Role of the coagulation system in the pathogenesis of sickle cell disease

Abstract

Sickle cell disease (SCD) is an inherited monogenic red blood cell disorder affecting millions worldwide. SCD causes vascular occlusions, chronic hemolytic anemia, and cumulative organ damage such as nephropathy, pulmonary hypertension, pathologic heart remodeling, and liver necrosis. Coagulation system activation, a conspicuous feature of SCD that causes chronic inflammation, is an important component of SCD pathophysiology. The key coagulation factor, thrombin (factor IIa [FIIa]), is both a central protease in hemostasis and thrombosis and a key modifier of inflammation. Pharmacologic or genetic reduction of circulating prothrombin in Berkeley sickle mice significantly improves survival, ameliorates vascular inflammation, and results in markedly reduced end-organ damage. Accordingly, factors both upstream and downstream of thrombin, such as the tissue factor–FX complex, fibrinogen, platelets, von Willebrand factor, FXII, high-molecular-weight kininogen, etc, also play important roles in SCD pathogenesis. In this review, we discuss the various aspects of coagulation system activation and their roles in the pathophysiology of SCD.

The Effect of Use of Individualized Pain Plans in Sickle Cell Patients Presenting to the Emergency Department

“…It is possible that such patients have increased hemolysis and severe disease. There are many proposed mechanisms by which hemolysis may lead to the hypercoagulability observed in SCD patients, including endothelial activation and thrombin formation, 13 increased inflammation, 14 and free-hemoglobin-induced oxidative damage. 15 This alludes to the potential of more severe disease in patients with history of venous thromboembolism, thereby leading to more hospitalizations.…”

Recent Advances in the Treatment of Sickle Cell Disease

“…Unraveling these pathophysiological targets has provided insights on clinical trials on anti-platelet and anti-adhesion agents, as well as anti-coagulation factors for the prevention of acute VOC pain in SCD (Telen, 2016;Nasimuzzaman and Malik, 2019;Telen et al, 2019). A case in point is the development of an anti-P-selection molecule (Crizanlizumab) for treatment of sickle VOC, recently approved by the FDA in November 2019 and marketed as Adakveo R .…”

“…Increased expression and activation of normally inactive erythroid adhesion molecules promote cytoadherence of sickle RBCs to the endothelium accompanied by platelets and leukocytes. Activated leukocytes and platelets further increase the risk to develop VOC (Nasimuzzaman and Malik, 2019;Sundd et al, 2019;Telen et al, 2019).…”

The molecular basis for the prothrombotic state in sickle cell disease

“…41,93 Moreover, overwhelming evidence for thrombin-mediated vasculopathy is derived from elegant studies in sickle mouse models. 40,41,94 In the aftermath of the initial thrombin burst generated by the TF-VIIa complex, a continuous supply of thrombin generation is required for pathological thrombosis. Thrombin generation is sustained in SCD patients even during the steady state, as demonstrated by the observation of elevated plasma levels of thrombin-anti thrombin complexes, D-dimers, and prothrombin fragment 1.2 [95][96][97] and elevated in vitro thrombin generation potential.…”

“…In addition to pathological thrombosis occurring as a result of the TF/VIIa complex (as described above), cell surface TF expression leads to inflammation. TF-mediated inflammation occurs either via the effects of downstream coagulation proteases (see above) on other vascular endothelial and blood cells 94 or intracellularly, via its cytoplasmic tail. 88 Thrombin's subsequent interaction with endothelial cell surface protease activating receptors (PAR) accentuates vascular endothelial inflammation in SCD.…”