Coagulation factors deficiencies

Several disorders of coagulation and fibrinolysis have been identified that lead to thrombosis or bleeding. These include von Willebrand disease (vWD), hemophilia, coagulation factor deficiencies, acquired/congenital inhibitors of coagulation, and antiphospolipid syndrome. 

Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 427(6974) 537 L... 

The term coagulation factor deficiency is frequently ambiguous. Previously, it implied a deficit in the functional activity of a component because the clotting time tests measured only the ability of the component to support normal coagulation. The reference for normal functionality is the response of dilutions of plasma from pooled... 

Coagulation disorders result from a decreased number of platelets, decreased function of platelets, coagulation factor deficiency, or enhanced fibrinolytic activity. A series of complex actions and reactions of procoagulant and anticoagulant events regulate blood flow. Maintenance of blood flow involves the interplay of four major components (1) the vessel wall, (2) platelets, (3) the coagulation system, and (4) the fibrinolytic system. 

Spontaneous bleeding usually occurs when the activity of coagulation factors falls below 5% of normal. Typically, these deficiencies are the result of a chronic disease state, such as von Willebrand s disease or hemophilia. Management of an acute hemorrhagic event in a coagulation factor-deficient patient includes administration of the appropriate factors in concentrated form. The... 

Recessively inherited coagulation disorders (RICDs) refer to relatively rare deficiencies in factor II, V, VII, and X-XIII resulting in either decreased clotting factor production or production of a dysfunctional molecule with reduced activity.19 The clinical severity of bleeding varies and generally is poorly correlated with the factor blood levels. Table 64-6 illustrates these clotting factor deficiencies and some of their characteristics. 

The main goal of recessively inherited coagulation disorder (RICD) treatment is to prevent and control spontaneous and surgery-related bleeding episodes. Specifically, therapeutic options improve hemostasis via replacement of deficient blood coagulation factors while minimizing the development of immune tolerance.20... 

Vitamin K (phylloquinone) and similar substances with modified side chains are involved in carboxylating glutamate residues of coagulation factors in the liver (see p. 290). The form that acts as a cofactor for carboxylase is derived from the vitamin by enzymatic reduction. Vitamin K antagonists (e. g., coumarin derivatives) inhibit this reduction and consequently carboxylation as well. This fact is used to inhibit blood coagulation in prophylactic treatment against thrombosis. Vitamin K deficiency occurs only rarely, as the vitamin is formed by bacteria of the intestinal flora. 

Clinical pharmacology Activated factor IX in combination with activated factor VIII activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed. Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of Coagulation Factor IX (Recombinant) increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients. 

Factor VIII (FVIII) is an essential coagulation factor in the blood which serves as a cofactor in the complex blood-clotting cascade. A deficiency in FVIII is the... 

Replacement of deficient gene products or even of organs is also utilized in the treatment of genetic disorders for example, replacement of coagulation factor VIII in hemophilia A, of or-antitrypsin in persons deficient in this factor or of pancreatic islet cells in some forms of diabetes mellitus. 

Freeze-dried concentrates of plasma containing prothrombin, factors IX and X, and varied amounts of factor VII (Proplex, etc) are commercially available for treating deficiencies of these factors (Table 34-3). Each unit of factor IX per kilogram of body weight raises its activity in plasma 1.5%. Heparin is often added to inhibit coagulation factors activated by the manufacturing process. However, addition of heparin does not eliminate all thromboembolic events. 

Vandendriessche, T., Vanslembrouck, V., Goovaerts, I., Zwinnen, H., Vanderhaeghen, M. L., Collen, D. and Chuah, M. K. (1999). Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VUI-deficient mice. Proc. Natl. Acad. Sci. USA 96, 10379-10384. 

Vitamin K is essential for the synthesis of coagulation factors II, VII, IX, X, and proteins C and S. About half of the daily requirement is synthesized by the gastrointestinal flora. Deficiency leads to an impairment in the coagulation cascade, clinically presenting as purpura, ecchymoses, and hemorrhage anywhere in the body.29 The recommended daily allowance is 90 fig for females and 120 fig for males.71... 

Lin H-F, Maeda N, Sithies O et al. (1997) A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90 3962-3966... 

Cui J, O Shea KS, Purkayastha A et al. (1996) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384 66-68 Yang TL, Cui J, Taylor JM et al. (2000) Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression. Thromb Haemost 83 70-77... 

Dewerchin M, Liang Z, Moons L et al. (2000) Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 83 185-190... 

Connolly AJ, Ishihara H, Kahn ML et al. (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381 516-519 Cui J, O Shea KS, Purkayastha A et al. (1996) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384 66-68 Denis C, Methia N, Frenette PS et al. (1998) A mouse model of severe von Willebrand disease defects in hemostasis and thrombosis. Proc Nad Acad Sci USA 95 9524-9529 Dewerchin M, Liang Z, Moons L et al. (2000) Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 83 185-190... 

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