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)

Factors and inhibitors of coagulation and fibrinolysis were investigated on admission in 57 patients with acute leukaemia and they were correlated to the occurrence of haemorrhage. Coagulation disturbances were found in 98%. Seventeen of the patients with haemorrhagic symptoms had major bleeding. Severe thrombocytopenia (< 20 x 10(9)/l) was found in 16%. Patients with major bleedings had significantly lower concentrations of prothrombin complex, fibrinogen, protein C and platelets. Low levels of antiplasmin and fibrinogen were characteristic of 'bleeders' with promyelocytic and lymphoblastic leukaemia. We found a positive correlation between vWF:Ag and leukaemic cell count especially in lymphoblastic leukaemia (ks = 0.72). Reduced levels of antithrombin indicated a poorer prognosis.
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PMID:Bleeding complications and coagulopathy in acute leukaemia. 140 6

We describe a patient who developed a severe coagulopathy after being bitten by a red-necked keelback snake (Rhabdophis subminiatus), a species which is generally considered non-venomous. The patient's blood was incoagulable due to complete depletion of fibrinogen. Comprehensive coagulation studies were performed to identify the mechanism(s) by which the snake toxin caused the coagulopathy. It was found to contain a potent prothrombin activator, probably an activator of protein C and possibly also a factor X activating enzyme. The fibrinolysis was secondary to intravascular fibrin formation; there were no indications for a direct fibrinogenolytic activity in the snake toxin. Remarkably, there was virtually no consumption of antithrombin III, despite extensive thrombin formation; this feature appears to be not uncommon after snake bites, but is still unexplained.
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PMID:Haemostatic effects in vivo after snakebite by the red-necked keelback (Rhabdophis subminiatus). 142 Aug 21

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

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.
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PMID:Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. 144 May 17

The present study was undertaken to elucidate the effect on platelet aggregation of the prothrombin-converting reaction on platelets with or without activated protein C (APC). A reaction mixture of washed platelets from human individuals, Factor Xa and prothrombin markedly induced platelet aggregation; maximum aggregation rates, 31.3-92.5%, and times to reach to maximum aggregation, 11.6 to 20.1 min. This aggregation was inhibited by the addition of APC with 50% inhibition concentration (IC50) value of 14.4 U/ml. APC also inhibited thrombin generation in the reaction mixture in a dose-dependent manner with IC50 value of 0.96 U/ml. However, APC did not inhibit the thrombin (0.1 CU/ml)-induced platelet aggregation at concentrations of up to 30 U/ml. These findings suggest that APC has no direct inhibitory effect on platelet aggregation and that APC inhibits platelet aggregation through inhibition of thrombin generation.
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PMID:Inhibitory effect of activated protein C on platelet aggregation induced by the prothrombin-converting reaction. 144 May 35

The concentration of Ca2+ that produced 50% of the saturable intrinsic fluorescence change (C50) of wild-type (wt) recombinant (r) human protein C (PC) was 0.40 mM. The C50 for Ca2+ increased < 2.5-fold for the following r-PC variants (Gla is gamma-carboxyglutamic acid): [Gla6-->Asp]r-PC, [Gla7-->Asp]r-PC, [Gla14-->Asp]r-PC, [Gla19-->Asp]r-PC, or [Gla25-->Asp]r-PC, and approximately 4-6-fold for [Gla20-->Asp]r-PC and [Gla29-->Asp]r-PC. Much more dramatic increases in the C50 for Ca2+ were observed for [Gla16-->Asp]r-PC (> 75-fold) and [Gla26-->Asp]r-PC (ca. 30-fold). A substantially larger maximum fluorescence change (> 3-fold) as compared to that for wtr-PC, was also found in the case of the Ca2+/[Gla16-->Asp]r-PC complex, suggesting that the final Ca(2+)-induced conformation for this variant is dissimilar to that for wtr-PC and the above mutants. When a mutation was constructed at Arg15 ([Arg15-->Leu]r-PC), a residue conserved in all Gla-containing coagulation proteins, no fluorescence alteration occurred upon addition of Ca2+. The C50 for Ca2+ for promotion of the binding of the Ca(2+)-dependent, Gla-domain-directed, conformational monoclonal antibodies, JTC-1 and JTC-3, to wtr-PC was 3.0 and 4.0 mM, respectively. A similar C50 value was found for [Gla25-->Asp]r-PC. In the case of each antibody, approximately 4-6-fold higher C50 values for Ca2+ were found for the mutants; [Gla14-->Asp]r-PC, [Gla19-->Asp]r-PC, and [Gla29-->Asp]r-PC. Ca2+ did not promote binding of either of these antibodies to the following variants; [Gla6-->Asp]r-PC, [Gla7-->Asp] r-PC, [Arg15-->Leu]r-PC, [Gla16-->Asp]r-PC, [Gla20-->Asp]r-PC, and [Gla26-->Asp]r-PC. The results of this study suggest that adoption of the Ca(2+)-dependent conformation of PC is greatly dependent upon the presence of specific essential Gla residues, particularly those, namely Gla16 and Gla26, shown in the crystal structure of the prothrombin Gla domain/Ca2+ complex to be involved with coordination of Ca2+ ions not exposed to the surface. Of similar importance is Arg15. On the other hand, Gla residues at positions 14 and 19 are much less important in directing this same conformation. This finding is readily reconciled with the above crystal structure, which shows that these latter 2 residues are mainly responsible for coordination of a surface-exposed Ca2+ that is present at the end of the Ca(2+)-ion channel.
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PMID:Influence of specific gamma-carboxyglutamic acid residues on the integrity of the calcium-dependent conformation of human protein C. 146 19

Previous studies have demonstrated that platelets or aortic endothelial cells provide an appropriate surface that augments the proteolytic inactivation of factor Va by activated protein C (APC). We have examined the ability of three human tumor cell lines (HepG2, CAPAN-2 and J82) to support the inactivation of human factor Va by human APC in the presence and absence of human protein S. APC-mediated factor Va inactivation on these tumor cell lines was assessed by measuring the ability of residual cell-bound factor Va to augment the proteolytic activation of prothrombin by factor Xa. Each of the tumor cell lines studied supported factor Va inactivation by APC in the presence of calcium ions. HepG2 cell monolayers supported this reaction most effectively, with CAPAN-2 and J82 cell monolayers exhibiting moderate and weak effectiveness, respectively. Although not essential for this reaction, protein S moderately enhanced the rate of factor Va inactivation by APC on these tumor cell lines. In addition, pretreatment of each tumor cell line with rabbit antihuman protein S IgG had little, if any, effect on its ability to support factor Va inactivation by APC. Our data suggest that these, and perhaps other, tumor cells can provide an appropriate phospholipid surface for promoting factor Va binding and rapid inactivation by APC.
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PMID:Inactivation of factor Va by activated protein C on selected human tumor cell lines. 146 18

Haemostatic changes in 16 patients with Crohn's disease were studied from active disease into clinical remission and beyond. Elevated concentrations of fibrinopeptide A (FpA) and prothrombin fragments F1 + 2 (F1 + 2) were found at times of both active (FpA median 3.2, range [0.3-40] ng/ml and F1 + 2 median 2.3, range [0.3-18] nm/l) and inactive disease (FpA median 2, range [0.4-40] ng/ml and F1 + 2 median 1.3, range [0.2-20) nm/l]. We also measured the physiological inhibitors of coagulation and fibrinolysis; there was no significant difference in the levels of antithrombin III, protein C or the Exner ratio between active and inactive disease. Free protein S levels were significantly lower in active disease (median 34, range 9-54 U/dl) than in remission (median 40, range 12-65 U/dl). Plasminogen activator inhibitor type 1 (PAI-1) was significantly raised in remission (median 11, range 3-32 ng/ml) when compared to active disease (median 7, range 3-42 ng/ml). The D-dimer correlated significantly with fibrinopeptide A (P < 0.001), suggesting reactive fibrinolysis in some patients. Most (35/52, 67%) samples showed evidence of persistent haemostatic activation (elevated FpA and/or F1 + 2) during phases of apparent clinical remission in Crohn's disease, a factor that is not reflected by clinical activity scores. This study supports the hypothesis that coagulation is activated in the mesenteric vasculature of patients with Crohn's disease.
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PMID:Evidence for activation of coagulation in Crohn's disease. 148 98

Homozygous protein C (PC) deficiency is a rare genetic defect that usually results in fatal thrombotic complications (purpura fulminans and DIC), but it can be successfully managed with oral anticoagulants or PC replacement. The successful use of PC replacement for two individuals is described. The activity and antigen levels of PC in fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) are also reported. The concentration of PC in FFP is 87 +/- 15 units/dl. PC is present in all PCC analyzed; however, a ten-fold difference between the various brands and/or lots is noted. The PC activity and antigen correlates well with no significant levels of APC. Upon infusion of FFP into two homozygous PC-deficient children, the PC levels obtained were less than or equal to 30 units/dl post-infusion and undetectable after 12-18 hr. With infusions of PCC, plasma levels of PC obtained were 100-145 units/dl and less than 10 units/dl after 48 hr. The percent recovery and half-lives of PC from FFP and PCC were 49.8% and 7.8 hr, and 84% and 7.4 hr, respectively. One infant was treated every 48 hr for 2 years without significant purpura fulminans or DIC complications. The levels of the other PC system components did not change during the infusion of the PC-rich material. Based on this information, a specific replacement protocol has been developed using a PC-rich concentrate. However, several problems may arise with the "less pure" PC-rich concentrates: catheter-tip thrombosis, related large vessel thrombosis and blood-transmitted diseases. With a specific PC concentrate, replacement therapy is a viable alternative for the long-term management/treatment of homozygous PC deficiency.
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PMID:Protein C survival during replacement therapy in homozygous protein C deficiency. 150 96

In 107 asymptomatic and untreated patients with inherited syndromes associated with thrombophilia (antithrombin III, protein C and protein S deficiencies), we compared in parallel two plasma peptides which reflect activation of the common coagulation pathway: the prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA). Both F1 + 2 and FPA were measured with simple, commercially available ELISA methods. High levels of F1 + 2 or FPA were found in about one fourth of the patients as a whole. When patients were divided according to the type of inherited thrombophilic syndrome, it appeared that F1 + 2 was more frequently elevated in protein C and protein S deficiencies than in antithrombin deficiency; and that, in general, it was no more frequently elevated than FPA. Although our data confirm the existence of a procoagulant imbalance in inherited thrombophilic syndromes due to defects of natural anticoagulant proteins, they do not confirm that such imbalance can be more frequently diagnosed by measuring F1 + 2 levels, particularly in patients with antithrombin deficiency.
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PMID:Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. 153 36


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