Upon completion of this chapter, the reader will be able to:
Describe the basics of the regulation of hemostasis and thrombosis.
Select appropriate nonpharmacological and pharmacological therapy for a patient with hemophilia in a given clinical situation and patient-specific scenario.
Calculate an appropriate factor-concentrate dose for a product, given the percentage correction desired based on clinical situation.
List possible complications from hemophilia bleeding episodes.
Choose an appropriate treatment strategy for patients with factor VIII or IX inhibitors.
Devise a treatment plan for a patient with a specific variant of von Willebrand disease.
Describe various recessively inherited coagulation disorders (RICDs) and role of specific factor replacement in RICD management.
Recommend first-line and a second-line treatment approaches for immune thrombocytopenic purpura.
Identify basic clinical features, causes, and management of thrombotic thrombocytopenic purpura.
Components of the Hemostatic System
Following endothelial injury, vessel-wall response involves vasoconstriction, platelet plug formation, coagulation, and fibrinolysis regulation. In normal circumstances, platelets circulate in the blood in an inactive form. After injury, platelets undergo activation, which consists of (a) adhesion to the subendothelium, (b) secretion of granules containing chemical mediators (eg, adenosine diphosphate, thromboxane A2, thrombin, etc), and (c) aggregation. Chemical factors released from the injured tissue and platelets stimulate the coagulation cascade and thrombin formation. In turn, thrombin catalyzes the conversion of fibrinogen to fibrin and its subsequent incorporation into the platelet plug.
The coagulation system consists of intrinsic and extrinsic pathways. Both pathways are composed of a series of enzymatic reactions that ultimately produce thrombin, fibrin, and a stable clot. In parallel with the coagulation, the fibrinolytic system is activated locally. Plasminogen is converted to plasmin, which dissolves the fibrin mesh (Figure 67–1).1
Cascade model of coagulation demonstrates activation via the intrinsic or extrinsic pathway. This model shows successive activation of coagulation factors proceeding from the top to the bottom where thrombin and fibrin are generated. (PK, prekallikrein; HK, high–molecular weight kininogen; TF, tissue factor.) (From Roberts HR et al. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Lichtman MA, Beutler E, Coller BS et al, eds. Williams Hematology, 7th ed. New York: McGraw-Hill, 2006:1665–1694.)
INHERITED COAGULATION DISORDERS
Etiology and Epidemiology
Hemophilia A and B are coagulation disorders that result from defects in the genes encoding for plasma coagulation proteins. Hemophilia A (classic hemophilia) is caused by the deficiency of factor VIII, and hemophilia B (Christmas disease) is caused by the deficiency of factor IX. The incidences of hemophilia A and B are estimated at 1 in 5000 and 1 in 30,000 male births, respectively. Both types of hemophilia are evenly distributed across all ethnic and racial groups.1