in angiogenesis, desmoplasia, and metastasis.
Publication Types:
PMID: 6193869 [PubMed - indexed for MEDLINE]
-
[Development and dissemination of malignant tumors and hemostasis]
[Article in French]
Kher A, Hilgard P.
Strong circumstantial evidence suggests that the activation of the hemostatic system is involved in the growth and spread of malignant tumors. Nevertheless, the considerable experimental and clinical data presently available cannot be interpreted in one specific direction. The presence of a fibrin and/or a platelet thrombus in the environment of tumor cells only represents the visible end product of a complex biochemical and biophysical process during which other phenomena like haemodynamic changes and the generation of many biologically active enzymes occur. In the interpretation of experimental studies and clinical trials of anticoagulants in cancer disease, a wider concept of the hemostatic process and its multiple interactions with other biological systems is needed. The complement system, adhesive glycoproteins of the cell surface, chemotaxis, growth factors and prostaglandins are some examples of factors which interact with the hemostatic system as well as with the pathology of cancer. The definite pathogenic connection between the clinically observed hypercoagulability of patients with malignant disease and the biology of tumor growth and tumor dissemination remains unclear. Agents which modify hemostatic reactions must be evaluated in specific tumor categories using carefully controlled prospective trials. The results of such studies on tumor regression and also on longevity will permit to assess the efficacy of these agents as adjuvant therapy in the treatment of cancer.
Publication Types:
PMID: 6760066 [PubMed - indexed for MEDLINE]
-
[Coagulation disorders in tumors and hemoblastoses]
[Article in German]
Zurborn KH, Bernsmeier R, Schamerowski F, Stohr A, Bruhn HD.
Thromboembolic and haemorrhagic complications are not rarely seen in the course of malignant diseases. The underlying coagulation disorders were investigated by means of coagulation analysis in 61 patients with solid tumors and 60 control persons as well as 51 patients with leukemia and 50 control persons. As a cause for the thrombotic diathesis in patients with solid tumors and leukemias can be demonstrated a hypercoagulability (shortened PTT and raised factor VIII activity). In addition we found a raised level of fibrinogen, a hypofibrinolysis (prolonged euglobulin lysis time) and in increased platelet aggregation in patients with solid tumors. Predominantly bleeding complications in leukemias are caused by thrombopenia. Another reason, however, may be an activated fibrinolysis or a clot instability because of the reduction of factor XIII. Pathogenetic mechanisms, underlying the tumor induced coagulation disorders, as for example the release of tumor cell thromboplastins from malignant cells are discussed.
PMID: 6755331 [PubMed - indexed for MEDLINE]
-
[Fluctuations in pulmonary fibrin decomposing activities (plasmin and non-plasmin activities) in an endotoxin DIC model in rats]
[Article in Japanese]
Okamoto U, Sasaki K, Nagao N, Naiki I, Nagamatsu Y.
Non-plasmin fibrinolysis enzyme was extracted from the lung and spleen of conventional rats (Thrombos. Haemostas., 1979), although the enzyme was not found in germfree rats, suggesting the possibility that the enzyme may participate in the defence mechanism of the body. The present study was made in an attempt to determine the behavior of non-plasmin fibrinolysis enzyme of the lung tissue in the DIC model of conventional rats induced by a single injection of bacterial endotoxin. The plasminogen-activator activity of the lung tissue, and the fibrinogen level, platelet count, urea nitrogen and plasminogen-activator activity in the blood were also measured. Examination of the lung tissue in the DIC rats indicated a remarkable increase in non-plasmin fibrinolysis activity and a disappearance of plasminogen-activator activity. Inhibitor studies using t-AMCHA and DFP demonstrated that the increased non-plasmin fibrinolysis activity was not derived from activated plasmin, but from serine protease. The disappearance of plasminogen-activator activity in the lung and increase of plasminogen-activator activity in the blood suggested a release of the activator from the lung into the blood due to the endotoxin injection.
PMID: 6221092 [PubMed - indexed for MEDLINE]
-
[Intravascular blood coagulation and its role in malignant neoplasms]
[Article in Russian]
Pavlovskii DP.
PMID: 7023043 [PubMed - indexed for MEDLINE]
-
Tumor interaction with the fibrinolytic system.
Malone JM, Gervin AS, Moore WS, Keown K.
PMID: 439891 [PubMed - indexed for MEDLINE]
-
[Functional significance of the clotting and anticlotting of the blood in the development of malignant neoplasms in the body]
[Article in Russian]
Kudriashov BA, Kalishevskaia TM, Kolomina SM.
Publication Types:
PMID: 157648 [PubMed - indexed for MEDLINE]
-
[Pathophysiological aspects of malignant tumor metastasis]
[Article in Russian]
Tereshchenko IP, Kashulina AP.
Publication Types:
PMID: 370752 [PubMed - indexed for MEDLINE]
-
[Role of hemostasis in metastatic spread]
[Article in Russian]
Balitskii KP, Sopotsinskaia EB.
Blood fibrin being deposited around the circulating tumor cells seems to contribute to metastatic spread, thus enhancing the cell implantation. Whereas the same fibrin hampers cells detachment from a tumor node and their further dissemination in the organism. The anticoagulation blood system interfers with the fibrin formation, whereby inhibiting the cell implantation and metastatic spread, but is may also enhance them, contributing to detachment and dissemination of tumor cells. In this respect, to enhance the antimetastatic resistance of the body there must be a balanced interaction between the coagulation and anticoagulation blood systems with an unremoved tumor and the increased anticoagulation function after the tumor node resection especially in the early postoperative period.
PMID: 516581 [PubMed - indexed for MEDLINE]
-
Silent endocrine tumors. A steady-state analysis of the effects of changes in cell number for biological feedback systems.
Verveen AA.
Some tumors of hormonal organs are clinically active, while others are not. The "silent" tumors may be discovered by accident or because of effects due to their increase in size. From a simple steady state analysis of hormonal feedback systems follows that hormonal cell multiplication does not significantly influence the systems steady state behaviour (hence the clinical silence).--Exceptions to this rule occur in three situations: when the gain of the system is low; when the growth concerns cells with isolated sensor or reference functions; or because of the growth of autonomous cells. In many biological systems the dangerous situation of clamping to low levels upon sensor cell multiplication has been prevented by lumping, such as the combination of sensor and comparator functions into sensor-comparator cells.
PMID: 728491 [PubMed - indexed for MEDLINE]
-
[Fibrin deposits and fibrinolysis in pre and early stages of arteriosclerosis]
[Article in German]
Kopec M.
Already in the early stages of atherosclerosis still before the appearance of coarsely visible changes subendothelially fibrin-like material is found in the places of predilection known, which reveals electron-microscopically the typical periodicity. Lesions of the endothelium with increase of permeability, release of coagulation factors and mitogenic substances which stimulate the proliferation of smooth muscle cells always precede. There are several mechanisms for the penetration of fibrinogen or fibrin into the vascular wall, the proportion of which changes with the progressing of the atherosclerosis. They are discussed in detail. Mechanisms of fibrinolysis, in which plasmin or activators of plasmin occupy a key position, effect against this process. By histochemical estimation of this activator the fibrinolytical potential of the vascular system can be investigated under various clinical conditions. For this a series of instances is cited.
PMID: 151992 [PubMed - indexed for MEDLINE]
-
Fibrinolysis and antifibrinolytic drugs in the growth and spread of tumours.
Peterson H.
In the last few years increased release of fibrinolytic enzymes from malignant cells has been observed, but the significance of this property in relation to malignant growth is still not fully understood. Antifibrinolytic drugs decrease the growth rate of some experimental tumours and might have a similar effect on human malignant tumours. Antifibrinolytic drugs might also decrease the intravascular shedding of tumour cells from primary tumours, but might on the other hand enhance the lodgement of those metastatic tumour cells already in the vascular bed of recipient organs.
PMID: 589607 [PubMed - indexed for MEDLINE]
-
[Microangiopathic hemolytic anemia in neoplastic diseases]
[Article in Polish]
Judkiewicz L, Augustyniak W.
PMID: 905162 [PubMed - indexed for MEDLINE]
-
[A model of the blood coagulation system]
[Article in French]
Iliadis A, Cheruy A, Daver J, Desnoyers P.
PMID: 143350 [PubMed - indexed for MEDLINE]
-
Platelet-cancer cell interaction in metastasis formation: a possible therapeutic approcach to metastasis prophylaxis.
Gastpar H.
The mechanism of the early stage of metastasis formation by sticky blood-born cancer cells is discussed. Abnormal platelet aggregation to circulating and lodged cancer cells, as well as alterations of blood coagulation and fibrinolysis play an important role. The reducing effect of several platelet aggregation inhibitors on cancer cell stickiness and tumor embolism mortality has been investigated in rats after intravenous transplantation of 1 X 10(6) Walker-256 carcinosarcoma cells. The tested substances diminished platelet aggregation to circulating cancer cells, leading to a dose-dependent inhibition of cancer cell lodgment to the endothelium. Furthermore, some of the substances prevented lethal pulmonary tumor cell embolism which was observed in 60% of the controls. These results are interpreted by assuming an inhibition of disseminated intravascular coagulation which occured after intravenous transplantation of Walker-256 carcinosarcoma. On this basis a clinical long-term study for metastasis prophylaxis was started more than 4 years ago with one of the tested substances, the dipyridamole derivative RA 233, in 40 patients with sarcoma or malignant lymphoma of the head and neck region. The provisional results obtained in matched pairs are discussed.
PMID: 268396 [PubMed - indexed for MEDLINE]
-
Thrombophlebitis and cancer. A review.
Oster MW.
Thrombophlebitis has been associated with virtually all cancers, especially gastrointestinal, urogenital, and lung neoplasms. Although occurring infrequently in cancer patients, thrombophlebitis may appear before the cancer has become symptomatic and may lead to an earlier diagnosis of cancer. The phlebitic syndrome associated with cancer, although not unique, is distinctive. It is often recurrent and migratory, often involves unusual locations, and is often resistant to anticoagulation therapy. Pulmonary emboli are frequent complications. The pathogenesis of phlebitis in cancer patients is not well understood. Evidence suggests that many cancer patients are hypercoagulable, with abnormalities in platelets, coagulation factors, and the fibrinolytic system. These changes may results from the elaboration of thromboplastin-like substances from the cancer tissue.
Publication Types:
PMID: 802883 [PubMed - indexed for MEDLINE]
-
Thrombogenic activity of mouse and human tumors: effects on platelets, coagulation, and fibrinolysis, and possible significance for metastases.
Gasic GJ, Koch PA, Hsu B, Gasic TB, Niewiarowski S.
Twelve mouse tumors and 29 human malignancies were assayed in vitro for their capacity to aggregate platelets and induce release of radiolabelled serotonin, and for their ability to coagulate blood plasma and digest the fibrin clot. It was discovered that many human and mouse tumors can induce release of radiolabelled serotonin but that the quantitative relationships between this activity of tumors and their capacity to aggregate platelets was variable, permitting tumors to be classified into 3 different types. The procoagulant and fibrinolytic activity was also quite variable. Since no correlation was found between the 4 assayed tumor activities they appear to be independent, separate thrombogenic properties of tumors. Although the information gathered by this study is still fragmentary, some speculations can be made about the role of these activities in treatment of malignant tumors and in determing patterns of body distribution and control of metastases.
PMID: 136101 [PubMed - indexed for MEDLINE]
-
The blood vessels of the skin.
Ryan TJ.
During the last 25 years, cutaneous biologists have been particularly interested in abnormal cutaneous vascular patterns, the profusion of capillary anastomoses, the leakiness of venules, clotting, fibrinolysis, and blood viscosity. As a result, the effects of hypoxia and the factors that encourage new vessel proliferation are better understood than before. Only when the biologic behavior of the two extremes of growth from hypoplasia to hyperplasia is studied and compared can the blood supply of a tissue be understood. Hyperplastic tissues are seen in wounds, psoriasis, cancer, and in selected sites of chronic stasis and hypoxia where the vessels are extremely permeable, where blood cells easily escape, and where lymphatics dilate and proliferate. The proliferation of other tissues, such as endothelium, epithelium, mast cells, and probably of locally infective organisms, is also encouraged in hyperplasia. Moreover, fibrinolysis does not occur and fibrin is deposited, the electrostatic charge on the internal vascular surface becomes more positive, and the organ is more vulnerable to subsequent injury. Atrophic or hypoplastic tissues have a reduced cellular turnover and are less hypoxic. The vessels are less permeable, blood cells do not escape, there is only a slight tendency to clot, and fibrinolysis is often increased. Lymphatics are sparse and infection is not a feature. The electrostatic charge on the internal surface of the vessel is negative.
Publication Types:
PMID: 778283 [PubMed - indexed for MEDLINE]
-
[Letter: Blood coagulation and tumor spreading]
[Article in German]
Gross R.
PMID: 1261408 [PubMed - indexed for MEDLINE]
-
[Changes in the blood coagulation system and fibrinolysis during growth and metastasis of malignant neoplasms]
[Article in Russian]
Bergut FA.
Publication Types:
PMID: 790595 [PubMed - indexed for MEDLINE]
-
Effect of potato protease inhibitor on the clotting system and fibrinolysis in the dog.
Worowski K, Glowinski S.
The potato inhibitor of proteolytic enzymes was found to inhibit the plasma clotting and fibrinolytic systems in the dog. The anticoagulative action of potato inhibitor consists in a prolongation of clotting time, inhibition of thromboplastin generation, reduction of prothrombin consumption and of the retractility of the blood clot. The potato inhibitor prolongs the euglobulin fibrinolysis time and causes a rise in the plasma antiplasmin level.
PMID: 1028667 [PubMed - indexed for MEDLINE]
-
[Coagulation, fibrinolysis and various diseases: cancer]
[Article in Japanese]
Nira H, Yamashita T.
PMID: 4858911 [PubMed - indexed for MEDLINE]
-
A review of the basic mechanisms of fibrinogen to fibrin conversion and of fibrinolysis: intravascular coagulation versus primary fibrinolysis.
Colick JA, Fisher LM.
Publication Types:
PMID: 4276992 [PubMed - indexed for MEDLINE]
|