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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.
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These changes include thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis, and platelet activation.
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Limited studies to date suggest that biomarkers of activation can be affected by currently available antithrombotic drugs, and
Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics
Section snippets
Key points
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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Cited by (38)
Thrombin generation in vivo and ex vivo in sickle cell disease patients
2021, Thrombosis ResearchCitation Excerpt :A link between sickle red blood cells, the coagulation system, and SCD pathophysiology has long been investigated and activation of the coagulation system and inflammation are important features of this disease [7]. Procoagulant hemostatic changes and the high prevalence of thrombotic complications in SCD certify that this disease predisposes to a state of hypercoagulability [8–12]. Studies have sought to identify how hemostatic biomarkers are expressed in SCD considering variables such as genotype, age, the use or not of hydroxyurea (HU) and clinical conditions (clinical stability or complications, mainly vasocclusive) [1,13–16].
Association between MTHFR 677C>T polymorphism and vascular complications in sickle cell disease: A meta-analysis
2019, Transfusion Clinique et BiologiqueSickle cell disease: Hemostatic and inflammatory changes, and their interrelation
2019, Clinica Chimica ActaCitation Excerpt :PAI-1 inhibits tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA), thus preventing the conversion of plasminogen to plasmin [91]. Plasmin is an enzyme that cleaves the fibrin clot in degradation products, being D-Dimer (D-Di), a fragment widely used as a biomarker for coagulation activation [92] in disseminated intravascular coagulation and in venous thromboembolism diagnosis and monitoring [58]. PAI-1 is synthesized by several cell types (e.g. vascular endothelium, platelets, hepatocytes and fibroblasts) and its excess is related to thrombosis increased risk [93].
The role of platelets in sickle cell disease
2019, Platelets62 - The Lung in Sickle Cell Disease
2019, Kendig's Disorders of the Respiratory Tract in Children
Z. Pakbaz has no conflict of interest. T. Wun receives grant funding from Glycomimetics, Inc.