Hereditary Disorders of Fibrinogen

Abstract

Fibrinogen, a 340‐kDa plasma protein, is composed of two identical molecular halves each consisting of three non‐identical Aα‐, Bβ‐ and γ‐chain subunits held together by multiple disulfide bonds. Fibrinogen is shown to have a trinodular structure; that is, one central nodule, the E domain, and two identical outer nodules, the D‐domains, linked by two coiled‐coil regions. After activation with thrombin, a pair of binding sites comprising Gly‐Pro‐Arg is exposed in the central nodule and combines with its complementary binding site a in the outer nodule of another molecules. By using crystallographic analysis, the α‐amino group of αGly‐1 is shown to be juxtaposed between γAsp‐364 and γAsp‐330, and the guanidino group of αArg‐3 between the carboxyl group of γAsp‐364 and γGln‐329 in the a site. Half molecule‐staggered, double‐stranded protofibrils are thus formed. Upon abutment of two adjacent D domains on the same strand, D‐D self association takes place involving Arg‐275, Tyr‐280, and Ser‐300 of the γ‐chain on the surface of the abutting two D domains. Thereafter, carboxyl‐terminal regions of the α‐chains are untethered and interact with those of other protofibrils leading to the formation of thick fibrin bundles and networks. Although many enigmas still remain concerning the exact mechanisms of these molecular interactions, fibrin assembly proceeds in a highly ordered fashion. In this review, these molecular interactions of fibrinogen and fibrin are discussed on the basis of the data provided by hereditary dysfibrinogens on introducing representative molecules at each step of fibrin clot formation.

Hereditary fibrinogen A α-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

“…The gene for the fibrinogen A ␣-chain with 610 amino acid residues is localized on chromosome 4 and has 6 exons. 30 Mutations in any of the 3 genes encoding for fibrinogen polypeptides can cause dysfibrinogenemias, and recently identified mutations in the A ␣-chain gene can lead to hereditary systemic amyloidosis. 12 Six amyloidogenic mutations in the fibrinogen A ␣-chain gene have been described to date.…”

Identification of Respective Lysine Donor and Glutamine Acceptor Sites Involved in Factor XIIIa-catalyzed Fibrin α Chain Cross-linking

“…Previous studies have shown that naturally occurring truncated forms of fibrin ␣ chains retain certain cross-linking capabilities (48,49). It is believed that the retention of cross-linking on degraded fibrin ␣ chains balances the fibrinolytic process and maintains the stability of the fibrin network.…”

Fibrinogen Philadelphia, a hypodysfibrinogenemia characterized by abnormal polymerization and fibrinogen hypercatabolism due to γ S378P mutation

“…10,11 Genetic disorders involving fibrinogen have been classified as quantitative alterations (mainly afibrinogenemia and hypofibrinogenemia), alterations of function (dysfibrinogenemia), and combined defects (hypodysfibrinogenemia). [12][13][14] Approximately 300 families with dysfibrinogenemia have been described and more than 50 molecular defects have been identified. 12,15,16 The clinical expression of dysfibrinogenemias varies; roughly 60% are clinically silent, and the other 40% are almost equally associated with bleeding and thrombosis, and in few instances the abnormal fibrinogen is associated with both manifestations.…”