European Journal of Obstetrics & Gynecology and Reproductive Biology
Genetic aspects of venous thrombosis
Introduction
Mutations in the genes coding for the proteins involved in blood coagulation may result in a bleeding tendency (haemophilia) or in a thrombotic tendency (thrombophilia). Diagnosis and treatment of the haemophilias have been studied extensively in the past. In general, it concerns monogenetic diseases where the absence of or the defect in a single clotting factor is the cause of the clinical phenotype. Inheritance can be autosomal dominant (e.g. von Willebrand disease), X-linked recessive (haemophilia A and B) or autosomal recessive, (e.g. deficiency of factors II, V, VII, X, XI). A systemic study of familial thrombophilia has started only in the seventies, although thrombophilic families had been reported in the literature since the beginning of the 20th century. Phenotypically, the disease seems to be autosomal dominant. This is easily explained by recent findings which support the hypothesis that in contrast to the genetic bleeding disorders, familial thrombophilia is an oligogenetic disorder [1].
Section snippets
Venous thrombosis
Thrombosis is defined as an unwarranted hemostatic process which occurs locally in veins or arteries and may result in the formation of an occlusive thrombus, locally or elsewhere in the circulation (embolus). The annual incidence of venous thrombosis has been estimated to be 1/1000. Thrombosis usually occurs in the superficial or deep veins in the legs but also may be found in veins in the brain, retina and mesentery. Thrombosis is an episodic disease. Some individuals experience only one
Prothrombotic gene defects
Blood group non-O has been recognised as a risk factor for venous thrombosis since 1969 [7]. Today, we think that it acts through the associated increase of VWF (the carrier protein of factor VIII in plasma) and factor VIII levels in plasma. More recently, it was demonstrated that elevated factor VIII levels (>150 IU/dl) form an independent risk factor for venous thrombosis which may occur in 25% of consecutive patients and 11% of healthy controls [6].
Antithrombin is an important anticoagulant
Familial thrombophilia
Among symptomatic patients that come from families with thrombophilia, the prevalence of the established genetic risk factors is much higher than that among consecutive patients: antithrombin, protein C and protein S deficiency, each occur in about 5% of these patients, the protrombin 20210A allele in about 18% and the factor V Leiden mutation in 45% of these patients (compare with data in Table 1). Within these families carriers of the defect have a significant increased risk of venous
Thrombophilia and use of oral contraceptives
Current use of oral contraceptives is a well established risk factor for a first deep venous thrombosis. During recent years, it has been established that there is a strong interaction between the more common prothrombotic risk factors (FV Leiden, PT 20210A) and current use of oral contraceptives. This was first shown by Vandenbroucke et al. in 1995 for deep vein thrombosis [25]. Female carriers of FV Leiden using oral contraceptives have a thirty-four-fold increased risk of a first deep vein
Thrombophilia and pregnancy
Pregnancy is considered to be a condition associated with an increased risk for venous thrombosis. The observation that prothrombotic risk factors are very prevalent among women who experienced venous thrombosis during pregnancy or puerperium, indicates that the presence of other risk factors than pregnancy importantly contribute to the risk. Of course, the more common genetic risk factors (FV Leiden, PT20210A) are more prevalent among these women than PC-, PS- and AT-deficiencies [28]. The
Summary
Venous thrombosis is a complex disease defined by multiple interactions between genetic and environmental components. One or more genetic risk factors for venous thrombosis can be found in about 2/3 of the families with thrombophilia. In the other 1/3, we cannot find any genetic risk factor. So there is still important information missing. The growing number of studies that report on gene–gene and gene–environment interactions has largely contributed to the concept that in an individual the
References (35)
- et al.
Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study)
Blood
(1995) - et al.
High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance)
Blood
(1995) - et al.
A common genetic variation in the 3′ untranslated region of the prothrombin gene is associated with elevated prothrombin levels and an increase in venous thrombosis
Blood
(1996) - et al.
Role of clotting factor VIII in effect of von Willebrand factor on occurence of deep-vein thrombosis
Lancet
(1995) - et al.
Venous thromboembolic disease and ABO blood type
Lancet
(1969) The protein C anticoagulant system: inherited resistance to activated protein C as basis for venous thrombosis
Thromb. Res.
(1995)- et al.
Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect
Lancet
(1993) - et al.
Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families
Blood
(1994) - et al.
Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S
Blood
(1995) - et al.
Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation
Lancet
(1994)
Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral anti contraceptives
Am. J. Obstet. Gynecol.
The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis
Am. J. Obstet. Gynecol.
Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G 20210 A and methylene tetrahydrofolate reductase C677T mutation
Am. J. Obstet. Gynecol.
Venous thrombosis: a multicausal disease
Lancet
Thrombophilia as a multigenic disorder
Thromb. Haemost.
Factor V Leiden and other coagulation risk factor mutations affecting thrombotic risk
Clin. Chem.
Inherited antithrombin III deficiency causing thrombophilia
Thromb. Diath. Haemorrh.
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