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)

Protein C inhibitor is a plasma protein whose ability to inhibit activated protein C, thrombin, and other enzymes is stimulated by heparin. These studies were undertaken to further understand how heparin binds to protein C inhibitor and how it accelerates proteinase inhibition. The region of protein C inhibitor from residues 264-283 was identified as the heparin-binding site. This differs from the putative heparin-binding site in the related proteins antithrombin and heparin cofactor. The glycosaminoglycan specificity of protein C inhibitor was relatively broad, including heparin and heparan sulfate, but not dermatan sulfate. Non-sulfated and non-carboxylated polyanions also enhanced proteinase inhibition by protein C inhibitor. Heparin accelerated inhibition of alpha-thrombin, gamma T-thrombin, activated protein C, factor Xa, urokinase, and chymotrypsin, but not plasma kallikrein. The ability of glycosaminoglycans to accelerate proteinase inhibition appeared to depend on the formation of a ternary complex of inhibitor, proteinase, and glycosaminoglycan. The optimum heparin concentration for maximal rate stimulation varied from 10 to 100 micrograms/ml and was related to the apparent affinity of the proteinase for heparin. There was no obvious relationship between heparin affinity and maximum inhibition rate or degree of rate enhancement. The affinity of the resultant protein C inhibitor-proteinase complex was also not related to inhibition rate enhancement, and the results showed that decreased heparin affinity of the complex is not an important part of the catalytic mechanism of heparin. The importance of protein C inhibitor as a regulator of the protein C system may depend on the relatively large increase in heparin-enhanced inhibition rate for activated protein C compared to other proteinases.
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PMID:Heparin binding to protein C inhibitor. 131 38

Most people who experience venous thrombosis have normal hemostasis. Some people have inherited deficiencies of protein C, protein S, and antithrombin iii. They tend to have deep venous thrombosis which increases their risk for pulmonary emboli. Some acquired disorders which predisposes people to thrombosis include defective fibrinolysis which often occurs after surgery or infection, Trousseau's syndrome (excessive coagulant activity linked with adenocarcinoma), and lupus anticoagulant which is an immunoglobulin G or M antibody directed against negatively charged phospholipids. Hormones and probably not a dilution effect reduces free and bound protein S levels during pregnancy. Functional protein S activity is still 40-50% below normal levels 1-3 days after delivery. This decrease appears to protect against bleeding but does have venous thrombosis and pulmonary emboli during pregnancy as side effects. Non-oral-contraceptive (OC) users have greatly higher protein S levels than do OC users (28.6 mcg/ml vs. 24.3 mcg/ml; p.005) which gives more credence to the belief that hormones are responsible for the fall in protein S activity during pregnancy. OCs reduce free and total protein S levels almost 20%. Smoking may even further reduce these levels in women during pregnancy and who use Ocs. Women who have had venous thrombosis should not use OCs. Physicians should also consider family history especially age of affected family member, severity of thrombotic episodes, and the clinical setting. They should look for an underlying abnormality in patients who develop thrombosis while using OCs. If thrombosis develops during pregnancy, physicians should call for a venogram, venous duplex scanning, and, if required, invasive tests. The most sensible treatment is intravenous heparin for 5-7 days then therapeutic doses of heparin. Heparin therapy should stop before delivery and be reinstituted shortly thereafter and continued throughout the postpartum period. Physicians should take extra precautions when performing surgery on an OC user.
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PMID:Recent advances in understanding clotting and evaluating patients with recurrent thrombosis. 141 44

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.
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PMID:Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy. 142 56

Deep venous thrombosis and pulmonary embolism are relatively frequent occurrences in pregnancy and the postpartum period. The diagnosis of deep venous thrombosis and pulmonary embolism requires accurate objective tests because clinical diagnosis is unreliable. Procedures that expose the fetus to ionizing radiation must sometimes be performed to make an accurate diagnosis; current evidence suggests that the adverse effects to the fetus associated with such procedures are minimal. Heparin is the anticoagulant of choice during pregnancy and is used for both the treatment and prevention of venous thrombosis and pulmonary embolism. Patients with deficiencies of antithrombin III, protein C, or protein S as well as patients with antiphospholipid antibodies are at increased risk for thrombotic complications and require particular vigilance during pregnancy.
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PMID:Deep venous thrombosis and pulmonary embolism in pregnancy. 147 24

Anticoagulation is being used increasingly in the critical care areas. Thrombolytic therapy is now commonly used in emergency departments and coronary care units for treatment of AMI. Heparin therapy for unstable angina and for a 48 to 72 hour period following thrombolytic therapy for AMI is becoming commonplace. Beginning warfarin therapy concomitantly with heparin to decrease the total duration of heparin and the duration of hospital stay for DVT therapy is encouraged. The use of low-dose warfarin to prevent DVT in hip surgery, improve catheter patency, and prevent catheter-related subclavian thrombosis is increasing. Along with the increased use of anticoagulation must come a greater appreciation of the complications associated with the agents used, and of how to prevent or treat the hemorrhagic or thrombotic morbidity that may arise. Acute hemorrhage with thrombolytic agents must be recognized and the immediate implementation of conservative and aggressive measures begun. Heparin-induced thrombocytopenia with thrombosis is an often-unrecognized problem that may occur in 1% to 2% of heparin recipients and result in limb amputations. A delayed onset (6-10 days) requires frequent platelet counts for early diagnosis and treatment. The resurgence of warfarin use for prevention of cardiovascular and cerebrovascular disorders demands observation for skin necrosis from protein C and S inhibition. Early recognition of symptoms and syndromes associated with organ system hemorrhage in patients receiving chronic anticoagulation is imperative. The use of antagonists, such as protamine sulfate for heparin, vitamin K1 for warfarin, and antifibrinolytic drugs for thrombolytic agents, may be necessary in treating hemorrhagic events. However, their use may worsen the thromboembolic event initially treated.
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PMID:Toxic effects of drugs used in the ICU. Anticoagulants and thrombolytics. Risks and benefits. 186 82

The effect of purified human activated protein C (APC) on fibrinolysis was studied by using in vitro clot lysis techniques. Clots were formed from citrated blood or plasma (supplemented with 125I-labeled fibrinogen) by adding thrombin and Ca(2+)-ions; lysis of the clots was achieved by the addition of tissue-type plasminogen activator before clot formation. The gradual release of labeled fibrin degradation products from the clot into the supernatant was taken as a measure for the lysis rate. It was demonstrated that the acceleration of clot lysis by APC added before clot formation depends on the presence of Protein S, Ca(2+)-ions and phospholipids. These observations suggest a role of APC as anticoagulant in clot lysis, since the cofactors for the expression of its anticoagulant and profibrinolytic effect are very similar. Indeed, we could demonstrate that the profibrinolytic effect of APC in vitro is associated with reduction of thrombin generation through the coagulation cascade by inactivation of factor VIIIa and factor Va. For instance, APC did not accelerate the lysis of factor X deficient blood clots. More generally, thrombin generation was associated with retarded fibrinolysis in vitro. Consequently anticoagulants such as APC or Heparin are profibrinolytic, whereas pro-coagulants such as phospholipids (in cell-free plasma) inhibit fibrinolysis through the generation of thrombin. Thrombin thus plays a crucial role as a link between coagulation and fibrinolysis. As thrombin is able to inhibit the lysis of blood and plasma clots, and not of purified fibrin clots, we hypothesize that thrombin inhibits lysis through an as yet unidentified mediator in plasma.
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PMID:Protein C and fibrinolysis: a link between coagulation and fibrinolysis. 210 14

Heparin-free haemodialysis must be considered for all dialysis patients with a risk of haemorrhage. This technique is associated with increased danger of system coagulation with a blood loss of up to 250 ml. In 84 patients with a risk of haemorrhage, 296 heparin-free haemodialyses were recorded prospectively. First signs of coagulation were found very much more frequently in the venous airtrap than in the dialyser (146 vs 42). System coagulation occurred in 13 of the 296 dialyses (4%) and was prevented by prophylactic switching of the system and dialyser in 140 dialyses (47%). The time of system coagulation was on average 1.8 hours (+/- 0.2) after the beginning of dialysis. The 13 patients with system coagulation had a reduced blood flow on dialysis (217 +/- 52 vs 240 +/- 36 ml/min). Their initially normal clotting time (12 +/- 5 vs 14 +/- 4 min) was more significantly shortened after 2 h (4 +/- 3 vs 8 +/- 3 min). The activities of antithrombin III (87 +/- 34% vs 88 +/- 39%) and protein C (66 +/- 45% vs 59 +/- 37%) do not differ from those of 47 other patients, even at the time of system coagulation, as measured in five patients (92 +/- 34% for antithrombin III, 51 +/- 29% for protein C). System coagulation and shortening of clotting time thus cannot be regarded as a consequence of absorption of these inhibitory factors of plasmatic coagulation. The danger of system coagulation in heparin-free haemodialysis could probably be further reduced by an improvement of the biocompatibility of systems (airtrap) and dialysers (less activation of thrombocytes).
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PMID:Risk factors of system clotting in heparin-free haemodialysis. 212 54

The protein C activity assay of Francis and Patch (Thromb Res 1983; 32: 605-613) is based on the prolongation of the activated partial thromboplastin time in the presence of activated protein C isolated from the test samples. The assay was modified and standardized by Rapaport et al. (Am J Clin Pathol 1987; 87: 491-497), but could still only be used in patients on heparin therapy after chromatographic removal of the heparin. In this study we attempted to eliminate the heparin separation step without losing the advantages of the modified (Rapaport) method. Heparin was added to the isolated protein C to obtain a rapid and complete antithrombin effect after the thrombin activation step and polybrene was subsequently used to neutralize the excess heparin. Using this modified assay protein C activity ranged from 67 to 133% in the normal population, and from 9 to 25% in coumarin-treated patients. Precision of the modified method was acceptable in both normal and pathological PC ranges: within- and between-batch variations were 5.6 and 3.6%, and 8 and 14%, respectively. The assay correlated well (r = 0.84) with the ELISA technique in both healthy donors and non-coumarin-treated patients.
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PMID:The use of polybrene for heparin neutralization in protein C activity assay. 213 12

In 30 insulin-dependent diabetic patients protein C (PC) antigen and PC activity were significantly lower than those of matched control healthy subjects. An inverse correlation between fasting plasma glucose and both PC concentration and activity was present in diabetics, while a direct correlation between PC concentration and PC activity was observed. Induced hyperglycemia in diabetic and normal subjects was able to decrease both PC antigen levels and PC activity, and heparin reversed in part this effect. In diabetic patients euglycemia obtained by insulin infusion restored to normal the depressed PC levels. Heparin did not alter both the basal PC concentration and activity in healthy controls. These data stress the major role of hyperglycemia in determining PC decrease in diabetics, and suggest that PC reduction is probably associated to hyperglycemia-enhanced thrombin formation.
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PMID:Protein C deficiency in insulin-dependent diabetes: a hyperglycemia-related phenomenon. 177 24

Causes of haemorrhagic tendency in liver disorders have been widely studied. Deficiency of procoagulants is the best explanation for it. Not seldom a thrombotic tendency or even overt thrombosis occurs and may be satisfactorily explained. The level and function of two important natural anticoagulants, i.e. of antithrombin III and protein C is markedly reduced, first in liver cirrhosis. Heparin cofactor activity of AT III and/or heparin cofactor II may be especially diminished. The hypercoagulable state resulting from these changes may be further aggravated by a so-called hyper-adhesive state which is the consequence of the sustained high level of plasmatic vWFAg associated with liver cirrhosis. Altered haemostatic balance needs individual laboratory evaluation.
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PMID:Thrombosis promoting changes in chronic liver diseases. 246 26


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