Large-vessel occlusion in sickle cell disease: pathogenesis, clinical consequences, and therapeutic implications

Much of the morbidity and mortality in sickle cell disease (SCD) is caused by tissue ischemia and infarction resulting from vascular occlusion. Research in this area has been dominated by the hypothesis that vascular occlusion in SCD is due primarily to microvascular obstruction by sickle erythrocytes (SS RBC), yet there is no direct evidence that microvascular occlusion is responsible for any of the vasocclusive complications of SCD. In this paper an alternate hypothesis is proposed: that thrombotic occlusion of larger arteries and veins is an important factor in many of the vasocclusive complications of SCD. Large-vessel cerebral arterial disease (intimal hyperplasia with superimposed thrombosis) has clearly been established as the most important cause of stroke in SCD, and considerable evidence suggests that pulmonary arterial thrombosis/embolism is a major cause of pulmonary infarction and hypertension. The involvement of large-vessel thrombosis in painful crisis, aseptic necrosis of bone, priapism, leg ulcers, retinopathy, and miscarriage has not been adequately investigated. Large-vessel occlusion in SCD is probably a consequence of the abnormal adhesive and procoagulant properties of SS RBC, which produce endothelial damage, secondary intimal proliferation, and thrombosis. Techniques currently used to treat large-vessel occlusion in other disorders (antiplatelet and anticoagulant agents, thrombolytic therapy, angioplasty, endarterectomy, and vascular bypass surgery) should be considered in sickle cell subjects with large-vessel occlusion, especially in the cerebral vasculature.