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At least 163 records · Page 9Linked to original sources
PubMed2000

A novel two base pair deletion in the factor V gene associated with severe factor V deficiency.

We studied a family in which the proband, a 13-year-old boy, had unmeasurable plasma levels of coagulation factor V antigen and activity. Clinical symptoms were severe, with several episodes of haemorrhages in the mucosal tracts (gastrointestinal, nose and urinary) and recurrent haemarthroses that caused permanent arthropathy. Sequence analysis of the factor V gene demonstrated the presence of a novel 2 base pair (bp) homozygous deletion in exon 13 at positions 2833-2834. This mutation, present in the heterozygous state in the asymptomatic mother and absent in the healthy brother, introduced a frameshift and a premature stop at codon 900. This would predict the synthesis of a truncated factor V molecule, lacking part of the B domain and the complete light chain. Because of the existence of a surveillance mechanism that selectively recognizes and degrades mRNA molecules carrying premature termination codons, we analysed the relative abundance of mutant vs. wild-type mRNA molecules in the platelets of the heterozygous proband's mother. The mutant mRNA was significantly reduced in amount (mutant/wild-type ratio 0.35). This is the first reported mutation in the factor V gene causing severe factor V deficiency, the effect of which was quantitatively analysed at mRNA level.

Adolescent↗
PubMed1999

Arg506Gln factor V mutation and Val34Leu factor XIII polymorphism in Finnish patients with inflammatory bowel disease.

BACKGROUND: Earlier studies have indicated that inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is associated with thromboembolic complications, whereas inherited disorders of coagulation occur less often than expected in IBD patients. The point mutation Arg506Gln of factor V (Factor V Leiden), resulting in resistance to activated protein C, is the commonest inherited form of thrombophilia. Alterations in circulating levels of factor XIII (FXIII) have been reported among IBD patients. We investigated whether Factor V Leiden or inherited Val34Leu polymorphism of FXIII would associate with IBD or its clinical outcome. METHODS: Factor V Leiden mutation and FXIII Val34Leu polymorphism were assayed in 328 unrelated Finnish patients with UC and 235 patients with CD by solid-phase minisequencing techniques. The control groups comprised 142 apparently healthy Finnish subjects and 120 Finnish blood donors. RESULTS: The frequency of Factor V Leiden mutation among IBD patients (4.5%) was not significantly different from that in subjects living in the same area (2.1%). No significant differences could be observed in the FXIII Val34Leu polymorphism allele frequencies between patients and controls. Clinical features of IBD, including the disease extent, requirement for immunosuppressive drugs, and occurrence of complications, seemed to be independent of these two clotting factor variants analyzed. CONCLUSIONS: Our data do not support an aetiologic or disease-modifying role for the factor V mutation or factor XIII Val34Leu polymorphism in IBD.

Adult↗
PubMed2004

Absence of factor V Arg306--Thr and low factor V Arg306->Gly mutation prevalence in Thai blood donors.

Thrombosis among the Thai population is much lower than in western countries. The Thai population is protected to some extent against familial thrombophilia as by the very low prevalence of factor V Leiden, G20210A prothrombin and C677T methylenetetrahydrofolate reductase mutations. The present study reports the prevalence of two mutations of the factor V gene involving the codon for Arg 306 among 500 healthy adult voluntary blood donors (males 285, females 215) and 30 children (boys 20, girls 10) experiencing a total of 36 thrombotic episodes. The blood donors' ages ranged from 18 to 60 years while the children's ages ranged from 9 months to 15 years. The allelic frequencies of the factor V gene mutation of G1091C and A1090G among blood donors were 0% and 0.4%, respectively. Additionally, both mutations were not present in any of the 30 children with thrombosis. The low prevalence of factor V gene mutations in the codon Arg 306 may be relevant to the low rate of thrombosis among the Thai population.

Adolescent↗
PubMed2000

Factor V antigen levels and venous thrombosis: risk profile, interaction with factor V leiden, and relation with factor VIII antigen levels.

Clotting factor V has a dual function in coagulation: after activation, procoagulant factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for activated protein C (APC) in the degradation of factor VIII/VIIIa, thereby reducing thrombin formation. In the present study, we evaluated whether plasma factor V levels, either decreased or increased, are associated with venous thrombosis. High procoagulant factor V levels may enhance prothrombinase activity and increase the thrombosis risk. Low anticoagulant factor V levels could reduce APC-cofactor activity in the factor VIII inactivation (APC-resistant phenotype), which might also promote thrombosis. Low factor V levels in combination with factor V Leiden could lead to a more severe APC-resistant phenotype (pseudohomozygous APC resistance). To address these issues, we have measured factor V antigen (factor V:Ag) levels in 474 patients with thrombosis and 474 control subjects that were part of the Leiden Thrombophilia Study (LETS). Factor V:Ag levels increased by 7.6 U/dL for every successive 10 years of age. Mean factor V:Ag levels were 134 (range 41 to 305) U/dL in patients and 132 (range 47 to 302) U/dL in controls. Neither high nor low factor V:Ag levels were associated with venous thrombosis. We found that factor V:Ag and factor VIII antigen levels in plasma were correlated, but factor V did not modify the thrombotic risk of high factor VIII levels. The normalized APC ratio was not influenced by the factor V:Ag level in subjects with or without factor V Leiden. We conclude that neither low nor high factor V:Ag levels are associated with venous thrombosis and that factor V:Ag levels do not mediate the thrombotic risk associated with high factor VIII levels.

Adolescent↗
PubMed1998

The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V.

Factor V (FV) is recently shown to express anticoagulant activity. It functions as a synergistic cofactor with protein S to activated protein C (APC) in the degradation of factor VIIIa (FVIIIa). FV is composed of multiple domains, A1-A2-B-A3-C1-C2. Thrombin cleaves FV at Arg-709, Arg-1018, and Arg-1545 that leads to the generation of a procoagulant FV species which functions as a cofactor to factor Xa (FXa) in the activation of prothrombin to thrombin. During the activation process, the B-domain is released from the heavy (A1-A2) and light chains (A3-C1-C2) which constitute the active FV (FVa). To elucidate which effect the different thrombin cleavages in FV have on the ability of FV to express APC-cofactor activity, seven recombinant FV mutants containing all possible combinations of mutated and native thrombin cleavage sites were tested in a FVIIIa degradation assay. Thrombin cleavage at Arg-709 and/or Arg-1018 yielded FV molecules that were still able to function as APC cofactors, whereas cleavage at Arg-1545 led to a complete loss in APC-cofactor function. This suggests that the APC-cofactor function of FV depends on the B-domain remaining attached to the A3 domain. The importance of the FV B-domain for expression of APC-cofactor activity was further investigated using two B-domain deleted FV molecules, FV des-709-1545 (with the whole B-domain deleted) and FV des-709-1476 (with amino acids 710-1476 of the B-domain being removed). FV des-709-1476 expressed APC-cofactor activity, whereas the FV des-709-1545 was completely devoid of such activity. Thus, the C-terminal part of the B-domain (residues 1477-1545) was crucial for the APC-cofactor function. FV and factor VIII (FVIII) are homologous proteins having similar domain organization. A FV/FVIII chimera, harboring the B-domain from FVIII (FVBVIII) instead of the FV B-domain did not work as an APC cofactor, further illustrating the importance of the FV B-domain for the APC-cofactor function.

Animals↗
PubMed1998

Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene.

Factor V (FV) deficiency (parahaemophilia) is an autosomal recessive bleeding disorder with an incidence of 1:10(6). We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0.3% and <1.6% of normal, respectively). Both parents showed plasma levels of factor V activity of about 50% of normal. Sequence analysis of the 5'- and 3'-untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13. Subsequent screening of members of the family for the mutation showed that both parents were heterozygous for the mutation, that one healthy sister carried only normal alleles, and that the patient was homozygous for the mutated allele. The mutation introduced a frameshift and a novel premature stop codon in codon 1303, and would predict the synthesis of a truncated factor V molecule that lacks part of the B domain and the complete light chain. However, no factor V heavy chain could be detected in the plasma of the patient. Furthermore, factor V activity could not be detected in the patients' platelets. This is the first reported mutation in the factor V gene that predicts a type I quantitative factor V deficiency. Surprisingly, the patient, who is homozygous for the mutation, so far has only a very mild bleeding tendency.

Amino Acid Sequence↗
PubMed1999

Recurrent optic nerve head infarctions associated with combined factor V Leiden- and factor II:G20210A-mutation.

PURPOSE: To demonstrate the association of bilateral recurrent optic nerve head infarctions with thrombophilia due to combined factor V:R506Q- and factor II:G20210A-mutation. METHODS: Case report. We examined a 55-year-old man with a two-year history of three segmental optic nerve head infarctions. Visual acuity was 20/80 on the left and 20/25 on the right eye. RESULTS: Ophthalmologic, cardiologic, radiologic, neurologic and hematologic-immunologic examinations were unremarkable except for increased APC-resistance (APC ratio: 1.4; normal value >2) due to heterozygous factor V:R506Q-mutation and high factor II-levels due to factor II:G20210A-mutation. Therapy with coumarin was instituted at INR 2.0-3.0 and no relapse has occurred over the past 1-year period. CONCLUSION: Combined occurrence of thrombogenic factor II:G20210A-mutation and factor V:R506Q-mutation may be causally linked to recurrent optic nerve head infarctions.

Factor V↗