Chapter 34

A 25-year-old woman presents to the emergency department complaining of acute onset of shortness of breath and pleuritic pain. She had been in her usual state of health until 2 days prior when she noted that her left leg was swollen and red. Her only medication was oral contraceptives. Family history was significant for a history of "blood clots" in multiple members of the maternal side of her family. Physical examination demonstrates an anxious woman with stable vital signs. The left lower extremity demonstrates erythema and edema and is tender to touch. Ultrasound reveals a deep vein thrombosis in the left lower extremity; chest computed tomography scan confirms the presence of pulmonary emboli. Laboratory blood tests indicate elevated D-dimer levels. What therapy is indicated acutely? What are the long-term therapy options? How long should she be treated? Should this individual use oral contraceptives?

Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs. Either extreme—excessive bleeding or thrombosis—represents a breakdown of the hemostatic mechanism. Common causes of dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer. The drugs used to inhibit thrombosis and to limit abnormal bleeding are the subjects of this chapter.

### Mechanisms of Blood Coagulation

The vascular endothelial cell layer lining blood vessels has an anticoagulant phenotype, and circulating blood platelets and clotting factors do not normally adhere to it to an appreciable extent. In the setting of vascular injury, the endothelial cell layer rapidly undergoes a series of changes resulting in a more procoagulant phenotype. Injury exposes reactive subendothelial matrix proteins such as collagen and von Willebrand factor, which results in platelet adherence and activation, and secretion and synthesis of vasoconstrictors and platelet-recruiting and activating molecules. Thus, thromboxane A2 (TXA2) is synthesized from arachidonic acid within platelets and is a platelet activator and potent vasoconstrictor. Products secreted from platelet granules include adenosine diphosphate (ADP), a powerful inducer of platelet aggregation, and serotonin (5-HT), which stimulates aggregation and vasoconstriction. Activation of platelets results in a conformational change in the α IIbβIII integrin (IIb/IIIa) receptor, enabling it to bind fibrinogen, which cross-links adjacent platelets, resulting in aggregation and formation of a platelet plug (Figure 34–1). Simultaneously, the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot, which stabilizes the platelet plug (see below). Knowledge of the hemostatic mechanism is important for diagnosis of bleeding disorders. Patients with defects in the formation of the primary platelet plug (defects in primary hemostasis, eg, platelet function defects, von Willebrand disease) typically bleed from surface sites (gingiva, skin, heavy menses) with injury. In contrast, patients with defects in the clotting mechanism (secondary hemostasis, eg, hemophilia A) tend to bleed into deep tissues (joints, muscle, retroperitoneum), often ...

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