Article

Bertina, R.M. 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: 42.35). 05/1994; 369(6475):64-7. DOI: 10.1038/369064a0
Source: PubMed

ABSTRACT 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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    • "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.
    Thrombosis Research 07/2015; DOI:10.1016/j.thromres.2015.07.020 · 2.43 Impact Factor
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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.
    Studies in History and Philosophy of Science Part C Studies in History and Philosophy of Biological and Biomedical Sciences 09/2014; 47. DOI:10.1016/j.shpsc.2014.03.007
    • "The following polymorphisms were analyzed. The G1691A polymorphism of the factor V gene (factor V Leiden) [12]. The G-to-A substitution was detected by amplifying a region of exon 10 and the adjacent intron of the factor V gene by PCR. "
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    ABSTRACT: Introduction The pathogenesis of idiopathic sudden sensorineural hearing loss (ISSNHL) is still unknown. Systemic hemostasis derangement causing local vascular occlusion might be one of the pathogenetic mechanisms. Material and Methods Forty-one patients with ISSNHL and 48 healthy subjects were investigated. We measured thrombin generation in the presence or absence of thrombomodulin in platelet-poor or platelet-rich plasma by means of a home-made method based on calibrated automated thrombin generation, which should mimic much more closely than any other conventional coagulation test the balance of coagulation operating in vivo. DNA analyses for the most common prothrombotic genotypes such as factor V Leiden, prothrombin G20210A, MTHFR or platelet GPIIIa A1/A2 were also carried out in patients and controls. Results Patients generated as much thrombin as controls both in platelet-rich and platelet-poor plasma and the frequency of the most common prothrombotic genotypes were similar in patients and controls. Conclusions The results suggest that the pathogenesis of ISSNHL is not due to systemic blood hypercoagulability. Other culprits such as local vascular abnormalities, viral infections, immune-mediated mechanisms or abnormalities of inner ear and central nervous system should be advocated to explain ISSNHL.
    Thrombosis Research 06/2014; 133(6). DOI:10.1016/j.thromres.2014.03.031 · 2.43 Impact Factor
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