Disease relevance of F5

• However, APCR predicts risk for thrombosis independently of FVL [1].
• In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5) [2].
• Inherited APC resistance, which is found in 20% to 60% of patients with venous thrombosis, is caused by a single point mutation in the FV gene predicting substitution of arginine [R] at position 506 with a glutamine (Q) [3].
• RESULTS: There was no indication of an effect of the child's FVL alleles on preeclampsia risk [4].
• By the use of an FV-dependent prothrombin activator, the assay is not influenced by FVIII concentration or lupus anticoagulants [5].

Psychiatry related information on F5

• Their use as adjuncts for the diagnosis, prognosis, prediction of disease or targeting therapy for these disorders has begun, good examples being the Factor V Leiden mutation for venous-thromboembolism, lipoprotein lipase mutations for hypertriglyceridaemia and the apolipoprotein E4 variant for Alzheimer's dementia [6].

High impact information on F5

• BACKGROUND: Factor V and prothrombin-gene mutations are independent risk factors for venous thrombosis; it is debated whether a mutation in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine metabolism, also increases the risk of venous thrombosis [7].
• Gene linkage analysis in the mouse indicated that these genes and serum coagulation factor V (FV) all map to a region of distal mouse chromosome 1 that is syntenic with human chromosome 1, with no crossovers identified between these four genes in 428 meiotic events [8].
• Identification of this gene should provide new insight into the biology of Factor V and Factor VIII production [9].
• Confirming these results, both inhibitor IgG and Fab fragments interfered with phosphatidylserine-specific binding of Factor V [10].
• A patient was described who developed a Factor V inhibitor that neutralized the procoagulant activity of Factor V and resulted in a fatal hemorrhagic diathesis (Coots, M. C., A. F. Muhleman, and H. I. Glueck. 1978. Am. J. Hematol. 4:193-206) [10].

Chemical compound and disease context of F5

• FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only [11].
• Protein C inhibitory activity is not detectable in plasmas from four unrelated patients with combined Factor V/VIII deficiency but is present in normal amounts in plasmas from patients with simple factor V deficiency or Factor VIII deficiency [12].
• These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism [13].
• CONCLUSIONS: The authors propose that inheritance of Factor V Leiden significantly increases the risk of thrombosis in patients who receive tamoxifen therapy [14].
• 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 [15].

Biological context of F5

• However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1) [1].
• A combination of the heterozygous FV G1691A mutation with increased Lp(a) (n = 11) or the MTHFR TT677 genotype (n = 5) was found in 10 [16].
• This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms [1].
• RESULTS: Among the controls, 2 (2.2%) carried the FV Leiden mutation, 19 (20.4%) were TT MTHFR homozygotes and 1 (1.6%) carried the prothrombin A20210 allele [17].
• Maternal, paternal, and fetal DNA were genotyped for the methylenetetrahydrofolate reductase (MTHFR) C677T and Factor V Leiden (FVL) G1691A SNPs [4].

Anatomical context of F5

• Alterations in the level of anticoagulant proteins, disturbances of endothelial cell function, and the presence of cardiolipin antibodies and Factor V Leiden mutation may increase the cumulative thrombotic risk in MPD besides the risk imposed by platelet activation [18].
• Plasmas containing varying concentrations of normal FV, FV(Leiden), or FV(R2) were assayed with an APC resistance assay that specifically measures the APC cofactor activity of FV in FVIIIa inactivation, and with the activated partial thromboplastin time (aPTT)-based assay, which probes both the susceptibility and APC cofactor components [19].
• Site-directed mutagenesis of FV cDNA was used to introduce the identified mutation, and wild-type as well as mutant FV proteins were expressed by transient transfection in COS-1 cells [20].
• The Asp2194Gly mutation was found to play a key role in the impaired secretion of the mutant FV by interfering with its transport from the endoplasmic reticulum to the Golgi complex [21].
• The prevalence of the prothrombin 20210 G-->A mutation, factor V Leiden (FVL) mutation and the C677T mutation in the MTHFR gene was compared in cases to that observed in random unselected cord blood controls [22].

Associations of F5 with chemical compounds

• We conclude that FVL and the PT-20210A are risk factors for VT as well as Hcy levels, but the MTHFR and PAI-1 polymorphisms do not appear to be associated with VT in our country [23].
• These mutations affect the APC cleavage site at arginine (Arg) 306 in the heavy chain of activated FV [24].
• In the three models, the generation of thrombin can be described in terms of an initiation phase in which pmol/l concentrations of the coagulation serine proteases are generated and the cofactor proteins factor V (FV) and FVIII are activated [25].
• Activated protein C (APC) acts as a potent anticoagulant enzyme by inactivating Factor V and Factor VIII [26].
• This mutation creates an additional potential N-linked glycosylation site (Asn-X-Ser/Thr) in factor V (FV) at Asn357 that could interfere with secretion and/or protein interactions [27].

Physical interactions of F5

• RESULTS: Western blot analysis showed TSP1 forming a complex with FVa(HNE) within a region corresponding to the heavy chain of FV [28].
• COAT-FV platelets bound annexin-V, indicating exposure of aminophospholipids and were enriched in young platelets as identified by the binding of thiazole orange [29].

Enzymatic interactions of F5

• Western blotting using a monoclonal antibody that recognizes an epitope between amino acid residues 307 and 506 of human FV showed that FV was completely cleaved by APC at the beginning of the rhFVIII inactivation process [30].
• Human factor V (FV) can be cleaved by HNE thereby providing FV with cofactor activity (FVa(HNE)) [28].

Regulatory relationships of F5

• The protein C pathway cannot act in the absence of thrombin and therefore only influences the duration of the propagation phase by inactivating activated FV [25].
• However, the ORs for carriers of the FV R506Q mutation were not significantly influenced by MTHFR gene C677T homozygosity [31].
• The relative importance of these cleavages in tissue factor (TF) induced thrombin generation in plasma and in a purified system was elucidated with recombinant FV in which the three sites had been eliminated one by one or in combinations [32].
• In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present [33].
• Our results are consistent with hyperproduction of IL-2 by some patients with RA which is suppressed by F5 [34].

Other interactions of F5

• Frequencies of PS deficiency, FVL and FII 20210A allele were similar to the reference population as well as to published data in the general caucasian population [35].
• As a result of its high prevalence, the FV mutation is not uncommon among patients with other inherited defects such as deficiency of PS, PC, or antithrombin [3].
• Wild-type and mutant probes are used to identify triplexes containing FVL G1691A, MTHFR C677T and CFTR mutations [36].
• When glycosidase-treated FV was analyzed in an aPTT (activated partial thromboplastin time)-based APC sensitivity assay, the APC sensitivity ratio (APC-SR) increased from 2.34 to 3.33 [37].
• Treatment of purified FV with N-glycanase and neuraminidase under nonprotein-denaturing conditions removed approximately 20-30% of the carbohydrate from the heavy chain region of the molecule [37].

Analytical, diagnostic and therapeutic context of F5

• Our estimates of effects of maternal MTHFR and FVL alleles were consistent with estimates from case-control studies [4].
• The prevalences of FVL and FII G20210A were lower in the study group than in the control group (3.7 versus 6.1% for FVL and 4.6 versus 6.1% for FII respectively); however, the difference was not statistically significant [38].
• The thrombosis risk of genetically characterized pseudohomozygotes (n = 6) was compared with that of FV Leiden heterozygotes (n = 683) and homozygotes (n = 50) recruited within a large cohort study on familial thrombophilia [39].
• An enzyme immunoassay detected low FV antigen levels both in the conditioned media of cells expressing the mutant protein and in cell lysates [20].
• The whole plasmid pUC3A containing a 1.5-kb cDNA sequence for FV was 32P-labeled for Southern analysis and 3H-labeled for in situ hybridization to metaphase chromosomes [40].

References