Excerpt from Hemostatic Disorders, Nonplatelet


Synonyms, Key Words, and Related Terms: afibrinogenemia, dysfibrinogenemia, nonplatelet hemostasis, coagulation, thrombosis, thromboses, clotting, thrombophilia, hemorrhage, bleeding, factor V deficiency, FV deficiency, Owren disease, parahemophilia, factor VII deficiency, FVII deficiency, factor VIII deficiency, FVIII deficiency, factor X deficiency, FX deficiency, factor XI deficiency, FXI deficiency, factor XII deficiency, FXII deficiency, factor XIII deficiency, FXIII deficiency, factor V Leiden deficiency, disseminated intravascular coagulation, DIC, protein C deficiency, activated protein C resistance, aPCR, protein S deficiency, hemophilia, antithrombin III deficiency, hemostatic disorders, hypoprothrombinemias, cryoglobulinemias, multiple myeloma, Waldenstrom macroglobulinemia, Henoch-Schönlein purpura, hyperglobulinemic purpura, cavernous hemangioma, hereditary hemorrhagic telangiectasia, pseudoxanthoma elasticum, Ehlers-Danlos syndrome, scurvy, Cushing syndrome, Shwartzman phenomenon, vitamin K deficiency, von Willebrand disease, Waterhouse-Friderichsen syndrome, Wiskott-Aldrich syndrome

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Blood coagulation is triggered by the exposure of tissue factor at injury sites, leading to the generation of minute quantities of thrombin. Thrombin, in turn, activates platelets, factors XI, VIII, and V, and triggers the sequential activation of factors XI, IX, X, and prothrombin on the activated platelet surface, leading to the generation of sufficient thrombin to convert fibrinogen to fibrin and affect hemostasis. Platelets localize coagulation to the hemostatic thrombus and protect coagulation enzymes from inhibition by both plasma and platelet inhibitors thus preventing disseminated intravascular coagulation (DIC). Abnormalities in this pathway can lead to abnormal hemostasis that is independent of the platelet protective mechanisms; these may be inherited or acquired.

Disorders of nonplatelet hemostasis can be divided into 2 groups based on whether they increase or decrease coagulation. The former may lead to thrombosis, the latter to hemorrhage. Such a division is not absolute, since some disorders may have both hemorrhagic and thrombotic manifestations. The following list divides known disorders into these groups:

Disorders of nonplatelet hemostasis

  • Coagulation-promoting conditions

    • Procoagulant afibrinogenemia/dysfibrinogenemia

    • Protein C deficiency

    • Protein S deficiency

    • Antithrombin III deficiency

    • Factor V Leiden deficiency

    • Activated protein C resistance (aPCR)

    • DIC

  • Coagulation-impeding conditions

    • Anticoagulant afibrinogenemia/dysfibrinogenemia

    • Factor V deficiency

    • Factor VII deficiency

    • Factor X deficiency

    • Factor XI deficiency

    • Factor XII deficiency

    • Factor XIII deficiency

    • Hemophilia A

    • Hemophilia B

    • Hypoprothrombinemias

Hemostatic disorders may also be separated according to origin, ie, inherited or acquired.

Pathophysiology

Fibrinogen disorders may have both congenital and acquired etiologies. They may be qualitative and quantitative. Congenital afibrinogenemia is defined as a deficiency or absence of fibrinogen (coagulation factor I) in the blood. Dysfibrinogenemias are classified as qualitative alterations in the conversion of fibrinogen to fibrin that are caused by structural defects.

Approximately 300 abnormal fibrinogens have been reported, and about 83 structural defects have been identified (Martinez, 1997). The most common structural defect involves the fibrinopeptides and their cleavage sites; the second most common involves the gamma-chain polymerization region.

Mechanisms of dysfibrinogenemias vary and include impaired release of fibrinopeptides, defective fibrin polymerization, abnormal cross-linking by factor XIIIa, abnormal interactions with platelets, defective fibrinolysis, defective assembly of the fibrinolytic system, and abnormal calcium binding. Some patients with dysfibrinogenemia have additional hemostasis defects, including antithrombin, protein C, protein S, and factor V Leiden deficiencies (Mosesson, 1999).

The true prevalence of congenital fibrinogen disorders is unknown. The condition appears to be rare, however, with only 250 cases reported as of 1995 (Haverkate, 1995). Of these patients, 55% were asymptomatic (their cases detected by chance), 25% had bleeding symptoms, and 20% presented with thrombosis. The prevalence of dysfibrinogenemia in patients with a history of venous thrombosis is low (0.8%), as deduced from 9 studies in 7 countries on 2376 subjects (Haverkate, 1995). No variation by race, age, or sex is known. Mortality is related to the severity of bleeding and/or to thrombotic complications at presentation.

Presentation

While most patients with dysfibrinogenemia are clinically asymptomatic, some present with a bleeding diathesis, others with thrombophilia, and others with both bleeding and thromboembolism (Mosesson, 199 .....

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