Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

Abstract

Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activatorinduced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogenand fibrin-degradation products. (Blood. 2010;116(5):801-805) IntroductionReplacement of Arg506 with Gln in coagulation factor V (the factor V Leiden [FVL] mutation) 1 results in the loss of an important cleavage site for activated protein C (aPC). Factor Va carrying the FVL mutation is less sensitive to inactivation by aPC. In addition, FVL may display an impaired cofactor function in the degradation of factor VIIIa by aPC. FVL predisposes for the development of venous thrombosis. 2 The high prevalence of FVL in the European population 3 indicates some survival advantage, which might be related to less blood loss on injury or childbirth or to improved wound healing. 4 This may be a consequence of enhanced fibrin formation due to the impaired inactivation of factor Va.Presence of disseminated intravascular coagulation (DIC) in sepsis is associated with an adverse outcome. 5 DIC may lead to microvascular thrombosis, causing multiple organ dysfunctions, and it is conceivable that a prothrombotic disposition such as FVL would be associated with an increased rate of fibrin disposition, causing organ dysfunction and death in sepsis.Astonishingly, data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) and Extended Evaluation of Recombinant Human Activated Protein C in Severe Sepsis (ENHANCE) trials indicate that the FVL mutation might be associated with improved survival in severe sepsis. 6,7 In the PROWESS trial, mortality of patients with severe sepsis with heterozygous FVL was 15.6%, compared with 31.0% in patients without FVL in the patient group not treated with recombinant aPC (Drotrecogin alfa [activated]). In patients treated with Drotrecogin alfa (...

Sepsis and Thrombosis

“…Finally, however, in a more subtle model of endotoxin-induced coagulation activation in humans, it was demonstrated that heterozygous carriers of factor V Leiden had a more pronounced increase in markers of thrombin generation and fibrinogen to fibrin conversion. 70 The authors also found an increase in fibrinolytic activity in factor V Leiden-affected individuals, which they attributed to the facilitating role of soluble fibrin for endogenous fibrinolysis.…”

Polyunsaturated fatty acid biosynthesis pathway and genetics. implications for interindividual variability in prothrombotic, inflammatory conditions such as COVID-19✰,✰✰,★,★★

“…Methylation at the ELOVL2 locus has been proposed as a measure of again in forensics [98] and the principle appears to be similar for chimpanzees [144]. The plasma kinetics of 13 C-DHA is strongly related to age [145], while EPA is only slightly related to age and AA is not [146,147]. While these fatty acids are not immediate products of ELOVL2, it is tempting to speculate that methylation of this gene with aging plays a role.…”

“…For instance, increased risk of thrombotic events and recurrence occur in patients with homozygous and compound heterozygous for Factor V Leiden (FVL) and prothrombin G20210A mutations [11,12]. Patients with FVL mutation displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma [13].…”

Venous Thrombosis with Both Heterozygous Factor V Leiden (R507Q) and Factor II (G20210A) Mutations

“…There is the observation and suggestion that F V Leiden may confer a survival advantage in patients with severe sepsis. 23,24 Recent studies have contradicted the purported survival advantage. 25,26,27 It remains to be seen if this sepsis survival is substantiated.…”