Combination of congenital coagulation disorders: Factor II gene mutation G20210A, Factor V Leiden gene mutation G1691A and protein S deficiency. a family study.

The thromboembolic phenomenon is nowadays considered to be a multicausal disease, in which the fact of being the carrier of a congenital prothrombotic disorder is not the cause, but rather an additional risk factor in the onset of thrombosis occurring as the result of the sum of various risk factors. These factors are usually a combination of external circumstances (precipitating factors) and a predisposition to thrombosis in the patient, which may be either hereditary or acquired. The literature describes various combinations of congenital deficiencies in two or more natural coagulation inhibitors, as well as combinations of these deficiencies with Factor II and V mutations or combinations of mutations in these factors. In this article we describe an unusual family case with three associated congenital disorders, a coagulation inhibitor deficit and two associated mutations, leading to different thrombotic processes in different members of the same family. A thrombophilia study was carried out on a patient who presented an episode of thrombosis in the superior mesenteric vein, initially suspected after ultrasound examination of the abdomen and confirmed by exploratory laparotomy. The patient had antecedents of repetitive thrombophlebitis without having suffered any prior thromboembolic process . A family study was made of the patient’s daughter, his sister and two of her children. After drawing up a clinical history, including possible precipitating risk factors and previous thromboembolic processes, an analytical study consisting of a haemogram, a coagulation study (PT, APTT, fibrinogen, antithrombin III, total, free and functional protein S, functional protein C, FII activity, APCR-V) and a genetic study were performed. Factor II (FII) activity was determined by means of a coagulometric method on an ACL 7000 Coagulation Analyzer (Izasa). As a consequence of an excess of Factor V-deficient plasma the activated protein C resistance ratio (APCR-V) was also determined on an ACL 7000 Coagulation Analyzer (Izasa) by measuring APTT prolongation. The relationship between the APTT of plasma containing FV-deficient plasma and non-FVdeficient plasma gives the ratio of the resistance to activation of protein C (standard R>2). The amount of free protein S was evaluated by turbidimetric immunoanalysis, that of functional protein S by a coagulometric method, and that of total antigenic protein S by enzyme immunoanalysis. A genetic study was carried out on the above-mentioned family members for the existence of prothrombin gene mutation G20210A and gene mutation G1691A (Factor V Leiden), both assays being performed using a real-time multiplex PCR system (Light Cycler, Roche Molecular Biochemicals) according to the method established by van der Bergh F et al.. Figure 1 shows the genotype observed in the family study. A coagulation study, which due to the underlying pathology was non-evaluable, was performed on the patient (I1), a 60-year-old male who was being tested for thrombophilia as a result of a clinical episode of thrombosis. The genetic study revealed heterozygosis for both mutations assayed. The patient had been a smoker (20 cigarettes/day) since he was 20, but was neither hypertensive nor obese, and showed no dyslipemia. The results of the coagulation factor activity analysis and the genetic analysis of the various family members are shown in table 1. The presence of venous thromboembolism has been repeatedly associated in the literature with reduced inhibitor levels in the coagulation cascade or with increased levels of coagulation factors, the risk being greater when genetic defects are combined. The case presented in this study is extremely unusual, due to the low prevalence of protein S deficiency, which in the absence of confirmed data has been estimated at 1.3 &endash; 5% of patients with venous thrombosis. Factor V Leiden has a prevalence of 5% in the European population, whilst that of the prothrombin gene mutation G20120A is between 1 &endash; 4%. Mesenteric vein thrombosis (MVT) is a serious thrombotic process that occurs only occasionally, and in which a high proportion (75%) of mutation has been observed, such as homozygosis of methylene tetrahydrofolate reductase for C677T, or heterozygosis for Factor V Leiden or prothrombin gene mutation G20210A, with a high proportion of patients (33%) having more than one mutation. The presence of these mutations leads to a higher risk of MVT, as is shown by the odds ratios of 4.52, 6.19 and 6.85 for C677T, Factor V Leiden and G20210A respectively, when comparing the prevalence of the mutations present in twelve patients with MTV with the prevalence of these same mutations in four hundred and thir-