Role of Extracellular Hemoglobin in Thrombosis and Vascular Occlusion in Patients with Sickle Cell Anemia

Abstract

Sickle cell anemia (SCA) is a common hemolytic disorder caused by a gene mutation in the β-globin subunit of hemoglobin (Hb) and affects millions of people. The intravascular hemolysis releases excessive amount of extracellular hemoglobin (ECHb) into plasma that causes many cellular dysfunctions in patients with SCA. ECHb scavenges NO which promotes crisis events such as vasoconstriction, thrombosis and hypercoagulation. ECHb and its degradation product, heme, are known to cause oxidative damage to the vessel wall and stimulate the expression of adhesive protein ligands on vascular endothelium. Our study shows that ECHb binds potently to VWF—largest multimeric glycoprotein in circulation—through the A2-domain, and significantly inhibits its cleavage by the metalloprotease ADAMTS13. Furthermore, a subpopulation of VWF multimers bound to ECHb exists in significant amount, accounting for about 14% of total plasma VWF, in SCD patients. The Hb-bound VWF multimers are resistant to ADAMTS13, and are hyperactive in aggregating platelets. Thus, the data suggest that Hb-bound VWF multimers are ultralarge and hyperactive because they are resistant to the protease. The Hb-bound VWF multimers are elevated parallely with the level of ECHb in patients' plasma, and is associated with the pathogenesis of thrombosis and vascular occlusion in SCA.

Venous Thromboembolism in Adults with Sickle Cell Disease: A Serious and Under-recognized Complication

“…1–3 Various mechanisms have been hypothesized to contribute to thrombogenesis in sickle cell disease patients including erythrocyte adhesion, 4 endothelial dysfunction, 5 leukocyte activation in the setting of chronic inflammation, 6 platelet aggregation, 7–10 coagulation defects, 11 and free hemoglobin-induced oxidative damage. 10, 12 Nitric oxide scavenging secondary to intravascular hemolysis also results in hypercoagulability in sickle cell disease and may be an important mediator of thrombotic complications. 10 While it is widely recognized that sickle cell disease is associated with a hypercoagulable state, most research has focused on in-situ thrombosis as the primary clinical manifestation, and previous reports investigating the risk and characteristics of venous thromboembolism have yielded conflicting results.…”

Creating adequate pulsatility with a continuous flow left ventricular assist device

“…Similarly to the above discussion on ventricular unloading, this phenomenon is not a direct consequence of low pulsatile flow but, rather, of continuous flow LVAD design, which employs a rotor mechanism. Although the exact pathophysiology of device thrombosis has not been elucidated, over the past few years a number of important observations have been made: (1) during transit through the rotors, blood elements are exposed to a shear stress well above that at which hemolysis occurs [41]; (2) as a result, there is a chronic low level hemolysis in all continuous flow LVADs, which appears to be greater in axial than in centrifugal pumps [42]; and (3) hemolysis, in addition to being a marker of device thrombosis, likely contributes to its development as a prothrombotic factor [43,44]. In this regard, pulsatility may be important for the pump itself by providing an intermittent 'wash out' of the rotors to prevent adherence of red blood cells and in turn decrease levels of hemolysis.…”

Fatal pulmonary thromboembolism associated with hemoglobin SC disease in a 15 year-old boy

“…HbC is also caused by a mutation in the beta chain, resulting in the substitution of glutamic acid by lysine. [2][3][4]6,7 Hemoglobin HbS shows peculiar biochemical properties, which leads to polymerization when deoxygenated. HbS polymerization leads to sickling of red blood cells.…”

“…Furthermore, the hemoglobin release inhibits endothelial nitric oxide signalling, leading to endothelial cell dysfunction and nitric oxide resistance. 6,7 In patients with sickle cell disease there is a hypercoagulable state due to high levels of thrombin, abnormal activation of fibrinolysis, decreased levels of anticoagulant proteins, activation of platelets and increased circulating levels of soluble tissue factor. 3,14,15 The painful vasoocclusive crises and osteomyelitis represent the most frequent complications requiring hospital admissions among patients with SCD.…”