Dissertation > Medicine, health > Internal Medicine > Blood and lymphatic system diseases

Study on Molecular Pathology of Inheritary Deficiency of Factor V and Phenotype of 2A Type Von Wil Lebrand Disease

Author HouLiHong
Tutor YangLinHua
School Shanxi Medical
Course Hematological Diseases
Keywords Hereditary bleeding disorder Coagulation factor V deficiency Gene mutation Pedigree analysis Von Willebrand Clinical phenotype
Type PhD thesis
Year 2004
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Hereditary hemorrhagic diseases, including hereditary coagulation protein abnormalities caused by the lack of variety of clotting factor activity or functional defects. Von Willebrand disease (von Willebrand Disease, vWD), hemophilia A and hemophilia B common hereditary bleeding disorder, has been carried out in-depth study of molecular biology, genetic abnormalities found reached more than 1000 kinds of developed countries into the study of gene therapy. Rare clotting factor defect, such as FV, ??F Ⅺ, prothrombin and fibrinogen and other hereditary bleeding disorder caused by a lack due to sickness resources constraints, only a few reports worldwide, China is in its infancy. Coagulation factor V (factorV, FV) is a single chain of a molecular weight of approximately 333KD glycoprotein, under physiological conditions almost exist in an inactive state in the plasma. Under the action of thrombin, plasma FV is converted to the activation of the clotting activity of FV (activated Fv, FVA). FVa as a cofactor in the plasma, and F Ⅹ a, calcium and phospholipids (cell membrane) together constitute the prothrombin complex involved in the activation of prothrombin. F Ⅹ a catalytic prothrombin activation due to the the FVa participation, making the ability to increase the 104-5 times. FVa but also through the activation of protein C (activated protein C, APC) cleavage is inactivated by APC pathway directly or indirectly involved in the clotting process. Short, FV clotting process in promoting coagulation pathway and the cross point of the anti-coagulation pathway, plays a vital role in the maintenance of the coagulation balance. FV molecule consists of 2196 amino acid residues, comprising three homologous A region, a B region and two homologous C region, in the order A1-A2-B-A3-C1-C2. The molecule comprises a heavy chain region and a light chain region, the heavy chain region is located in the amino-terminal, composed of the A1 and A2 regions, a molecular weight of about 105 kD; light chain region is located in the carboxyl end, by A3, C1, and C2 regions, and a molecular weight of about 74 The the KD; heavy chain and light chain are connected by the Zone B. FV gene is located on chromosome 1q23, a total length of 80 Kb, contains 25 exons and 24 introns. Its cDNA about 7kB, coding for 28 amino acids of the mRNA in the leader peptide and the 2196 amino acid mature protein. The 1-12 exons encoding the signal peptide and A1-A2 District 13 coding exons complete Area B, 14-25 outside exon encoding A3-C1-C2 area. Depending on the generation mechanism, FV defects can lead to hereditary FV deficiency, causing bleeding; cause APCR cause thrombosis. lt; WP = 6 gt; hereditary coagulation factor V deficiency (hereditary deficiency of factor V) is a rare autosomal recessive hereditary hemorrhagic disease, the incidence is about one millionth. The disease is caused due to lack of the normal activity of plasma coagulation factor V. Heterozygotes are usually asymptomatic, and clinical manifestations of homozygous or compound heterozygous for varying degrees of bleeding, but most of them than hemophilia minor, and has the following laboratory features: prothrombin time (prothrombin time, PT) and activated partial thromboplastin time (activated partial thromboplastin time, APTT) were prolonged, and can be corrected by normal adsorbed plasma. The diagnosed often need clotting factor activity and antigen assay. In addition, should also note that except FV and other coagulation factors combined deficiency. Due to lack of hereditary FV the disease low incidence and FV gene complexity, few studies of its molecular mechanism. So far around the world on hereditary FV deficiency A Case reports of about 200 cases reported about 20 kinds of hereditary FV deficiency type of mutation, gene mutation types, including base substitutions, nucleotide insertion and base deletion etc., lead to nonsense mutations, frameshift mutations and missense mutations. Mutations were concentrated in exons coding region have been reported, almost all involving a single exon, and gene mutations occur in the exons encoding FV B 13, this might exon 13 (representing FV about 40% of the full-length cDNA). vWD (von Willebrand disease) is the most common hereditary bleeding disorder, one is due to the the plasma of vWF (von Willebrand factor) the quality or quantity of defects, and this defect is due to the vWF gene mutation caused. According to the results of the multi-center study estimated symptoms of vWD patients up to 113/106 or higher, and have vWD dangerous number of up to 1480-3580/106. vWF is a poly plasma glycoprotein. Plasma vWF to participate in various forms in vivo hemostatic process. On one hand, vWF plays an important role in the early hemostasis: endothelial cell injury, vWF subendothelial collagen combined with platelet membrane glycoprotein Gp Ⅸ and Gp Ⅱ b / Ⅲ a combination promote platelet activation, adhesion and aggregation. On the other hand, the plasma vWF and F Ⅷ in the form of non-covalently binding, plays a stable F VIII and prolong its half-life of the role. vWD is a highly heterogeneous disease. With the continuous study of the molecular basis of vWF the 1994 International hemostasis and thrombosis Committee based on the vWD clinical manifestations, pathological features and molecular pathological mechanism proposed new classification criteria will vWD divided into three types. Type 1 vWD refers to part of the lack of vWF amount. Plasma vWF function is normal, the polymer distribution normal or near normal. Type 2 vWD refers to abnormal vWF qualitative, but also often accompanied by abnormal amount, accounting for 20-30% of the vWD. Is divided into 2A, 2B, 2M and 2N four kinds of LT; WP = 7 GT; subtypes. Type 3 vWD the vWF primary completely lack Joint performance of initial hemostasis and coagulation defects. The F Ⅷ level is usually less than 10% of normal, a few less than 1% of spontaneous bleeding occurred joints and soft tissue. Type 2A vWD is the most common type of the exception vWF quality, which is characterized in plasma large, medium molecular weight polymers disappeared, and lead to functional deficiencies of vWF-dependent platelet adhesion. Clinical manifestations of mild to moderate bleeding, APTT may be normal or slightly longer, varying degrees of vWF antigen and activity reduction reflects vWF interaction with platelet ristocetin-induced platelet aggregation test (ristocetin-induced platelet aggregation, RIPA) was significantly reduced. The subject in the screening process outpatients with congenital bleeding tendency, found one case of severe coagulation factor V deficiency patients. Subsequently, than the the turbidimetric clotting factor activity was measured BA-ELISA method, Western blot, PCR, and its related technologies, such as biochemistry, immunology and molecular biology, a variety of methods, proband and family . Based on the clinical features of the proband clinical phenotype is a heavy-duty: born after earlier onset of more serious bleeding, including intracranial hematoma, gastrointestinal bleeding, as well as the past two years of joint bleeding and multiple abdominal bleeding. PT, APTT

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