Upon completion of the 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.
Calculate an appropriate factor-concentrate dose for a product, given the percentage correction desired based on clinical situation.
List possible complications from hemophilia-induced 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 (vWD).
Describe various recessively inherited coagulation disorders (RICDs) and the role of specific factor replacement in RICD management.
Recommend first-and second-line treatment approaches for immune thrombocytopenia (ITP).
Identify basic clinical features, causes, and management of select thrombotic microangiopathies (TMAs).
Components of Hemostatic System
Following vessel injury, the endothelium is activated, and a series of physiological responses to prevent bleeding are initiated. The endothelial response involves vasoconstriction, platelet plug formation, coagulation, and fibrinolysis regulation. Under 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, and thrombin), and (c) aggregation. The chemical factors that are released from the injured tissue and platelets activate coagulation cascade and formation of thrombin. In turn, thrombin catalyzes conversion of fibrinogen to fibrin and its subsequent incorporation into the platelet plug. In parallel with coagulation, the fibrinolytic system is activated locally. Plasminogen is converted to plasmin, which dissolves the fibrin mesh (Figure 70–1).1
Coagulation and thrombolytic cascade model. This model shows successive activation of coagulation factors proceeding from the top to the bottom where thrombin and fibrin are generated. (Ca2+, calcium; PAI, plasminogen activator inhibitor; PL, phospholipids; TF, tissue factor [thromboplastin]; TFPI, tissue factor pathway inhibitor; t-PA, tissue plasminogen activator; vWf, von Willebrand factor. All clotting factors are shown as Roman numerals and the addition of an “a” indicates “activated.”) (From Hammer GD, McPhee SJ. Blood disorders. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8th ed.; 2019, Figure 6–5.)
INHERITED COAGULATION DISORDERS
Epidemiology and Etiology
Hemophilia A (classic hemophilia) and B (Christmas disease) are coagulation disorders (RICDs) that result from defects in the genes encoding for plasma coagulation proteins, factor VIII (FVIII) and factor IX (FIX), respectively. The incidences of hemophilia A and B are estimated at 1 in 5000 and 1 in 30,000 male births. The disease manifests as mostly spontaneous bleedings that are either intra-articular, with 70%–80% of episodes that can lead to painful muscle atrophy and arthropathy in turn resulting in poor ...