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Hemostatic activation is a hallmark of sickle cell disease (SCD). Cellular activation and hyperadhesion, sterile inflammation, hemolysis, and hemostatic activation contribute to a chronic coagulopathy that exacerbates during vaso-occlusive episodes. This chapter will review the main clinical manifestations of thrombophilia in SCD and explore its pathogenic mechanisms, including the role of whole blood cellular components in the activation of the intrinsic and extrinsic coagulation pathways, the main alterations of procoagulant and anticoagulant pathways in SCD, and the role of hemolysis and nitric oxide depletion, with their downstream effects on endothelial and mitochondrial dysfunction. Finally, the role of established and novel therapeutic strategies will be discussed.

The Coagulation Cascade

The coagulation cascade refers to an interactive series of enzymatic reactions mediated by serine proteases and cofactors that collectively maintain hemostasis (the physiologic process of halting bleeding due to vascular injury). However, although these reactions are often presented as a series of sequential protein-protein interactions (Figure 22-1), they are in fact highly dependent on vascular and blood cell–dependent contributions. Exposure of tissue factor (TF), a transmembrane glycoprotein receptor, is considered to be the primary event in activation of coagulation. Under physiologic conditions, TF is expressed at high levels by perivascular cells and is essential for hemostasis. Following blood vessel injury, exposure of blood to TF results in the formation of a complex with circulating factor (F) VIIa that activates both FIX and FX. This is known as the extrinsic pathway of coagulation activation. The ultimate result is thrombin generation; thrombin cleaves soluble fibrinogen to form insoluble fibrin, activates platelets, and thereby results in platelet-fibrin clots that prevent blood loss. However, aberrant expression of TF by circulating blood cells or excessive exposure of perivascular TF resulting from breakdown of the endothelial barrier can promote unwanted intravascular thrombosis that results in impairment or cessation of blood flow.


Abnormalities of the coagulation cascade in sickle cell disease. F, factor; SCD, sickle cell disease; TF, tissue factor; TFPI, tissue factor pathway inhibitor. Used with permission from Lydia Perkins, PhD.

In addition to the extrinsic pathway, the coagulation cascade can be activated via FXIIa-dependent activation of FXI, with subsequent activation of FIX by FXIa. This mechanism is known as the intrinsic pathway. Although this pathway is readily demonstrable in blood ex vivo, controversy remains whether FXII/XIIa plays any role in thrombosis, although there is little doubt that FXI/FXIa is important. Thrombosis can occur in any vascular bed and may be divided into arterial, venous, or microvascular thrombosis. Arterial thrombosis is frequently the terminal event in myocardial infarction and ischemic stroke, whereas venous thrombosis results in deep vein thrombosis and may lead to pulmonary embolism. However, in addition to these macrovascular occlusive events, regional or systemic activation of coagulation (that is not in response to bleeding) may contribute in a subtler fashion ...

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