<b>Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance</b>

Bokarewa, Maria; Falk, Gunnar; Bremme, Katarina; Blombäck, Margareta; Wiman, Björn

doi:10.1046/j.1365-2362.1997.1180660.x

Cited by 10 publications

(4 citation statements)

References 22 publications

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“…However, to date no mutations have been found in the APC-cleavage sites of FVIII. 100 In recombinant FVIII, mutagenesis of individual APC-cleavage sites in FVIII did not result in an APC-resistance phenotype. This was only achieved when both APC-cleavage sites in FVIII were mutated.…”

Section: Other Genetic Defects In Fv or Fviii Associated With Apc Resmentioning

confidence: 99%

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Dahlbäck¹

1999

Semin Thromb Hemost

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Inherited resistance to activated protein C (APC) is the most common genetic risk factor of venous thrombosis. It is caused by a single point mutation in the factor (F)V gene which predicts replacement of Arg506 with a Gln (FVR506Q, FV: Q506 or FV Leiden). This mutation affects the function of the protein C system, a physiologically important natural anticoagulant pathway. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V (FV/FVa) and factor VIII (FVIII/FVIIIa). Degradation of FVa by APC is stimulated by protein S, whereas inactivation of FVIIIa requires the synergistic cofactor function of protein S and FV proteolytically modified by APC. Thus, FV has the potential to express opposing functions, as a procoagulant after cleavage by thrombin or FXa and as an anticoagulant after cleavage by APC. The FVR506Q mutation not only confers partial resistance of FVa to APC but also impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for expression of the anticoagulant activity of FV. The impaired degradation of both FVIIIa and FVa yield a hypercoagulable state conferring a lifelong increased risk of thrombosis. The FV mutation is common in Caucasians, whereas it is rarely found among other groups worldwide. In patients with severe thrombophilia having other inherited defects such as deficiencies of protein S, protein C, or antithrombin, APC resistance is often found as a contributing genetic risk factor. Individuals with combined genetic defects have a high risk of thrombosis, and it is now generally accepted that thrombophilia is a multigenetic disease.

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Section: Other Genetic Defects In Fv or Fviii Associated With Apc Resmentioning

confidence: 99%

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Dahlbäck¹

1999

Semin Thromb Hemost

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“…The effect of FVIII levels is specific for the intrinsically triggered aPTT‐based assay. Remarkably, while elevated FVIII levels are a prevalent cause of APC resistance [8,47–50], mutations affecting the APC‐cleavage sites in FVIIIa have never been identified in APC‐resistant individuals [78–80]. Elevated FIX(a) and FX(a) levels may cause APC resistance via increased protection of their cofactors FVIIIa and FVa from APC‐mediated inactivation [18,19,26].…”

Section: Fvleiden‐independent Apc Resistancementioning

confidence: 99%

APC resistance: biological basis and acquired influences

Castoldi

Rosing

2010

Journal of Thrombosis and Haemostasis

108

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To cite this article: Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8: 445-53.Summary. Proteolytic inactivation of factors Va (FVa) and VIIIa (FVIIIa) by activated protein C (APC) and its cofactors protein S and factor V (FV) is a key process in the physiological down-regulation of blood coagulation. Functional abnormalities of this pathway, which manifest themselves in vitro as a poor anticoagulant response of plasma to added APC (APC resistance), are prevalent in the general population and are associated with an increased risk of venous thrombosis. APC resistance was originally discovered in thrombophilic families and later shown to be associated with the common FV Arg506Gln (FV Leiden ) mutation, which abolishes one of the APC-cleavage sites in FV. Although FV Leiden is the major cause of hereditary APC resistance, it is becoming increasingly clear that several other genetic and acquired conditions contribute to APC resistance and thereby increase the risk of venous thrombosis. This paper reviews the multifactorial etiology of APC resistance and discusses its clinical implications.

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“…21,22 Similarly, no mutation associated with thrombosis was found in the gene regions encoding the two cleavage sites on factor VIII, the other substrate of APC. 23,24 There are observations of very rare nucleotide substitutions in the prothrombin gene near the G20120A mutant allele, 25 but the association with thrombosis is uncertain. A search of mutations in genes that are considered plausible candidates because they encode proteins involved in thrombogenesis was fruitless so far (anticoagulants such as tissue factor pathway inhibitor and thrombomodulin; procoagulants such as coagulation factors; and fibrinolysis components such as thrombin-activated fibrinolysis inhibitor, tissue plasminogen activator, and its type 1 inhibitor).…”

Section: New Genetic Markersmentioning

confidence: 99%

Laboratory Detection of Inherited Thrombophilia: A Historical Perspective

Mannucci¹

2005

Semin Thromb Hemost

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Considerable progress has been made in determining the molecular bases of inherited thrombophilia in the last 25 years. There are several genetic abnormalities that can be detected in the laboratory and are currently recognized to be unequivocally associated with an increased tendency to develop venous thrombosis. Testing for inherited and acquired causes of thrombophilia may make counseling more focused in ostensibly healthy members of thrombophilic families (i.e., those in which a measurable abnormality was identified in one or more asymptomatic persons). In other situations, including women who start taking oral contraceptives, become pregnant, or consider hormone replacement therapy, screening is generally not useful. It is hoped that because we currently have such simple and clinically useful global tests of hypocoagulability as the prothrombin time and activated partial thromboplastin time, it may soon become possible to measure multifactorial thrombophilia without resorting to the multiplicity of tests now necessary.

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Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance

Cited by 10 publications

References 22 publications

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

APC resistance: biological basis and acquired influences

Laboratory Detection of Inherited Thrombophilia: A Historical Perspective

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