Bertina, R. M., Koeleman, B. P. C., Koster, T., Rosendaal, F. R., Dirven, R. J., de Ronde, H. D. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369, 64-67

Leiden University, Leyden, South Holland, Netherlands
Nature (Impact Factor: 41.46). 05/1994; 369(6475):64-7. DOI: 10.1038/369064a0
Source: PubMed


Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.

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Available from: Pieter A van der Velden
    • "The coefficient of variability (CV%) for RDW is 3.0%. Thrombophilia testing included DNA analysis for factor V Leiden and G20210A polymorphism in the prothrombin gene [27] [28], functional assay for plasma factor VIII, functional and immunoassays (when required ) for plasma antithrombin, protein C and protein S [29], antiphospholipid antibodies (lupus anticoagulant, anticardiolipin and anti-β 2 glycoprotein I antibodies) [30], fasting and post-methionine load homocysteine [31] "
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    ABSTRACT: An association between high red cell distribution width (RDW) and venous thromboembolism (VTE) has been observed. However, it is not known whether this association differs within various manifestations of VTE, nor if there is an interaction between RDW and thrombophilia abnormalities on the risk of VTE. To investigate whether RDW is a marker of the risk of VTE; to identify subgroups of patients in which the association between RDW and VTE is stronger; to investigate a possible interaction between RDW and thrombophilia abnormalities. Case-control study on 730 patients with a first objectively-confirmed VTE episode (300 unprovoked and 430 provoked) consecutively referred to our Center between 2007 and 2013, and 352 healthy controls. Blood was taken for a thrombophilia work-up and a complete blood count, including RDW, at least three months after VTE. Individuals with RDW above the 90(th) percentile (>14.6%) had a 2.5-fold increased risk of VTE compared to those with RDW ≤90(th) percentile, independently of age, sex, body mass index, other hematological variables and renal function (adjusted odds ratio: 2.52 [95%CI:1.42-4.47]). The risk was similar for unprovoked and provoked VTE, and slightly higher in patients with pulmonary embolism (adjusted odds ratio 3.19 [95%CI:1.68-6.09]) than in those with deep vein thrombosis alone (2.29 [95%CI:1.22-4.30]). No interaction between high RDW and thrombophilia abnormalities on the risk of VTE was observed. Our findings confirm RDW as an independent and easily available marker for stratification of the risk of VTE. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "The " new cofactor " has now been identified as " old " factor V. Since APC cofactor 2 turns out to be factor V, we must conclude that the plasma of patients with APC resistance contains factor V molecules that are normal in procoagulant activity but abnormal in terms of promoting their own destruction by activated protein C. This awkward and byzantine explanation is probably superseded by the results published in this issue of The Lancet and in the recent paper from Bertina et al. (Tuddenham, 1994) As so succinctly shown by the last sentence of the above quote, the identification of the factor V Leiden mutation made it easier for Tuddenham (and other scientists) to disregard Dahlbäck's hypothesis that factor V serves as a cofactor to APC. Instead, it was perhaps more straightforward to think of the APC resistance as being due to the inability of APC to cleave the mutant factor V Leiden. "
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    ABSTRACT: Since its initial discovery in the 1940s, factor V has long been viewed as an important procoagulant protein in the coagulation cascade. However, in the later part of the 20th century, two different scientists proposed novel anticoagulant roles for factor V. Philip Majerus proposed the first anticoagulant function for factor V in 1983, yet ultimately it was not widely accepted by the broader scientific community. In contrast, Björn Dahlbäck proposed a different anticoagulant role for factor V in 1994. While this role was initially contested, it was ultimately accepted and integrated into the scientific framework. In this paper, I present a detailed historical account of these two anticoagulant discoveries and propose three key reasons why Dahlbäck's anticoagulant role for factor V was accepted whereas Majerus' proposed role was largely overlooked. Perhaps most importantly, Dahlbäck's proposed anticoagulant role was of great clinical interest because the discovery involved the study of an important subset of patients with thrombophilia. Soon after Dahlbäck's 1994 work, this patient population was shown to possess the factor V Leiden mutation. Also key in the ultimate acceptance of the second proposed anticoagulant role was the persistence of the scientist who made the discovery and the interest in and ability of others to replicate and reinforce this work. This analysis of two different yet similar discoveries sheds light on factors that play an important role in how new discoveries are incorporated into the existing scientific framework.
    Full-text · Article · Sep 2014 · Studies in History and Philosophy of Science Part C Studies in History and Philosophy of Biological and Biomedical Sciences
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    • "In terms of genetic predisposition, it is known that common variants in the ABO [24], factor V (F5) [25], prothrombin (F2) [26], fibrinogen γ-chain (FGG) [27] and factor XI (F11) [28] genes influence risk of VTE. However, no study has systematically investigated whether known coronary artery disease (CAD)-associated SNPs that have emerged through genome-wide association (GWA) studies of CAD also increase the risk of VTE. "
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    ABSTRACT: Introduction We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case–control study (n = 2753) from Sweden. Materials and Methods 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. Results Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181). Conclusions It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.
    Full-text · Article · Aug 2014 · Thrombosis Research
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