Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coagulation factor V (FV) and factor VIII (FVIII) are usually decreased in septicemic DIC. Low doses of endotoxin administered to healthy volunteers stimulate activation of the fibrinolytic, contact and coagulation systems, but not clinical DIC. Following the administration of endotoxin (4 ng/kg) to normal volunteers (n = 15), we applied new assays for FV antigens using monoclonal antibodies to the activation peptide (C1) and to the light chain of FV. At 5 hours, FV coagulant activity was significantly decreased (64 +/- 9%), as was the FV light chain antigen (74 +/- 6%), without a change in factor V C1 antigen or total protein C. In contrast, FVIII coagulant activity was greater than preinfusion levels at 2-5 hours. The decrease in FV activity may be due to APC cleavage of FV heavy chain, but the loss of light chain antigen suggests that plasmin and/or calpain also contribute. APC may not be the only enzyme responsible for cofactor inactivation. FV is one of the most sensitive markers, even reflecting subclinical activation of coagulation.
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PMID:Cofactors V and VIII after endotoxin administration to human volunteers. 858 99

Although patients with thromboembolic disease frequently have family histories of thrombosis, well-defined defects such as inherited deficiencies of anticoagulant proteins are found only in minority of cases. Herein, we present a family study of 42 years old woman with recurrent deep vein thrombosis which occurred first time four years ago during pregnancy, in subclavian vein, in relation to cardiac stimulator implantation because of atrio-ventricular III(0) block. Her laboratory investigation demonstrated normal APTT time, prothrombin time, platelet number, antithrombin III and protein C activity. Plasma antiphospholipid antibodies contents was within the normal range. The result of activated protein C(APC) resistance test was abnormal (R=1.64). Family study revealed similar degree of APC-resistance defect in her DVT symptomatic mother and two healthy young daughters (R=1.73 and 1.54 respectively). Additionally, a slightly reduced total protein S plasma concentration was found in the patient and her two children. The influence of a slightly reduced protein S level on the results of APC-resistance was excluded by evaluation of normalized activated protein C sensitivity ratio (nAPC-SR) as described de Ronde and Bertina.
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PMID:[Thrombophilia in a family with resistance to activated protein C and protein S deficiency]. 861 15

We have previously proposed that a cluster of surface-exposed hydrophobic amino acids, viz., F4, L5, and L8, present at the amino-terminus of the Ca(2+)-bound form of gamma-carboxyglutamic acid domain (GD) of human protein C (PC), contributes a substantial portion of the total functional binding energy of PC and its activated form, APC, to acidic phospholipid (PL) vesicles. A deeper understanding of the importance of the hydrophobic nature of sequence position 5, and the particular relevance of leucine at that location, was sought by examination of the properties of a series of mutant proteins containing A5, V5, I5, and W5 as replacements for L5 in recombinant (r)-PC and APC. The Ca(2+)- and PL-dependent plasma-based anticoagulant activities of [L5A]r-APC, [L5V]r-APC, [L5I]r-APC, and [L5W]r-APC were determined to be approximately 28%, 51%, 98%, and 105%, respectively, of that of wild-type r-APC. A similar trend in activities of the mutant enzymes was observed in in vitro factor V/Va and factor VIII/VIIIa inactivation assays. Apparently normal Ca(2+)-dependent conformations were adopted by each of the mutant proteins, but the Ca(2+)-bound form of [L5A]r-PC was relatively the most defective of the mutants in its binding to PL. These results confirm the importance of the hydrophobic character at sequence position 5 as critical to the functional binding of PC to PL.
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PMID:The hydrophobic nature of residue-5 of human protein C is a major determinant of its functional interactions with acidic phospholipid vesicles. 867 35

Oral contraceptives increase the natural incidence of venous thromboses of 1-2/10,000 women per year 3-to 4fold. Recent investigations have shown that during intake of desogestrel or gestodene containing formulations the risk is twice that with older low-dose ovulation inhibitors. This difference is larger in first time users than in women who had previously used an oral contraceptive. During pregnancy, the incidence of thromboses rises up to 10/10,000 women-years and post partum up to 40/10,000 women-years. In about 60 % of thromboses no causal explanation can be found. It is suggested that in 40 % of all cases an inherited thrombophilia is present. Among the hereditary types of thrombophilia, the resistance against activated protein C (APC-resistance) represents nearly 50 %, while altogether 15 to 20 % is based on a deficiency of antithrombin III, protein C or protein S. APC-resistance the prevalence of which is 3-5 % in the general population, increases the risk of thrombosis 8fold and in users of oral contraceptives 35fold. Protein C-deficiency (prevalence 0.1-0.5 %) increases the risk of thrombosis 9fold and in users of oral contraceptives 15fold, while antithrombin III-deficiency (prevalence 0.02-0.05 %) enhances the risk in pill-users 8fold. Ovulation inhibitors do not influence risk of thrombosis in women with protein S-deficiency. Antiphospholipid-antibodies the concentration of which may increase during treatment with oral contraceptives, represent a considerably enhanced risk of thrombosis, too. A positive family history (before age of 40 years) indicates an inherent thrombophilia. In these risk groups, the cost/benefit ratio of a selective screening is unfavorable, as at most 70 % of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception per year. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder which as yet cannot be substantiated. It is not yet clarified whether a selective screening is superior to a careful assessment of individual and family history. A general screening cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an enhanced risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombosis, cannot be identified in advance. If in patients with thrombophilic disorders and/or other risk factors the use of oral contraceptives represents a particularly high risk, other contraceptive methods should be taken into consideration. If a patient with risk factors decides for the use of oral contraceptives, she has to be informed that in the case of symptoms indicating a thrombosis, the physician has to be consulted immediately. The earlier an appropriate therapy is initiated, the more effectively an acute pulmonary emboli or permanent damages, e.g. the post-thrombotic syndrome, can be prevented.
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PMID:[Significance of hereditary thrombophilia for risk of thrombosis with oral contraceptives]. 870 22

Inherited resistance to activated protein C (APC-resistance), caused by a point mutation in the factor V gene leading to replacement of Arg(R)506 with a Gln (Q), and inherited protein S deficiency are associated with functional impairment of the protein C anticoagulant system, yielding lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is often an additional genetic risk factor in thrombosis-prone protein S deficient families. The plasma concentration of prothrombin fragment 1 + 2 (F1 + 2), which is a marker of hypercoagulable states, was measured in 205 members of 34 thrombosis-prone families harbouring the Arg506 to Gln mutation (APC-resistance) and/or inherited protein S deficiency. The plasma concentration of F1 + 2 was significantly higher both in 38 individuals carrying the FV:Q506 mutation in heterozygous state (1.7 +/- 0.7 nM; mean +/- SD) and in 48 protein S deficient cases (1.9 +/- 0.9 nm), than in 100 unaffected relatives (1.3 +/- 0.5 nM). Warfarin therapy decreased the F1 + 2 levels, even in those four patients who had combined defects (0.5 +/- 0.3 nM). Our results agree with the hypothesis that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.
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PMID:Elevated levels of prothrombin activation fragment 1 + 2 in plasma from patients with heterozygous Arg506 to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. 881 75

We have developed a simple screening assay for evaluating the global activity of the protein C/protein S system. The new test consists of measuring the prothrombin time (PT) with bovine thromboplastin before and after activation of the PC present in the plasma sample by PROTAC, derived from Agkistrodon contortrix snake contortrix venom. Prolongation of the PT was directly related to the activity of the PC/PS system. One hundred and nineteen thrombophilic patients including 36 with PC deficiency, 22 with PS defect, 35 with APC resistance and 26 with other genetic defects predisposing to thrombosis were tested with the new assay together with 112 healthy subjects. The new test showed a high sensitivity for detection of inherited defects related to the PC/PS system (92%, 91% and 97% for PC defects, PS defects and APC resistance, respectively). Since it can be performed automatically the test could be used to screen for patients predisposed to thrombosis due to impairment of the PC/PS system and those patients who might eventually require more extensive evaluation of the PC/PS system by single component assays.
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PMID:A new global test for the evaluation of the protein C-protein S system. 883 99

The effect of oral contraceptive therapy was studied in five patients with homozygous activated protein C resistance. Patients with this congenital abnormality, in contrast to those with antithrombin, protein C or protein S deficiencies, showed only a mild thrombotic tendency. In fact, only two of six observations (one patient took the pill on two separate occasions many years apart) showed deep vein thrombosis. No patient had pulmonary embolism. Two additional patients had a superficial vein thrombosis of the legs. In two instances, a superficial vein thrombosis and a deep vein thrombosis, concomitant risk factors were present (immobilization and surgery for an ovarian cyst, respectively). However, compared with heterozygous for the same abnormality, the symptomatic homozygous patients with APC resistance appeared to develop thrombosis after a shorter period of oral contraception.
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PMID:Homozygous patients with APC resistance may remain paucisymptomatic or asymptomatic during oral contraception. 889 47

In this review we will discuss the possible interference of antiphospholipid antibodies with the protein C system. Antiphospholipid antibodies can interfere with the protein C system in different ways: (i) via inhibiting the formation of thrombin; (ii) via interference with the activation of protein C by the thrombomodulin-thrombin complex; (iii) via inhibition of the assembly of the protein C complex; (iv) via inhibition of the activity of protein C, directly or via its cofactor protein S, and (v) via antibodies directed against the substrates of APC, factors Va and VIIIa, thereby protecting them for inactivation. The experimental and theoretical indications that one of these mechanisms will explain the pathogenesis of the antiphospholipid syndrome is critically examined.
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PMID:Protein C and other cofactors involved in the binding of antiphospholipid antibodies: relation to the pathogenesis of thrombosis. 890 88

Activated protein C resistance ratio (APC-Rr), factor VIIIC (FVIIIC) and plasma fibrinogen levels were studied in patients with inflammatory disease. The patient mean APC-Rr was significantly lower than in the control group. This decreased ratio in inflammatory diseases appeared to be connected with increased FVIIIC. Moreover, supplementation of plasmas with purified factor VIII decreased the APC-Rr in plasma from both groups, and suppressed the difference between groups. These data suggest that factor VIIIa and factor Va compete for protein C-catalysed cleavage. Ratios were identical in both groups when FVIIIC level was lowered by dilution in factor V deficient plasma.
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PMID:Role of factor VIII on activated protein C resistance ratio in inflammatory diseases. 890 3

Resistance to activated protein C (APC resistance) was measured in 284 individuals (169 females, 115 males) with a history of objectively confirmed venous thrombosis and/or pulmonary embolism. A decreased APC resistance ratio was found in 75 patients (26%), 47 were females, 28 males. Factor V Leiden was investigated in 60 of 75 patients with APC resistance, of whom 46 were heterozygous, 4 homozygous. In 10 APC resistant patients the Arg 506 Glu mutation was not identified. The median age of the first thromboembolic event in patients with APC resistance was 42 years (range 15-82 years). Most patients had a history of deep vein thrombosis (83%), 28% had experienced pulmonary embolism. More unusual sites of thrombosis were the deep arm veins (7%) and mesenteric veins (one patient, 1.3%). 53% of patients developed the first thromboembolic event spontaneously. Precipitating conditions for thromboembolism were surgery in 9.3% and trauma in 8%. In one third of female patients the first thromboembolic event occurred in conjunction with pregnancy and delivery (14.8%) or oral contraceptives (19%). At the time of investigation 40% of patients with APC resistance had experienced recurrent thromboembolic events. The family history was positive in 60% of patients. We conclude that the clinical feature of APC resistance is similar to the feature of a deficiency of antithrombin, protein C and protein S. Pregnancy, delivery and oral contraceptives seem to be a relevant additional risk factors for thrombosis in females with APC resistance.
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PMID:Thrombotic tendency in 75 symptomatic, unrelated patients with APC resistance. 892 76


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