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)

Venous thromboembolism occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium and remains a diagnostic and therapeutic challenge. In the general population the incidence of pregnancy associated VTE has been estimated to vary from 1 in 1000 to 1 in 2000 deliveries. The risk of VTE is five times higher in a pregnant woman than in a nonpregnant woman of similar age. Postpartum VTE is more common than antepartum VTE. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. In individuals with well defined hereditary thrombosis risk factors, such as the factor V:R506Q mutation, the factor II:G20210A variation, antithrombin-deficiency or protein C-deficiency, a relative risk of pregnancy associated VTE between 3.4 and 15.2 has been found. Women with previous VTE have an approximately 3.5 fold increased risk of recurrent VTE during pregnancy compared to non-pregnant periods. Our ability to diagnose deep-vein thrombosis clinically is generally poor and is further hampered during pregnancy since dyspnea, tachypnea, swelling and discomfort in the legs are common. Objective diagnosis is essential for treatment decisions. Exposure to radiation of less than 50,000 microGy (5 rad) has not been associated with a significant risk of fetal injury. Therefore, besides sonography, routine diagnostic procedures should be performed, if clinically necessary. Heparin does not cross the placenta and is therefore the anticoagulant treatment of choice during pregnancy. In case of acute new onset of thrombosis during pregnancy, treatment is performed like in non-pregnant patients with acute deep vein thrombosis or pulmonary embolism. There is ongoing debate, whether or not pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. In patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality or a history of a severe thrombotic event (pulmonary embolism, extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Post partum prophylaxis should be given in all women with an increased risk for VTE.
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PMID:Thrombosis during pregnancy: risk factors, diagnosis and treatment. 1367 66

HEPARIN-INDUCED THROMBOCYTOPENIA (HIT): Management of heparin-induced thrombocytopenia (HIT) and treatment options have significantly changed recently. Heparin may induce two types of thrombocytopenia. Type I, occurring earlier with a much higher rate of incidence (5-30%), is characterized by mild thrombocytopenia without significant clinical manifestations. Type II, is less frequent (0.5-2%), life threatening immune type, develops following a period of minimum 5-7 days upon introduction of heparin therapy (patients earlier treated with heparin are excluded). Type II heparin-induced thrombocytopenia with severely reduced platelet count may be clinically manifested by thrombosis in 20-50% cases within the period of 30 days. HIT is suspected in persons resistant to heparin with relatively reduced platelet count, though HIT is described in person with normal platelet counts, as well. None of available assays used for HIT detection is completely reliable. Sensitivity of a highly specific platelet aggregation assay is only 36%, sensitivity and specificity of 14C-serotonin release assays amounts to 95%, while ELISA using a heparin/platelet factor-4 target has a sensitivity of 85%. Thus, it is sometimes necessary to combine functional and antigen assays. Furthermore, new classes of antigen assays, like antibody detection tests of complexes between heparin and neutrophil-activating peptide-2 as well as those between heparin and interleukin-8, have been used. CURRENT THERAPY OPTIONS: Current therapy options exclude formerly applied low-molecular-weight heparins due to the existing cross-reactivity of 80-100%. Danaparoid sodium exhibits in vitro cross-reactivity of 10-61%, clinically manifested in less than 5% of patients. Two drugs are drugs of choice in HIT type II treatment: lepirudin, especially in patients without renal failure, and argatroban, particularly in patients with renal failure. The following procedures and agents are also efficient: asmapheresis in the first four days, high-dose intravenous gammaglobulin, antiaggregans, especially ADP antagonists, aspirin, dipirydamole, dextran, prostacyclin analagoues, thrombolytic therapy as well as thromboembolectomy. Oral anticoagulants are not administered in active HIT type II, in deep vein thrombosis with high international normalized ratio (INR) and thrombin-antithrombin complexes, and low protein C levels to avoid the possibility of venous limb gangrene development. They can be administered in a stable phase, when the thrombin generation is controlled by previous administration of one of the above-mentioned alternative anticoagulants.
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PMID:[Heparin-induced type II thrombocytopenia--new views on diagnosis and therapy]. 1456 48

Venous thromboembolism is a common and potentially fatal disease. If properly used, anticoagulation therapy is effective in preventing recurrence of venous thromboembolism and in improving survival. Symptomatic patients with an objective diagnosis of acute deep vein thrombosis (DVT) or pulmonary embolism (PE) should receive immediate systemic heparin anticoagulation at dosages sufficient to rapidly prolong the activated partial thromboplastin time into the laboratory-specific therapeutic range; this range corresponds to a plasma heparin concentration of 0.2 to 0.4 IU/ml (as measured by protamine sulfate titration), or 0.3 to 0.7 anti-Xa IU/ml. An oral vitamin K antagonist (e.g. warfarin) should be started within 24 hours after starting heparin; the starting dose should be the estimated patient-specific daily dose with no loading dose. Heparin and warfarin anticoagulation should be overlapped for at least 4 to 5 days and until the international normalized ratio (INR) is within the therapeutic range (2.0 to 3.0) on 2 measurements made at least 24 hours apart. The duration of warfarin anticoagulation should be individualized based on the respective risks of venous thromboembolism recurrence and anticoagulant-related bleeding. In general, warfarin should be continued for at least 3 months, and longer for patients with recurrent or idiopathic venous thromboembolism, malignant neoplasm, neurologic disease with extremity paresis, obesity, or laboratory evidence of a lupus anticoagulant/anticardiolipin antibody, homozygous carrier or combined heterozygous carrier for the factor V R506Q (Leiden) and prothrombin G20210A mutations, and possibly deficiency of either antithrombin, protein C, or protein S. Low molecular weight heparin (LMWH) is effective and well tolerated as acute therapy for patients with DVT or stable PE, and does not require laboratory monitoring or dose adjustment. Outpatient LMWH therapy is also well tolerated and cost effective for most patients with DVT, and possibly for selected patients with PE.
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PMID:Current management of acute symptomatic deep vein thrombosis. 1472 51

A 53-year-old man with lung adenocarcinoma developed pulmonary embolism and bilateral popliteal venous thrombosis. Treated with intravenous unfractionated heparin and discharged home on warfarin, he returned a week later with extending thrombosis. Treatment with heparin followed by warfarin was reinitiated. Twenty-four hours following the re-administration of warfarin, the patient's INR increased to 14.5. The platelet count dropped by more than 50%, and he developed venous limb gangrene of the left leg and skin necrosis of the right leg. Heparin-induced thrombocytopenia was ruled out, and coagulation studies showed a severe depletion of protein C as well as increased thrombin generation. The patient was transfused with fresh frozen plasma, and vitamin K was given. Heparin was continued, and after 4 weeks, the patient improved markedly showing only minimal necrosis of the toes. Venous limb gangrene is a major complication associated with warfarin therapy. Its pathogenesis is explained by a transient hypercoagulable state produced by protein C depletion that leads to microvascular thrombi progressing to venous limb gangrene. The present case emphasizes the importance of careful anticoagulation with heparin followed by slow initiation of low-dose warfarin, in order to minimize thrombotic complications.
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PMID:Warfarin-induced limb gangrene in the setting of lung adenocarcinoma. 1516 86

The main objective of treatment of venous thromboembolism (VTE) is the prevention of the extension, embolization, and recurrence of thrombosis. The long-term aim is to prevent late recurrences and the post-thrombotic syndrome. Heparin and oral anticoagulants (OACs) have been the cornerstones of VTE treatment in the last 30 years. Low molecular weight heparins (LMWHs) have been introduced more recently in the treatment of the acute phase of VTE, and they have allowed the home treatment of deep vein thrombosis (DVT) in selected cases. The optimal duration of OAC therapy after VTE is still controversial. Several studies have been conducted, and several are ongoing with the aim to stratify patients into risk categories for recurrence. Patients at high risk are candidates for long-term oral anticoagulation as the benefits of extended oral anticoagulation would outweigh the risk of bleeding. Patients are currently stratified into risk categories on the basis of clinical characteristics of the VTE event: (1) first or recurrent event; (2) idiopathic or due to a transient risk factor such as surgery, trauma, hormonal therapy, or immobilization; (3) presence of active cancer; (4) location (proximal DVT and/or pulmonary embolism, PE, or distal DVT); and (5) presence of known hereditary or acquired thrombophilia. Patients with distal VTE or VTE due to a transient risk factor are at a low risk of recurrence and short-term anticoagulation is indicated (3 months). Patients with an idiopathic event or with known thrombophilic defects such as FV Leiden or the G20210A prothrombin mutation are candidates for a longer course of therapy (6 months). Patients with cancer, antiphospholipid antibodies syndrome, recurrent idiopathic event, antithrombin deficiency, protein C or protein S deficiency, homozygosity for FV Leiden, and double heterozygosity are candidates for extended long-term anticoagulation. More recently, studies have indicated that other factors such as D-dimer levels after the discontinuation of OAC therapy or the residual vein thrombosis could be additional predictive factors for recurrences. In patients with VTE and cancer, oral anticoagulation poses a higher risk of bleeding, and such patients are more prone to recurrences. Alternative treatment with LMWH could be safer and more effective in these patients.
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PMID:Oral anticoagulant therapy in venous thromboembolism. 1519 64

Disturbances of the embryo-maternal interaction, i.e. impaired implantation, are seen in only a minor fraction of couples. These malfunctions become evident as recurrent spontaneous abortions (RSA), or repetitive implantation failure (RIF) in cases with IVF or ICSI procedures. The antiphospholipid syndrome (APL) is the only consensus-defined syndrome associated with RSA (anticardiolipin antibodies and/or lupus anticoagulant plus clinical symptoms). Since antiphospholipid antibodies directly interfere with hemostasis (increased coagulation), heparin is an established treatment option in these cases resulting in unequivocal benefits. There is no defined antibody syndrome in RIF even if it may be assumed that it exists. Conclusive evidence for a benefit of heparin (and aspirin) in this situation is lacking as well. However, the majority of investigations including our own experience indicate that anticoagulation may be useful. Besides the extensively studied anticardiolipin antibodies, other - by far less thoroughly investigated - antiphospholid antibodies have been described. So far it is unclear if heparin may exert positive effects in women carrying these antibodies. Autoreactive immune processes may also become apparent by the emergence of further antibodies, such as antinuclear (ANA), thyreoglobulin (TGA) and thyreoperoxidase antibodies (TPO) etc. However, there is no established definition of a syndrome associated with these antibodies, TGA and TPO probably being the most relevant. - Most studies in this area including our own experience indicate that heparin may be a useful. The detection or autoantibodies per se is probably not of pathophysiological relevance if there is no ongoing pathological activation of the immune system. However, an acute autoimmune response associated with irregular antibodies may represent the pathophysiological basis of a reproductive autoimmune failure syndrome. In these cases, immune-equilibrating interventions appear to be more appropriate than heparin therapy. - Coagulation disorders, namely thrombophilia, are a frequent cause of RSA and probably RIF as well, the most relevant being antithrombin deficiency, Factor V Leiden and prothrombin mutations. Deficiencies of protein S, protein C and factor XII and XIII are of minor importance. There is a varying degree of evidence for a benefit of heparin/aspirin in these syndromes. Heparin not only reduces the abortion rate but also lowers the risk for developmental retardation, premature birth and preeclampsia. - The effects of heparin are not restricted to anticoagulation. It is directly or indirectly (e.g. via heparan sulfate proteoglycans or heparin-binding EGF) involved in the adhesion of the blastocyst to the endometrial epithelium and the subsequent invasion. Actually, prolonged heparin treatment (14 days) resulted in an increased pregnancy rate in our patient population. Shorter courses of heparin where not effective.
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PMID:Effectivity of heparin in assisted reproduction. 1521 Apr 1

The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel at 35 women, a basic group, who used the oral contraceptive in the duration of 12 months and a control group (n=35), who do not use the pills. We found statistically significant increase of Antithrombin III (ATIII) (p<0.011), Cofactor II of Heparin (HCII) (p<0.001), the activity of plasminogen (p<0.026) and beta2-antiplasmin (0.026), significant decrease of Protein C (PrC) (p<0.0001) and of total Protein S (TPrS) (p<0.03) in the basic group in comparision with the control one. We do not observe significant changes in the rest of the haemostatic variables between the two groups. During the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis.
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PMID:[Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol/150 ug desogestrel on haemostasis]. 1531 40

New anticoagulants are under development to improve on current ones that, although effective, have limitations in efficacy, safety and convenience. We have reviewed the use of these agents as thromboprophylactic drugs. These new agents have more specific modes of action and can be divided into three groups. Inhibitors of the initiation of coagulation work via inhibition of the factor VIIa/tissue factor complex. Inhibitors of propagation of coagulation include parenteral and oral factor Xa inhibitors, factor IXa inhibitors, inhibitors of factor Va and VIIIa, activated Protein C, soluble thrombomodulin and SNAC-Heparin. Finally, direct inhibitors of thrombin are under development both for parenteral and oral administration. Several new drugs, such as fondaparinux, hirudin, argatroban, bivalirudin and ximelagatran, have already been licensed for specific indications and are being investigated for more general usage. Other drugs reviewed are in much earlier stages of development.
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PMID:New antithrombotics in the prevention of thromboembolic disease. 1608 52

Immunoglobulin G (IgG) isolated from the blood plasma of a patient with secondary antiphospholipid syndrome (APS) expresses fibrinogen-clotting and amidolytic activity (the thrombin activity in 20 micromole IgG is equivalent to approximately 5 nmole pure thrombin), and activates factor XIII. Hirudin (1 microM) decreases the intrinsic thrombin activity of the APS IgG by only 25%, whereas it inhibits completely pure thrombin with equivalent activity. Under conditions, when antithrombin inactivates 60% of the thrombin activity in the presence of normal IgG, the APS IgG protects almost completely the added thrombin against inactivation by antithrombin. Heparin, however, partially relieves this protective effect and at the same time it facilitates the inhibition of the intrinsic thrombin activity by antithrombin. The APS IgG reduces the thrombin activity in protein C activation assay by 50% compared to the activity in the presence of normal IgG. All described properties are related to the Fab fragment of the antibody. The IgG preserving the fibrin-generating activity of thrombin with concomitant protection against inhibitors unravels a new aspect of the thrombotic mechanism in APS. This condition is probably rare: only one out of 23 examined patients with primary or secondary APS expresses IgG with the described properties.
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PMID:Impaired inactivation by antithrombin and hirudin and preserved fibrinogen-clotting activity of thrombin in complex with anti-thrombin antibody from a patient with antiphospholipid syndrome. 1611 88

Cardiopulmonary bypass (CPB) poses great risks for hypercoagulable patients and requires management techniques to ensure an optimal outcome free from thrombotic events. This case report reviews perfusion management techniques that may contribute to a safer CPB experience for a patient deficient in both protein C and protein S. A patient with heterozygous protein C deficiency is at increased risk of thrombosis, especially in the venous circulation. Since it is an essential cofactor for activated protein C, deficiency of free protein S is also linked to a hypercoagulable condition. A 52-year-old male presented to our institution with a past medical history of hypercoagulable state, multiple deep vein thromboses, pulmonary embolisms, and stroke. He was scheduled for two-vessel coronary artery bypass graft surgery to be followed by right carotid endarterectomy (RCEA) before discharge. The anesthesia and perfusion teams worked closely together to ensure that fresh frozen plasma (FFP) was given intraoperatively at appropriate times. Heparin dose response and protamine dosage was determined with hemostasis management system (HMS) analysis. The closed CPB circuit and cannulae were Carmeda bonded. Rapid autologous priming, along with the use of a hemoconcentrator, kept the hematocrit above 21 during CPB. Zero-balance ultrafiltration and leukocyte depletion were initiated during rewarming to aid in attenuation of the inflammatory response. To conserve coagulation factors, all pump blood was ultrafiltrated post-CPB and returned to the patient. Laboratory samples drawn on postoperative day (POD) one measured normal protein C activity with subnormal protein S activity. On POD six, the patient underwent RCEA and he was discharged on POD eight without complications.
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PMID:Cardiopulmonary bypass for a coronary artery bypass graft patient with heterozygous protein C deficiency and protein S deficiency. 1661 90


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