Arginine 506 to glutamin mutation in the factor V gene in infancy and childhood: evidence of fibrinolytic impairment

Nowak‐Göttl, Ulrike; Vielhaber, H.; Grohmann, Jochen; Schneppenheim, Reinhard; Koch, Hans-Georg

doi:10.1007/s004310050581

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…4b) were found to be significantly higher in children with APCR. 26,27 No difference was found in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism.…”

Section: Interaction Of the Factor V Leiden Mutation With Coagulationmentioning

confidence: 68%

“…Few studies [26][27][28] have described the interaction between APCR and the coagulation or fibrinolytic systems in symptomatic and asymptomatic infants. The results of these studies are summarized in Figures 2 to 4.…”

Section: Interaction Of the Factor V Leiden Mutation With Coagulationmentioning

confidence: 99%

“…2b) were clearly elevated in the APCR children. [26][27] In addition, infants and children with the Arg 506 -to-Gln mutation in the factor V gene (Fig. 3a) showed significantly increased thrombomodulin (TM) concentrations compared with relatives and healthy controls.…”

Section: Interaction Of the Factor V Leiden Mutation With Coagulationmentioning

confidence: 99%

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APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

Nowak‐Göttl¹,

Schneppenheim²,

Vielhaber³

1997

Semin Thromb Hemost

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Few studies of activated protein C resistance (APCR) and thromboembolism in childhood have been published. In the majority of childhood thromboses reported, the factor V Leiden mutation was associated with venous thromboses; however, one case report and three studies described arterial thromboembolism in infants and children due to the common mutation in the factor V gene. In one neonate purpura fulminans occurred, and heparin-induced thrombocytopenia type II was additionally documented. Two case reports and seven of nine studies reported associated clinical conditions together with inherited coagulation disorders. In three studies homozygous patients were mentioned. There are few studies describing the interaction between APCR and coagulation or the fibrinolytic system in symptomatic and nonsymptomatic infants. Compared with healthy brothers or sisters and a healthy age-matched control group, thrombin generation, D-dimer, PAI-1 activity, and t-PA antigen were found clearly elevated in children with APCR. In addition, infants and children with the Arg506-to-Gln mutation in the factor V gene showed significantly increased thrombomodulin concentrations along with normal protein C activities compared with relatives and healthy controls. No difference was recorded in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism. Until long-term data are available for the treatment of patients with APCR, such children should be treated in the same way as patients with deficiencies of protein C, protein S, or antithrombin.

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Section: Interaction Of the Factor V Leiden Mutation With Coagulationmentioning

confidence: 68%

Section: Interaction Of the Factor V Leiden Mutation With Coagulationmentioning

confidence: 99%

See 1 more Smart Citation

APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

Nowak‐Göttl¹,

Schneppenheim²,

Vielhaber³

1997

Semin Thromb Hemost

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“…[144][145][146][147] Several studies have demonstrated the presence of the FV : Q506 allele in around 50% of children with venous thromboembolism. 147,148…”

Section: Epidemiology and Clinical Manifestations Of Apc Resistancementioning

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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“…TM corrected the premature lysis of clots prepared from factor X, IX, VIII and XI deficient plasmas in vitro (24) and TAFI dependent down regulation of fibrinolysis was shown to be augmented by both soluble (15,25,26) and cellular (27) TM. Modulation of fibrinolysis by APC has been de-scribed both in vitro (19,20,22,28) and in vivo (29)(30)(31) whereas factor V Leiden , in which the inactivation of factor Va by APC is severely compromised due to a mutation in factor V (Arg 506 ǞGln), was shown to enhance the down regulation of fibrinolysis (32,33).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Fibrinolysis in Plasma by TAFI and Protein C Is Dependent on the Concentration of Thrombomodulin

Mosnier

Meijers²,

Bouma³

2001

Thromb Haemost

110

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SummaryThrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme, that after activation down regulates fibrinolysis. TAFI is activated by thrombin in the presence of the cofactor thrombomodulin (TM). By stimulation of TAFI activation TM down regulates fibrinolysis, however TM is also a cofactor in the activation of protein C. Activated protein C (APC) can up regulate fibrinolysis by limiting the activation of TAFI via the attenuation of thrombin production. We studied these counteracting fibrinolytic properties of TM in plasma by measuring the activation of TAFI during tissue factor induced coagulation. TAFI activation was stimulated at low concentrations of TM but decreased at higher concentrations of TM. Similarly, the clot lysis times increased at low concentrations of TM but decreased at higher concentrations of TM. The reduction of TAFI activation at high TM concentrations was found to be dependent on a functional protein C pathway. The concentration of TM is therefore an important factor in the regulation of TAFI activation and in the regulation of fibrinolysis. High concentrations of TM result in up regulation of fibrinolysis, whereas low concentrations of TM have a down regulatory effect on fibrinolysis. These results suggest that fibrinolysis might be differentially regulated by TM in different parts of the body depending on the local TM concentration in the vasculature. Abbreviations: TAFI, thrombin activatable fibrinolysis inhibitor; TAFIa, activated TAFI; CPI, carboxypeptidase inhibitor from potato tubers; tPA, tissue-type plasminogen activator; TM, thrombo-modulin; TM4-6, Thrombomodulin fragment containing EGF domains 4 to 6; HMEC, human microvascular endothelial cell.

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Arginine 506 to glutamin mutation in the factor V gene in infancy and childhood: evidence of fibrinolytic impairment

Abstract: Our data indicate that hypercoagulability in children with the Arg506 to Gln mutation in the factor V gene is mainly attributed to the genetic aetiology of the disease.

Cited by 8 publications

References 22 publications

APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

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

Regulation of Fibrinolysis in Plasma by TAFI and Protein C Is Dependent on the Concentration of Thrombomodulin

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