Genetics of Bleeding Disorders

Genetic bleeding disorders form an important presentation among various genetic disorders occurring in children. A prevalence of 6 per 100,000 population has been reported in India. Bleeding disorders constitute a heterogenous group of disorders with varying clinical presentations. The common bleeding disorders are Hemophilia A and B, von Willebrand disease, and inherited thrombocytopenias. In addition, there are a number of other defects of coagulation pathway and platelet function, about which only limited knowledge is available. This review article attempts to organize the information available regarding the clinical presentations, molecular defects and methods available for molecular diagnosis of these disorders. Homeostasis maintains blood flow and the integrity of blood vessels. It involves coordinated action of more than 100 proteins. This complex, highly regulated system has evolved in higher organisms and consists of extensive interactions between the endothelial lining of the blood vessel, blood platelets and an intricate cascade of coagulation factors (Dahlbäck 2000) The diseases caused due to inherited defects in the hemostatic system can be broadly classified as: 1. Platelet number (thrombocytopenia) or function (thrombasthenia) defects 2. Coagulation factor defects The details of various disorders, inheritance, related clinical features, and investigations are shown in Table 1. EPIDEMIOLOGY OF BLEEDING DISORDERS IN INDIA There are a number of studies reporting on the prevalence of different types of bleeding disorders in India (Mehta and Agarwal 1981; Mohanty et al. 2002). A prevalence of 6 per 100,000 population has been reported with about 50,000 patients affected and 1300 new patients born every year in India (Mehta and Agarwal 1981; Chandy et al. 1993; Pandey 2003). Shanthala Devi et al. (1999) reported a study of 430 cases of bleeding disorders, of which 266 were due to inherited coagulopathies, 21 were due to qualitative platelet defect and 17 due to acquired coagulation defect. A study from western part of India reported on 630 patients, diagnosed to have hereditary bleeding diathesis. Amongst these, 598 (95%) patients had a coagulation disorder and 32 (5%) patients had a platelet function abnormality. In a group of coagulation disorders, hemophilia A (70.5%) was the most common disorder followed by hemophilia B (14%) and von Willebrand disease (10.8%). However Glanzman’s thrombasthenia (84.3%) was found to be the most common platelet function disorder followed by Bernard-Soulier syndrome (12.5%) (Manisha 2002). Kashyap et al. (1996) reported a series of rare inherited defects of coagulation which included 8 of factor X deficiency, 7 of factor XIII, 4 each with factor VII and fibrinogen deficiency and 1 patient with factor V deficiency. Molecular Pathophsiology of Bleeding Disorders Since the cloning and characterization of the first coagulation factor gene in 1982, remarkable progress has been made in the use of molecular genetic strategies to assist in diagnosis of bleeding disorders.