Fibrinogen is not an additional risk factor of thromboembolic disease in factor V Leiden patients.

Venous thrombosis is a common disease, with an estimated annual incidence in the general population of 1 in 1000 persons (1). It is a major medical problem, which may cause death due to pulmonary embolism. Fibrinogen is a key component of the common clotting pathway; it is involved in the final phases of coagulation. It is also the coagulation factor whose plasma concentration is the highest (2-4 g/l), and with fibrin it provides structural support and scaffolding for the cellular and other blood elements comprising the thrombus in vivo. It is composed of three distinct polypeptide chains (A alpha, B beta and gamma) arranged as a dimer, and each of the fibrinogen chains is encoded by a separate gene; the three genes are present closely linked on the distal third of the long arm of the human chromosome 4. There is growing interest in fibrinogen after several epidemiological studies reported a strong association between elevated plasma levels of fibrinogen and an increased risk of myocardial infarction, stroke, thrombotic risk in patients with venous thrombosis. Koster et al. tested the hypothesis that fibrinogen could be a risk factor for venous thrombosis (2). They found a positive level related association between the plasma fibrinogen level and thrombotic risk, in patients with a first objectively confirmed episode of deep-vein thrombosis. Subjects with a plasma fibrinogen level between 4 and 5 g/l had a two fold higher risk than those in the reference category (<3 g/l). In addition, they analysed the Hae III beta chain fibrinogen polymorphism in their patients and the healthy controls; they observed that possession of an H1H2 genotype was associated with a 40% reduction in thrombotic risk but no association was present between plasma fibrinogen and polymorphic genotype. According to the authors, this finding points to an effect of fibrinogen on the risk of venous thrombosis, which cannot be explained by the plasma level. These observations arose our interest in proving that fibrinogen could play a role in thromboembolic disease. To elucidate the participation of fibrinogen in the process of deep-vein thrombosis, we decided to investigate the association between fibrinogen genotypes and venous thrombosis in factor V Leiden patients. This factor V nucleotidic variation was identified in 1994 by Bertina et al. (3). We chose to study four restriction fragment length polymorphic (RFLP) sites in the fibrinogen cluster: Taq I, Bcl I at the 3’ end of the alpha and beta genes, respectively; Hind III and Hae III at position -148 and -453 upstream from the start of transcription of the beta fibrinogen gene, respectively, in 24 thrombophilic families. Our study included 24 propositi who had all the mutation factor V Leiden and had experienced at least one venous thrombotic event (4). The families comprised 156 affected relatives who were classified in 4 groups: 1 patients who had venous thrombotic events and carrying the factor V Leiden mutation, 2 patients without venous thrombotic event and carrying the factor V Leiden mutation, 3 patients who had venous thrombotic events but without the factor V Leiden mutation and 4 patients without venous thrombotic events and without the factor V Leiden mutation. The control group was made of 158 bone marrow donors. All these individuals are from a population of Caucasian origin. Written informed consents were obtained from all these individuals. Genomic DNA was prepared from white blood cells by extraction, the four RFLP were genotyped after amplification of relevant DNA regions by PCR Fibrinogen Is not an Additional Risk Factor of Thromboembolic Disease in Factor V Leiden Patients Thromb Haemost 1999; 81: 659–60