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)

Factor VIII acts as an essential compound of the tenase complex of the coagulation system. Herein we report the cDNA of the rat factor VIII. The rat cDNA comprises 6777 nucleotides and encodes a protein of 2258 amino acids, 61 amino acids less than mouse and 92 amino acids less than human factor VIII. The over-all identity compared to human cDNA is 61% on the cDNA and 51% on the amino acid level. In cDNA, highest levels of sequence identity can be observed in the A and C domains (ranging between 68% and 73%), whereas B domain and the small acidic regions are more divergent (34% - 49%). Compared to mouse and human most sites for posttranslational modifications such as sulfatation and glycosylation as well as thrombin and protein C cleavage sites are conserved in rat. Alternative transcripts lacking exon 17 and/or comprising additional 26 bp due to alternative splicing of exon 20 were found. Furthermore, 13 polymorphisms (seven in exon 14, one in exon 20, 23, 24, and 25, two in the 3' UTR) three of which lead to an amino acid exchange could be detected. Our findings might provide new insights into the structure-function analysis of the factor VIII protein and might prove useful for future animal models addressing the function of factor VIII.
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PMID:Sequence of the rat factor VIII cDNA. 1469 66

Factor VIII, a metal ion-dependent heterodimer, circulates in complex with von Willebrand factor. At sites of vessel wall damage, this procofactor is activated to factor VIIIa by limited proteolysis and assembles onto an anionic phospholipid surface in complex with factor IXa to form the intrinsic factor Xase; an enzyme complex that efficiently converts factor X to factor Xa during the propagation phase of coagulation. Factor Xase activity is down-regulated by mechanisms that include self-dampening by dissociation of a critical factor VIIIa subunit and proteolytic inactivation by the activated protein C pathway. Recent studies identify putative metal ion coordination sites as well as ligands involved in the catabolism of the activated and procofactor forms of the protein. Our knowledge of these multiple intra- and inter-molecular interactions has been facilitated by the application of naturally occurring and site-directed mutations to study factor VIII structure and function. In this review, we document important and novel contributions following this line of investigation.
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PMID:Mutating factor VIII: lessons from structure to function. 1557 14

Thrombi, encapsulated hematomas, and granulation tissue are frequently seen in cerebral cavernous malformations (CCMs). We investigated the role that these histological changes play in repeated hemorrhages in CCMs as well as lesion growth, examining specimens of CCMs surgically harvested from 20 patients. The immunohistochemical study included thrombomodulin (TM) and endothelial cell protein C receptor (EPCR), which are important regulators of blood coagulation. Thick capsules, which contained blood degradation product, were seen in cases with encapsulated hematomas. Clusters of sinusoidal vessels were found outside of these thick capsules. Granulation tissue with inflammatory infiltrates and capillaries was seen in 4 cases with non-capsulated hematomas. Organizing thrombi were seen in sinusoidal vessels in 15 out of 20 cases. Factor VIII-related antigen staining demonstrated numerous capillaries in and around organizing thrombi and within the thickened vessel walls as well as in both the inner and outer sides of the hematoma capsule. TM and EPCR were positive in the endothelial cells of these capillaries, whereas they were negative in those of capillaries in the brain surrounding the lesions. Our study suggests that thrombosed sinusoidal blood vessels could gradually expand by repeated bleeding from numerous capillaries inside the wall and become encapsulated hematomas, and capillaries outside the thickened vessel wall could become sinusoidal blood vessels. Thrombosis within cerebral venules could be one of the causal factors of CCMs.
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PMID:Thrombus and encapsulated hematoma in cerebral cavernous malformations. 1575 26

We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common significant cause of sporadic first trimester miscarriage. We compared thrombophilia and hypofibrinolysis in 92 women (85 white, 5 black, 2 other) with 1 or more pregnancies and 1 miscarriage (143 live births, 92 miscarriages) (cases) and in 380 female controls (355 white, 21 black, 4 other) with 1 or more pregnancies and 0 miscarriages (964 live births). We used polymerase chain reaction techniques to characterize thrombophilic gene mutations (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic gene mutations (plasminogen activator inhibitor [PAI-1] activity 4G4G). We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]). Of the 380 controls, 6 (1.6%) had FV heterozygosity vs 12 heterozygous and 2 homozygous FV cases (15.2% [14/92]; P < .0001). Plasminogen activator inhibitor activity was high (> or =21.1 U/mL) in 21 (33%) of 63 cases vs 27 (18%) of 152 controls (P = .013). Factor VIII was high (>150%) in 15 (31%) of 48 cases vs 19 (18%) of 103 controls (P = .079). By logistic regression, with age and factor VIII (categorical [< or =150%, >150%]) as explanatory variables and group (cases, controls) as the dependent variable, after adjusting for age, high factor VIII was a significant predictor for miscarriage (odds ratio, 3.28; 95% confidence interval, 1.34-8.04; P = .01). There were no other group differences (P > .05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic first trimester miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and factor VIII, etiologies for sporadic miscarriage.
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PMID:The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage. 1615 34

We prospectively assessed whether thrombophilia and hypofibrinolysis, amplified by thrombophilic hormone replacement therapy (HRT), were associated with retinal vein occlusion (RVO). We studied 44 cases (18 men, 26 women), > or = 3 months after RVO, 42 with central RVO, 2 with branch RVO, in the consecutive order of their referral by 2 community-based ophthalmologists. PCR and serologic coagulation assays were compared to 83 and 40 healthy adult normal controls, respectively. The 4G allele frequency of the plasminogen activator inhibitor-1 (PAI-1) gene, associated with hypofibrinolysis, was 56 of 88 (64%) in cases vs 79 of 166 (48%) in controls, X(2) = 5.95, p = .015. The PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx), was higher in cases than controls (age-race-sex- adjusted mean 12.2 U/mL vs 6.3, p = .013). By stepwise logistic regression, the PAI-1 gene 4G allele was associated with RVO, odds ratio 1.94, 95% CI 1.12-3.34, p = .018. Thrombophilic resistance to activated protein C (RAPC) was present in 6 of 32 (19%) of cases vs 0 of 40 (0%) controls, Fisher's p [p(f)] = .006. Thrombophilic high factor VIII (> 150%) was present in 3 of 30 (10%) cases vs 0 of 40 (0%) controls, p = .041, p(f) = .07. Comparing 23 RVO cases < or = age 55 and controls < or = age 55 (n = 44 for PCR, n = 40 for serologic measures), RAPC was present in 17% of cases vs 0% controls (p(f) = .026), high Factor VIII in 17% vs 0% (p(f) = .026), heterozygosity for the G1691A Factor V Leiden mutation in 13% vs 2% (p(f) = 0.11), and the 4G allele frequency of the PAI-1 gene 74% vs 39% (p = .0001). PAI-Fx was higher in cases than controls (age-race-sex adjusted mean 12.7 U/mL vs 6.7, p = .016). The case-control odds ratio for the PAI-1 4G allele was 5.54, 95% CI = 1.86-16.7, p = .002. Of the 26 women, 9 (35%) took HRT; 4 of the 9 had PAI-1 gene 4G4G homozygosity, 2 had thrombophilic high anticardiolipin antibody (IgG), 1 was heterozygous for the G1691A Factor V Leiden mutation, and 2 were heterozygous for the thrombophilic PL A1/A2 mutation of the platelet glycoprotein IIb/IIIa gene. Associations between heritable coagulation disorders and RVO, most marked in cases < or = age 55, and often amplified in women by thrombophilic HRT, are, speculatively, causal.
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PMID:Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion. 1624 63

APC (activated Protein C) inactivates human Factor VIIIa following cleavage at residues Arg336 and Arg562 within the A1 and A2 subunits respectively. The role of the P1 arginine in APC-catalysed inactivation of Factor VIIIa was examined by employing recombinant Factor VIIIa molecules where residues 336 and 562 were replaced with alanine and/or glutamine. Stably expressed Factor VIII proteins were activated by thrombin and resultant Factor VIIIa was reacted at high concentration with APC to minimize cofactor inactivation due to A2 subunit dissociation. APC cleaved wild-type Factor VIIIa at the A1 site with a rate approximately 25-fold greater than that for the A2 site. A1 mutants R336A and R336Q were inactivated approximately 9-fold slower than wild-type Factor VIIIa, whereas the A2 mutant R562A was inactivated approximately 2-fold slower. No cleavage at the mutated sites was observed. Taken together, these results suggested that cleavage at the A1 site was the dominant mechanism for Factor VIIIa inactivation catalysed by the proteinase. On the basis of cleavage at Arg336, a K(m) value for wild-type Factor VIIIa of 102 nM was determined, and this value was significantly greater than K(i) values (approximately 9-18 nM) obtained for an R336Q/R562Q Factor VIIIa. Furthermore, evaluation of a series of cluster mutants in the C-terminal region of the A1 subunit revealed a role for acidic residues in segment 341-345 in the APC-catalysed proteolysis of Arg336. Thus, while P1 residues contribute to catalytic efficiency, residues removed from these sites make a primary contribution to the overall binding of APC to Factor VIIIa.
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PMID:Role of P1 residues Arg336 and Arg562 in the activated-Protein-C-catalysed inactivation of Factor VIIIa. 1650 79

Factor VIII, a non-covalent heterodimer comprised of a heavy chain (A1-A2-B domains) and light chain (A3-C1-C2 domains), circulates as an inactive procofactor in complex with von Willebrand factor. Metal ions are critical to the integrity of factor VIII, with Cu and Ca ions stabilizing the heterodimer and generating the active conformation, respectively. Activation of factor VIII catalyzed by thrombin appears dependent upon interactions with both anion-binding exosites I and II, and converts the heterodimer to the active cofactor, factor VIIIa. This protein, comprised of A1, A2, and A3-C1-C2 subunits, is labile due to weak affinity of the A2 subunit. Association of factor VIIIa with factor IXa to form the intrinsic factor Xase complex is membrane-dependent and involves multiple inter-protein contacts that remain poorly characterized. This complex catalyzes the conversion of factor X to factor Xa, a reaction that is essential for the propagation phase of coagulation. The role of factor VIIIa in this complex is to increase the catalytic efficiency for factor Xa generation by several orders of magnitude. Mechanisms for the down-regulation of factor Xase focus upon inactivation of the cofactor and include dissociation of the A2 subunit as well as activated protein C-catalyzed proteolysis.
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PMID:Factor VIII structure and function. 1651 27

Factor VIII (FVIII) inhibitors develop as either alloantibodies against exogenous FVIII in patients with congenital hemophilia A after FVIII-replacement therapy or as autoantibodies against endogenous FVIII in previously healthy, nonhemophilic individuals. The predominant immunoglobulin G (IgG) subclass of FVIII inhibitors is IgG(4). The main epitopic regions are known to be located, however, in the A2, A3, and C2 domains. The A2 and A3 epitopes have been identified between amino acid residues 484 and 509 and residues 558 and 565, respectively. Both of these regions are close to the binding sites for activated FIX (FIXa). Two regions have been identified in the C2 domain, one in the amino-terminal portion of the domain (residues 2181-2243) and the other in the carboxy-terminal portion of the domain (residues 2248-2312 and residues 2315-2330). In addition, a crystallographic analysis of a complex of the C2 domain and a human monoclonal IgG(4)(K) Fab revealed that this type of antibody is in direct contact with hydrophobic and basic residues of the membrane-binding surface. Inactivated FVIII is rapidly cleared from the circulation in the presence of inhibitors. The inhibitors also bind to essential FVIII ligand proteins, including von Willebrand factor, FIXa, FXa, and thrombin, and to surface membrane phospholipid. Some type 2 inhibitors interfere with binding to activated protein C.
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PMID:Characterization of factor VIII inhibitors. 1651 28

A 39 year-old man was admitted to our hospital because of severe headache with fever continuing over two weeks. Three days after admission he developed aphasia and right hemiparesis, when his CT revealed subarachnoid hemorrhage at the left sylvian fissure. He was diagnosed as suffering from cerebral venous thrombosis because empty delta sign was positive on the enhanced brain CT. Suprasagittal sinus and bilateral transverse sinuses were not detected on the cerebral angiography. He was also diagnosed as having Graves' disease for the first time on the basis of free T3 13.56 pg/ml, free T4 4.65 ng/dl, TSH < 0.01 IU/ml, anti-TSH receptor antibody 4.3 IU/l, and thyroid stimulating antibody 224%. On the examination, homocystine and activities of antithrombin III, protein C, and protein S were normal. Antinculear, anti-DNA, anti-Sm, anticardiolipin beta2GP-I antibodies, and PR3ANCA were negative. Factor VIII activity, however, markedly increased over 300%, which has been known to increase in the cases of hyperthyroidism. He recovered well after the treatment with thiamazole in addition to warfarin followed by intravenous heparin. There are only six cases of cerebral venous thrombosis due to hyperthyroidism with increased factor VIII level. All of those cases were female, and 5 of them were taking oral contraceptives. This is a first Japanese male case.
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PMID:[Case of cerebral venous thrombosis due to graves' disease with increased factor VIII activity]. 1676 94

Patients with severe gastrointestinal motility disorders are often found to have intravenous access clots or deep venous thrombosis. It has previously been reported that many patients who have intravenous access thrombosis have concomitant thrombotic risk factors. In this study, the goal was to determine the underlying prevalence of hypercoagulable risk in a series of patients with documented gastroparesis. Investigators studied 62 consecutive patients (52 female; mean age, 42 y) who had symptoms of gastroparesis. All patients were evaluated for placement of a gastric neural stimulation device, or they had had one placed previously. Patients underwent a hematologic interview and standardized coagulation measures of thrombotic risk. Laboratory studies measured acquired elevations of Factor VII, Factor VIII, fibrinogen, lupus anticoagulant panel, antiphospholipid antibody panel, homocysteine (in the setting of kidney disease), and activated protein resistance. Investigators also measured congenital factors: Factor VIII (with C-reactive protein levels), antithrombin III, protein C, protein S (total and free), Factor II mutation, Factor V Leiden, methylenetetrahydrofolate reductase, and homocysteine. Fifty-five patients (89%) were found to have detectable hypercoagulable risk factors. Twenty-five of the 62 patients (40%) had a documented history of abnormal clotting, including deep venous thrombosis, intravenous access thrombosis, and pulmonary embolism. All patients with a previous history of thrombosis had detectable clotting abnormalities. Of 56 patients, 40 (71%) had hypercoagulability and did not have diabetes (P=.036), and 20 (36%) had hypercoagulability and no known history of infection. However, this value was not statistically significant when infection and hypercoagulability were compared (P=.408). A high prevalence of acquired and congenital hypercoagulable defects has been observed in patients with gastroparesis, which may predispose them to arterial and venous clots. This unique finding warrants consideration of coagulation evaluation in patients with severe gastroparesis, especially when these patients are placed in high-risk thrombophilic situations, such as hospitalization, prolonged intravenous access, and surgery.
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PMID:Assessing thrombosis risk in patients with idiopathic, diabetic, and postsurgical gastroparesis. 1714 10


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