Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiphospholipid antibodies are autoantibodies that can be detected in plasma or serum with phospholipid-dependent coagulation tests or solid-phase immunoassays. The presence of these autoantibodies is strongly associated with an increased risk for arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. This paradoxical association of the in vitro prolongation of clotting assays and in vivo thrombosis has stimulated the search for the real antigen to which the autoantibodies are directed. A large number of potential pathological mechanisms have been proposed, and although disturbance of a certain metabolic pathway by the antibodies can explain a thrombotic tendency in one patient, no general pathological mechanism explaining thrombosis in the whole patient population has been found. This suggests that the antiphospholipid antibodies are a heterogeneous group of autoantibodies and is supported by the recent observations that antiphospholipid antibodies are not directed against phospholipids alone but against a combination of phospholipids and phospholipid-binding proteins. Both the phospholipid and the protein are part of the antigen. For the detection of antiphospholipids in an ELISA set-up, beta 2-glycoprotein I is the protein cofactor. In the coagulation tests, beta 2-glycoprotein, as well as prothrombin, can act as cofactor. However, the presence of these two proteins as a part of the epitope of the antiphospholipid antibodies does not explain the thrombotic tendency in the patient group. We have found that more physiologically relevant cofactors such as protein C and protein S, for which it is known that a partial deficiency is correlated with a thrombotic tendency, can also act as cofactors for the binding of antiphospholipid antibodies. It is concluded that antiphospholipid antibodies are a heterogeneous group of autoantibodies with varying affinity for different protein-phospholipid complexes and that inhibition of the biological activity of the protein part of the complex determines the pathological capacity of the antibodies.
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PMID:Antiphospholipid antibodies: specificity and pathophysiology. 802 48

A normally functioning hemostasis system is closely related to liver function. The liver parenchymal cells produce most of the factors and inhibitors of the clotting and fibrinolytic systems, and the RES of the liver greatly aids in the clearance of activation products. Hemostasis defects thus depend on the extent of liver damage. A wide spectrum of defects is found in patients with liver cirrhosis. Owing to impaired protein synthesis, most factors and inhibitors of the clotting and the fibrinolytic systems are markedly reduced. Additionally, abnormal vitamin K-dependent factor and fibrinogen molecules have been encountered. Most patients have hyperfibrinolysis that could be DIC in nature. Thrombocytopenia and thrombocytopathy are also found. Acute or chronic hepatocellular disease may display decreased vitamin K-dependent factor levels, especially factor VII and protein C, with other factors still being normal. If patients go into hepatic failure, the abnormalities resemble those found in liver cirrhosis. Vitamin K deficiency is associated with the production of poorly functioning vitamin K-dependent factors. All other hemostasis parameters are normal. Disturbances associated with liver surgeries again depend on the underlying liver problem. Peritoneovenous shunts (LeVeen) may lead to DIC; bleeding from partially resected liver surfaces is usually a mechanical problem. Severe bleeding is encountered with orthotopic liver transplantation. It is greatly influenced by the activation of the fibrinolytic system. This occurs during the anhepatic phase and during the reperfusion phase. The hyperfibrinolysis is mediated by an intense release of t-PA. Antifibrinolytic drugs, if used cautiously, have markedly reduced bleeding and thus reduced need for blood and blood product substitution.
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PMID:Coagulation defects in liver disease. 817 Feb 58

In this study Protein C (PC) and antithrombin III (AT III) levels in childhood acute leukemia were investigated. The mean PC activity levels in 19 newly diagnosed cases of acute leukemia were significantly lower as compared with the normal controls (p < 0.05). A significant increase was found (p < 0.01) in the patients in remission. Prior to treatment 78.8 percent of patients had decreased PC activity levels, but all patients had normal PC activity during remission. Decreased PC activity levels were found to be independent of the leukocyte count and liver function. No statistically significant difference was found in the AT III antigen levels between the untreated patients, the patients in remission and the control group. Our results indicate that apart from thrombocytopenia, low PC activity levels and alterations in fibrinolysis and coagulation may be responsible for the hemorrhagic manifestations observed in cases of acute leukemia.
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PMID:Protein C and antithrombin III in children with acute leukemia. 823 17

Heparin-induced thrombocytopenia is one of the most common and important immunological complications of drug therapy. Most patients with heparin-induced thrombocytopenia have isolated thrombocytopenia, which by itself seldom causes serious morbidity. However, a small proportion of patients also develop an acute arterial thrombotic episode which can be fatal. It remains uncertain why some patients have only isolated thrombocytopenia, whereas others have thrombotic complications. In this report we describe 53 patients with heparin-induced thrombocytopenia in whom the diagnosis was confirmed using the platelet 14C-serotonin release assay. The intent of the study was to look for laboratory or clinical characteristics that could be used to predict which patients will have the less serious thrombocytopenia and which patients will have thrombocytopenia plus thrombotic complications. The laboratory markers included AT-III, protein C, protein S and heparin cofactor II. No serological result identified whether a patient was at risk of having isolated thrombocytopenia or an acute thrombotic event. However, during the acute thrombocytopenic episode, there was evidence of global activation of the coagulation cascade as evidenced by reductions in the level of protein C, heparin cofactor II and antithrombin III. Following resolution of the thrombocytopenia, these inhibitory factors returned to normal indicating that the thrombotic complications were not caused by a familial deficiency. We did observe a highly significant association (P < 0.001) between concomitant cardiovascular complications and the occurrence of an arterial thrombosis in patients with heparin-induced thrombocytopenia. Recent surgery of any type was strongly associated with venous thrombi (P < 0.001). Our data suggest that heparin-induced thrombocytopenia is a procoagulant disorder with thrombosis tending to occur at sites of pre-existing pathology.
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PMID:Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. 839 37

Patients with epidemic infections caused by Neisseria meningitidis serogroup C were studied to assess the relationship of abnormal coagulation parameters to prognosis. Patients were categorized into stages within the first hour of observation according to severity of illness. During the epidemic years 1986 through 1991, 113 patients with bacteriologically proven N. meningitidis infection were observed, 15 of whom died. Purpura fulminans was seen in 28 patients, of whom 14 (50%) died. Among the 14 surviving patients who had purpura fulminans, 10 suffered gangrene with deforming autoamputation secondary to the dermal microvascular thrombosis and hemorrhagic necrosis. Evaluation of the induced diffuse intravascular coagulation in 59 patients included studies of the naturally occurring anticoagulants, focusing on protein C and protein S. The magnitude of the declining levels of protein C, the degree of thrombocytopenia, and the presence of fibrin split products are directly related to the clinical severity of the illness (P = .0053). Thus, in individuals with severe disease expression, the risk of purpura fulminans with death or deformity was significantly increased when the platelet count was < 50,000 cells/mm3 (P = .0001) and protein C levels were low (P = .0158). The immaturity of the protein C system in children who are < 4 years of age may contribute to the rapid and more frequent pathogenesis of purpura fulminans. Therapy directed at replacement of the naturally occurring anticoagulants, such as protein C, may ultimately improve the prognosis for individuals with purpura fulminans.
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PMID:Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. 839 77

A 38-year-old man with a non-Hodgkin's lymphoma of intermediate grade malignancy attained partial remission after three courses of CHOP (cyclophosphamide+hydroxydaunorubicin+vincristine+prednisolone). He was assigned to undergo autologous bone marrow transplantation (ABMT). The conditioning regimen consisted of cyclophosphamide and whole body irradiation. Two weeks later he developed veno-occlusive disease (VOD) of the liver. Doppler sonography confirmed the diagnosis showing a reversal of the blood flow in the portal vein. In addition a large thrombus was present in the inferior caval vein. Protein C level was strongly reduced (28%). Because of clinical deterioration intravenous urokinase was started. The transaminases normalised rapidly and the patient showed a dramatic clinical improvement. There were no major bleeding complications. Repeat Doppler sonography showed a normal antegrade flow in the portal vein. This case suggests that a coagulopathy in the hepatic vascular bed might contribute to the development of VOD and that patients with VOD are at risk for other thrombotic complications. Furthermore it shows that urokinase with platelet support can be given safely and effectively to a patient with VOD and severe thrombocytopenia.
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PMID:Successful treatment of veno-occlusive disease of the liver with urokinase in a patient with non-Hodgkin's lymphoma. 848 32

Pregnancy and especially delivery and the puerperium are associated with an increased risk of thromboembolic disease. Intravenous high dose heparin is the therapy of choice for manifest thromboembolic disease in pregnancy. However, high-dose heparin fails to prevent postthrombotic chronic venous insufficiency in more than one-third of the cases. Low-dose heparin may be used for antithrombotic prophylaxis during pregnancy. However, low-dose heparin may induce a substantial loss of bone density in up to 30% of cases and may be complicated by heparin-associated thrombopenia in up to 2%. This review discusses strategies to reduce these considerable risks. Prospective studies suggest that the risk of recurrence after prior deep vein thrombosis may be somewhat overestimated. These data suggest new therapeutic options in women with no risk factors other than a personal history of thrombosis. Improved diagnostic techniques may contribute to a better evaluation of the individual risk by assessing possible underlying problems such as resistance to activated protein C or deficiencies of coagulation inhibitors. Also, duration of prophylactic anticoagulation may be reduced by targeting treatment to periods of increased risk such as immobilisation, dehydration, surgery, delivery and the puerperium. Recently, evidence has been provided indicating that the use of low molecular weight heparins may be associated with reduced loss of bone density and a significantly attenuated risk of heparin-associated thrombopenia.
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PMID:[Prevention and treatment of thrombosis in pregnancy]. 876 88

Antiphospholipid' (aPL) antibodies are of important clinical significance because of their association with thrombosis both arterial and venous, recurrent foetal loss, specific neurological sequelae like seizures and chorea, cardiac valvular abnormalities and thrombocytopenia. Traditionally these autoantibodies have been assayed using phospholipid (PL) dependent tests and are classified as lupus anticoagulants (LA) and anticardiolipin (aCL) antibodies based on the method of detection. The antibodies thus, had been thought to bind PLs but it has now become clear that the true antigens are PL-binding proteins. The major protein consistently found as the target antigen for these autoantibodies is beta 2-glycoprotein I (beta 2-GPI). Other candidate PL-binding proteins have also been investigated including prothrombin, protein C and protein S but thus far appear to play less important roles in the binding of these antibodies.
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PMID:beta 2-Glycoprotein I: target antigen for autoantibodies in the 'antiphospholipid syndrome'. 890 65

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, beta 2-glycoprotein I is the best known and characterized antiphospholipid 'cofactor' (this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. 'Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.
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PMID:Non beta 2-glycoprotein I cofactors for antiphospholipid antibodies. 890 67

Antiphospholipid-protein antibodies (APA) represent a family of immunoglobulins which recognize protein-phospholipid complexes. A variety of proteins have been implicated including: prothrombin, annexin V, beta 2-Glycoprotein I, and protein S. APA are detected utilizing either coagulation-based tests to identify lupus anticoagulants (LA) or solid phase ELISA assays to identify anticardiolipin antibodies (ACA). APA may be seen in a variety of different clinical settings including convalescence from infections, resulting from exposure to certain drugs, or in association with autoimmune diseases. Autoimmune APA have been linked to a variety of thromboembolic complications involving both arterial and venous sites. In addition, recurrent fetal loss has been linked to a APA. The underlying pathophysiology of the thromboembolic events remains controversial. Given the diversity of anatomic sites, more than one thromboembolic mechanism(s) is likely. Abnormalities of the protein C system most likely account for the venous thromboembolic events. Because of the spectrum of clinical complications, virtually any clinician may encounter patients with the APA syndrome (thrombosis, thrombocytopenia, recurrent fetal loss coupled with positive LA or ACA testing).
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PMID:Lupus anticoagulants/antiphospholipid-protein antibodies: the great imposters. 890 75


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