Factor V Leiden pseudo‐homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes

Abstract

To cite this article: Duckers C, Simioni P, Tormene D, Carraro S, Rosing J, Castoldi E. Factor V Leiden pseudo-homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes. J Thromb Haemost 2011; 9: 864-7.The factor V (FV) R506Q mutation (FV Leiden) [1], which is present in approximately 5% of Caucasians, is associated with activated protein C (APC) resistance [2] and increases the risk of venous thrombosis seven-fold in heterozygotes and 80-fold in homozygotes [3]. The rare FV Leiden heterozygotes that carry a loss-of-function mutation on the counterpart FV allele (FV Leiden pseudo-homozygotes), express only the FV Leiden allele and have plasma FV levels of approximately 50% [4]. Based on APC resistance measurements, FV Leiden pseudo-homozygotes are generally considered to have a hypercoagulable state similar to that of FV Leiden homozygotes [4][5][6]. Their risk of venous thrombosis is not well established and was found to be similar to that of FV Leiden heterozygotes in a previous study [7] and to that of homozygotes in another study [6]. However, both studies may have been biased by the inclusion of probands in the analysis. Therefore, an intermediate phenotype such as thrombin generation may be more suitable to quantify the thrombotic tendency associated with FV Leiden pseudo-homozygosity.Recently, we have shown that plasma levels of tissue factor pathway inhibitor (TFPI) are markedly reduced in FV deficiency [8]. Since FV Leiden pseudo-homozygotes have low FV levels, we hypothesized that they might have reduced TFPI levels as well. This may exacerbate their hypercoagulable state, as low TFPI levels are also associated with an increased risk of venous thrombosis [9]. To test this hypothesis, we compared plasma TFPI levels and thrombin generation in FV Leiden pseudo-homozygotes and homozygotes.Nine FV Leiden pseudo-homozygotes (five males and four females, mean age 48.4 years), of whom five (55.5%) had experienced venous thrombosis, were included. Eighteen FV Leiden homozygotes (nine males and nine females, mean age 44.8 years), of whom six (33.3%) had experienced venous thrombosis, served as controls. Genotyping for the FV Leiden mutation was performed as described before [8]. All participants gave informed consent to participate in the study, which was carried out in accordance with the Declaration of Helsinki.Platelet-poor plasma was prepared from venous blood as described previously [8]. Plasma levels of prothrombin, FV, total protein S and free TFPI were measured as described before [8]. Pooled normal plasma, prepared by pooling plasma from 15 healthy individuals without FV Leiden (seven males and eight females, mean age 45.1 years), was used as a reference.Thrombin generation was determined using the Calibrated Automated Thrombogram method [10] under conditions that are sensitive to the TFPI anticoagulant pathway, i.e. at low (1.7 pM) tissue factor (TF) and at higher (6.8 pM) TF in the presence of APC. Measurements at low TF were performed in the absence and presence of inh...

Role of tissue factor pathway inhibitor in hormone-induced venous thromboembolism

“…In plasma, 80% of TFPI circulates in a C-terminus-truncated and bound to lipoproteins form and the other 20% exists in a free form, comprising fulllength TFPI that possesses the greatest anticoagulant Role of tissue factor pathway inhibitor in hormone-induced venous thromboembolism Arafat et al 235 activity, and a small proportion of different truncated forms [28]. Protein S and factor Va can modulate the anticoagulant activity of TFPI [29,30] and were also demonstrated to correlate with the plasma levels of TFPI [31]. Low levels of protein S and TFPI are associated with an increased risk of a first and recurrent VTE [32][33][34], although this association was weaker or even absent in several other studies [35,36].…”

The anticoagulant function of coagulation factor V

“…But in fact, pseudo-homozygosity results in a phenotype that is indistinguishable from homozygous R506Q-FV patients. In thrombin generation assays, pseudo-homozygous patient plasma may even be more thrombogenic than homozygous R506Q-FV patient plasma because of reduced plasma levels of tissue factor pathway inhibitor (39). Experiments measuring the APC sensitivity ratio of FV-deficient plasma, reconstituted with various combinations of normal FV and R506Q-FV showed that the APC resistance was not dependent on the absolute amount of R506Q-FV, but on the relative amount of normal FV (36,37,40).…”

Analysis of f5 gene polymorphism in men with coronary atherosclerosis using whole exome sequencing

“…Остальные (1%) являются гомозиготами или крайне редкими случаями компаунд-гетерозигот по FVL -вариант по другому аллелю F5, который вызывает дефицит фактора V, в результате чего FVL является его единственной доступной формой в циркуляции [8][9][10][11]. Эти пациенты, по-видимому, более склонны к тромбозам, чем гетерозиготные родственники с одним только FVL [12][13][14].…”