Mightier than the sickle cell.

Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. from patients with heparin-induced thrombocytopenia/ thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. Validation of the high-heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia. No significant improvement in diagnostic specificity of an anti-PF4/polyanion immunoassay with use of high heparin confirmatory procedure. In this issue of Blood, Chang and colleagues demonstrate that a synthetic small molecule inhibitor designed to displace ligand binding to E-selectin disrupts key signaling and activation events leading to vaso-occlusion in SCD. 1 T he age-old adage " the pen is mightier than the sword " reminds us that creativity and innovation eventually triumph over brute force in solving difficult challenges. Case in point, sickle cell disease (SCD) is a prevalent genetic disorder that poses a significant clinical challenge as it manifests as recurrent vaso-occlusion and chronic organ damage that results in significant morbidity and mortality. The report by Chang et al demonstrates the efficacy of a novel synthetic small molecule pan-selectin inhibitor denoted GMI-1070 in reversing vascular occlusions observed in a mouse model expressing defective human hemoglobin. 1 GMI-1070, under development by GlycoMimetics Inc to treat SCD, is designed to occupy the carbohydrate docking domain of selectin receptors and thereby block the heterotypic adhesive interactions supported by the binding of sialyl Lewis-x decorated glycoproteins presented on an adjacent cell membrane. One such interaction is the capture of red blood cells (RBCs) by neutro-phils as they roll on inflamed endothelium via membrane-expressed E-selectin. Indeed, the Frenette laboratory recently reported that E-selectin is predominant over P-selectin in activating integrins that capture sickle RBCs at the leading edge of a rolling neutrophil during inflammation in mice. 2 In human SCD, there is evidence that neutrophils in blood express constitutively active ␤ 2-integrins and respond with enhanced sensitivity to chemo-kine activation of adhesion. 3 Thus, the genetic advantage afforded by the sickle cell allele that provides RBC resistance to malaria infection also promotes their abnormal adhesion to neu-trophils. It is reasonable to ask why nature selected such an impractical process by which the clustering of E-selectin ligands on neu-trophils dynamically signals activation of ␤ 2-integrins and adhesion leading to vaso-occlusion. Leukocyte lore has it that the primary activation signal received by a neutrophil as it recruits to an inflamed venule is via engagement of G-protein– coupled chemokine receptors that in turn …