Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics

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Key points

  • Although the pathogenesis of sickle cell disease (SCD) lies in disordered hemoglobin structure and function, downstream effects of sickle hemoglobin include changes in the hemostatic system that overall result in a prothrombotic phenotype.

  • These changes include thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis, and platelet activation.

  • Limited studies to date suggest that biomarkers of activation can be affected by currently available antithrombotic drugs, and

Evidence for increased thromboembolic events in SCD

Stroke has an overall prevalence of 3.75% in patients with SCD and 11% in patients younger than 20 years with sickle cell anemia (HbSS), and is most often caused by large vessel arterial obstruction with superimposed thrombosis.20, 23 New and old thrombi in the pulmonary vasculature are prevalent in autopsy series.21, 24, 25 The analysis of a large discharge database in Pennsylvania from 2001 to 2006 found that the incidence of pulmonary embolism was 50-fold to 100-fold higher in the SCD

Evidence of hemostasis system alteration in SCD

The pathophysiology of hypercoagulability in SCD is multifactorial and is a result of alteration in almost every component of the hemostasis system (Table 1). These alterations in platelets, and procoagulant, anticoagulant, and fibrinolytic systems are overall prothrombotic.

Pathophysiology of hemostasis system activation in SCD

As shown previously, in SCD there is a chronic increase in plasma markers of thrombin generation, decrease in natural anticoagulants, and inhibited fibrinolytic system, and some data show these changes are accentuated during a VOC. Although the role of genetic predisposition for thrombophilia in SCD (separate from the sickle cell mutation itself) is still under investigation, several other factors have been identified as contributors to the altered hemostatic system in SCD. Although some of

Genetic predisposition for thrombophilia in SCD

Genetic modifiers with functional effects on the hemostatic system have been studied in patients with SCD. Many of the thrombophilic mutations described to date are not prevalent in people of African descent.117, 118 However, in some populations, patients with SCD might be carrying thrombophilic mutations more than the general population. Studies of human platelet alloantigen (HPA) polymorphism showed a possible prothrombotic role in these patients. Few investigators have studied the role of

Therapeutic implications of hemostatic system activation in SCD

Although hemostatic activation is somewhat downstream in the SCD pathophysiological cascade, it is plausible that a therapy targeted at decreasing platelet and coagulation activation might ameliorate or prevent sickle cell–related complications. This is analogous to the use of platelet inhibitors in atherosclerotic vascular disease and anticoagulants in venous thromboembolism. The underlying pathogenesis is not targeted; nonetheless, blocking downstream effects does decrease the incidence and

Summary

Although the pathogenesis of SCD lies in disordered hemoglobin structure and function, downstream effects of sickle hemoglobin include changes in hemostatic system that overall result in a prothrombotic phenotype. These changes include thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis, and platelet activation. Limited studies to date suggest that biomarkers of activation can be affected by currently available antithrombotic drugs, and provocative data from pilot

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    Z. Pakbaz has no conflict of interest. T. Wun receives grant funding from Glycomimetics, Inc.

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