Chapter 171

## Abstract

Abstract

1. Fibrinogen is a dimeric protein consisting of six polypeptide chains (αβγ)2 (MIM 134820, 134830, 134850) held together by disulfide bonds and folded in a trinodular structure where the globular nodules are connected by coiled coils. Thrombin converts fibrinogen to fibrin, which polymerizes into protofibrils through reciprocal half-staggered interactions. Protofibrils form macroscopic fibers through lateral aggregation and branch point formation. Crystallographic studies show that the polymerization pocket within the C-terminal region of the γ-chain is adjacent to but independent from the calcium-binding site. Fibrinogen is essential for platelet aggregation and wound healing. The genes for the constituent chains of fibrinogen are linked and are located on chromosome 4. Transcription of the fibrinogen genes is mediated by hepatocyte nuclear factor 1 and modulated by interleukin 6.

2. Genetic abnormalities of fibrinogen include afibrinogenemia (MIM 202400), hypofibrinogenemia, dysfibrinogenemia, and hyperfibrinogenemia. Afibrinogenemia is rare and is characterized by neonatal umbilical cord hemorrhage, intracranial and peritoneal bleeding, recurrent abortion, and autosomal recessive inheritance. Hypofibrinogenemia is characterized by fibrinogen levels below 100 mg/dl of plasma (normal 250–320 mg/dl) and can be inherited or acquired. The symptoms of hypofibrinogenemia are similar to but milder than those of afibrinogenemia. Dysfibrinogenemia is highly heterogeneous and may affect any one of the functional properties of fibrinogen, leading to manifestations that include hemorrhage, spontaneous abortion, and thrombosis. Most cases of dysfibrinogenemia are heterozygous for amino acid substitutions; homozygous occurrence is rare but known. Hyperfibrinogenemia is associated with an increased risk for myocardial infarction and stroke.

3. Factor XIII is a proenzyme for a plasma transglutaminase. It is converted to the active form, factor XIIIa, by thrombin in the presence of calcium ions. It catalyzes the formation of γ-glutamyl-ϵ-lysine bonds between fibrin monomers and between fibrin and α2-plasmin inhibitor. Factor XIII in plasma is a tetramer (A2B2) held together by noncovalent bonds. The A subunit contains the active site, and the B subunit is thought to stabilize the A subunit. The sequence around the active site is identical among all members of the transglutaminase family. The three-dimensional structure of the A subunit of factor XIII determined by x-ray crystallography demonstrated that it is composed of 5 distinct domains. The B subunit contains 10 tandem repeats, which have been designated as Sushi domains or GP-I structures. Homologous Sushi domains have been found in more than 30 other proteins/genes. The A subunit of plasma factor XIII is synthesized, in part, by hemopoietic cells, and is present in many tissues. The B subunit is synthesized in the liver.

4. The genes for the A and B subunits of factor XIII are localized at 6p24-p25 and 1q32-q32.1, respectively. Thus factor XIII deficiency is inherited as an autosomal recessive trait and is caused by the absence of either subunit. Recently, genetic defects have been identified at the DNA level in three patients with B-subunit deficiency (MIM 134580) and in 30 patients with A-subunit deficiency (MIM 134570). Their molecular and cellular bases also were explored in certain cases. This disease is characterized by delayed bleeding (“after bleeding”), though primary hemostasis is normal. Manifestations include neonatal bleeding from the umbilical cord, intracranial hemorrhage, and soft tissue hematomas. In addition, abnormal wound healing and recurrent spontaneous miscarriage are not rare. Infusion of factor XIII concentrates has been successful both for treatment of acute bleeding and for prophylaxis. Recombinant A subunit has been produced in yeast for clinical use.

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