Vascular complications of sickle cell disease

Abstract

Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the β-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These "vascular phenotypes" reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients with the disorder.

Keywords: Sickle cell disease; cerebral vasculopathy; nitric oxide; pulmonary hypertension; renal disease.

Fig. 1.

Model of overlapping subphenotypes of sickle cell disease. Published data suggest that patients with sickle cell disease with higher hemoglobin levels have a higher frequency of viscosity-vaso-occlusive complications closely related to polymerization of sickle hemoglobin, resulting in erythrocyte sickling and adhesion. Such complications include vaso-occlusive pain crisis, acute chest syndrome, and osteonecrosis. In contrast, a distinct set of hemolysis-endothelial dysfunction complications involving a proliferative vasculopathy and dysregulated vasomotor function, including leg ulcers, priapism, pulmonary hypertension, and possibly non-hemorrhagic stroke, is associated with low hemoglobin levels, and high levels of hemolytic markers such as reticulocyte counts, serum lactate dehydrogenase, plasma hemoglobin and arginase, producing a state of impaired nitric oxide bioavailability. The spectrum of prevalence and severity of each of these subphenotypes overlap with each other. ¹⁶Adapted from Kato et al. Blood Rev. 2007 January; 21(1): 37–47.

Fig. 2.

Salient pathogenic processes in the development of sickle cell nephropathy. Sickle cell nephropathy largely reflects an underlying functional vasculopathy. This vasculopathy leads to a perfusion paradox, wherein medullary hypoperfusion occurs in conjunction with kidney and/or cortical hyperperfusion. The renal vasculopathy also leads to aberrant renal vascular responses to stress that occur systemically or in distant organs and tissues. This response is characterized by enhanced renal vasoconstriction and resultant vasoocclusion. Recurrent cycles of ischemia and ischemia–reperfusion injury thus occur, thereby leading to subclinical and clinical acute kidney injury. These processes summate in the initiation and progression of sickle cell nephropathy. ^[131]Adapted from Nath et al. Nat Rev Nephrol. 2015;11 : 161–171.