Font Size: a A A

A Molecular Study Of Hereditary Bleeding And Thrombosis Associated Disorders

Posted on:2004-07-30Degree:DoctorType:Dissertation
Country:ChinaCandidate:H ZhengFull Text:PDF
GTID:1104360125957254Subject:Pathology and pathophysiology
Abstract/Summary:PDF Full Text Request
An inherited deficiency or dysfunction of the coagulation co-factor VIII (FVIII) results in hemophilia A, an X-linked recessive blood coagulation disorder. Hemophilia A is the most common severe inherited bleeding disorder with a prevalence of 1 in 5000 males.While approximately 45% of the cases of severe hemophilia A are due to the same gene inversion mutation, the genetic changes which are responsible for most cases of hemophilia A represent private mutations that have been found only rarely in other patients with hemophilia A. Most of the causative mutations identified from mild hemophilia A are missense changes.The inherited factor XIII deficiency is a severe bleeding disorder and affects all races and both sexes equally. It is inherited as autosomal recessive trait. In the majority of cases, inherited FXIII deficiency is commonly due to absence of the factor XIII-A subunit protein in the plasma and platelet. Over 200 cases have been reported from all parts of the world.The inherited FXIII deficiency is a highly heterogeneous disorder. To date, 47 different mutations of FXIII deficiency have been identified from FXIII A gene. All of them are family private mutations.Early diagnosis and treatment are the keys to minimizing the long-term complications of these hemorrhages.An extremely high prevalence of hemophilia A has been identified in Newfoundland and Labrador. The inhabitants of the island of Newfoundland consist mainly of descendants of English and Irish settlers who arrived in the 17th and 18th centuries. The geographical and social isolation of this island has ensured very little inward migration for several hundred years, thus has led to a small population with a relatively homogenous genetic background.Approximately 90% of hemophilia A patients identified from the Newfoundland province are mild hemophilia A. The great majority of those patients are originally from either an isolated Twilligate (Newfoundland) population (approximately 44 in 3,300 males) or a Forteau (Labrador) population (estimated 14 in 260 males). To investigate the bleeding disorder in Twilligate population, family histories from these patients enables us to link all affected individuals to one very large kindred that comprises more than 1 630 family members spanning ten generations. In Forteau population, all of 14 presently identified affected patients have been linked to one big kindred with approximately 567 individuals in six generations. Extremely high prevalence in small isolated population usually suggests a strong possibility of causative founder effects.The pathogenesis of myocardial infarction (MI) may involve an interaction between environmental influences and genetic predisposition. Genetic factors involving blood coagulation may contribute to the pathogenesis of atherosclerosis as well as play a role in the clinical progression to plaque rupture and localized occlusive thrombus formation. The gene variants, Factor V Leiden (FVL-R506Q) and prothrombin G20210A (FIIG20210A) are the two most commonly recognized genetic prothrombotic risk factors for venous thrombosis. Based on the increased thrombotic tendency in venous thrombosis studies, these two gene variants have also been examined for possible association with arterial thrombosis in MI. In contrast, a common gene variant, factor XIII-A Leu34 (FXHI-A Leu34) has recently been suggested to confer a protective role against MI based on a lower prevalence of FXIIIV34L in MI patients compared with controls. However, conflicting results have been also reported. Therefore, the role of these three gene variants in the pathogenesis of MI remains to be defined.Our analysis was not only attempted to correlate MI with each of the three gene variants but also examined possible gene-gene interactions among the three gene variantsin MI. The heterogeneous geographic and ethnic distributions for the FIIG20210A, FVL and FXIII-A Leu34 variants had been found world wide even within different Caucasian population. Determination of these gene frequencies in the Newfoundlan...
Keywords/Search Tags:bleeding disorder, coagulation factor, hemophilia A, FXIII deficiency, thrombosis, myocardial infarction, gene variant, allele frequency
PDF Full Text Request
Related items