Platelet activation and endothelial cell dysfunction in sickle cell disease is unrelated to reduced antioxidant capacity

Abstract

Possible pathogenetic processes in sickle cell disease include antioxidants, endothelial and platelet changes, and hypercoagulability. Hypothesizing relationships between these processes, we recruited 47 young adult patients (mean age 19 years) with homozygous sickle cell disease and 40 age-, race- and sex-matched healthy controls and measured plasma markers representative of these processes. We found raised plasma von Willebrand factor (P = 0.001) and intercellular adhesion molecule (P = 0.016, both marking endothelial perturbation, but the latter also marking inflammation), raised soluble P selectin (P = 0.002) (marking platelet activation) and inflammation marker C reactive protein (P = 0.021), but reduced antioxidant capacity (P = 0.002) in patients compared with controls. There was no difference in fibrinogen and there was no significant correlation between any of the indices. Our data suggest that changes in endothelial and platelet function in sickle cell disease are unrelated to reduced antioxidant capacity.

Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation

“…Mitochondrial dysfunction is associated with platelet activation and hemolysis SCD patients exhibit augmented platelet activation compared with healthy subjects. [13][14][15] This phenomenon was corroborated in our cohort in which SCD patient platelets showed a significantly greater percentage of activated platelets (21 6 6.9%; n 5 24) than controls (11.0 6 2.3%, n 5 19, P 5 .029; Table 1). Thus, we next sought to determine whether the bioenergetic dysfunction identified in SCD platelets was associated with aberrant platelet activation.…”

“…In addition to overt thrombus formation, activated platelets contribute to both acute and chronic vasculopathy in SCD patients through the secretion of soluble vasoactive and mitogenic factors, promoting vascular damage, red cell adhesion to the endothelium, and intimal hyperplasia. 13,14,[17][18][19] Consistent with this, augmented platelet activation observed basally in steady-state SCD patients is further elevated during acute vasoocclusive crisis and correlates with the severity of PAH, a chronic vascular proliferative complication and leading cause of mortality in adult SCD patients. [14][15][16][30][31][32] Although patients in vaso-occlusive For personal use only.…”

“…Although the primary dysfunction in SCD patients is the hypoxic polymerization of HbS, leading to diminished erythrocyte deformability and impaired microvascular blood flow, it is well documented that these patients demonstrate characteristics of chronic hemostatic activation, including elevated levels of platelet activation. [13][14][15][16] Although the molecular mechanism underlying this platelet dysfunction is unknown, platelet activation is associated with augmented erythrocytic hemolysis in these patients. 15 Clinically, platelet activation contributes to both acute and chronic vascular complications, including vaso-occlusive crisis and pulmonary arterial hypertension (PAH), through the secretion of vasoactive and mitogenic factors.…”

“…15 Clinically, platelet activation contributes to both acute and chronic vascular complications, including vaso-occlusive crisis and pulmonary arterial hypertension (PAH), through the secretion of vasoactive and mitogenic factors. 13,14,[17][18][19] Notably, although aberrations in mitochondrial redox signaling and bioenergetics have been implicated in the pathogenesis of both systemic 20 and pulmonary 21 vasculopathies, mitochondrial function has never been assessed in SCD patients.…”

Platelets and Thrombosis in Myeloproliferative Diseases

“…Intriguingly, some studies have suggested that cytoreductive therapy may not reverse all abnormal markers of platelet, coagulation pathway and endothelial activation; specifically plasma fibrinogen, Pselectin, von Willebrand factor and soluble vascular cell adhesion molecule (sVCAM). 17 Currently, the pathogenesis of platelet activation in MPD is unknown, although a large proportion of patients have a deficiency of lipoxygenase, which could increase availability of endoperoxides to produce thromboxane A2. 18 The same patients however have tendency to a hemorrhagic rather than thrombotic diathesis.…”