Fetal Hemoglobin Protects Against Activation of Hemostasis Endothelial and Circulating Blood Cells in Sickle Cell Anemia.

To determine whether fetal hemoglobin (HbF) protects against activation of hemostasis, endotheliium, and circulating blood elements, infants, children and young adults with homozygous SS disease (n=35) were studied. F-cell numbers, biomarkers of endothelial activation (including sVCAM-1, sE- and sP-selectin), white cell and platelet activation (sL-selectin and sP-selectin respectively) and markers of hemostatic activation, including D-Dimer and prothrombin fragment F1.2 were analyzed. Subjects with HbSS demonstrated significant increases (P<0.001) in all cell activation and hemostatic biomarkers. Analyses revealed a dominant, statistically significant correlation between F-cell and biomarkers of endothelial, white cell and hemostatic activation. F-cells correlated inversely with sVCAM-1 (R = −0.64, P<0.00005), sE-selectin (R = −0.51, P = 0.03) and sP-selectin (R = −0.41, P<0.02). Since HbF protects against HbS polymerization, our data suggests a role for the sickle erythrocyte in endothelial activation and is consistent with reported decreases in sVCAM-1 following hydroxyurea therapy or a chronic transfusion regimen. sP- and sE-selectin levels correlated with neutrophil counts (R = 0.63 and R = 0.42, P<0.00006 and P<0.02 respectively) while no relationship between platelets and sP-selectin was noted. An additional correlation between sP- and sE-selectin (R = 0.50, P<0.003) was also observed, reflecting enhanced neutrophil-endothelial interaction as part of an inflammatory and prothrombotic HbSS phenotype. Surprisingly, a positive correlation between sL-selectin and F-cells occurred (R = 0.4, P<0.02) with the young infant with HbSS demonstrating higher levels of this leucocyte activation marker than the older subject. A dysregulation of L-selectin shedding following neutrophil activation has been proposed to occur in sickle cell anemia. Our results suggest that HbF protects against this dysregulation. D-Dimer levels correlated negatively with F-cells (R = −0.76, P<0.000001), with a striking relationship between D-Dimer and markers of endothelial activation, including sVCAM-1 (R = 0.53, P<0.001), sE-selectin (R = 0.39, P<0.03) and sP-selectin (R = 0.41, P<0.02). Such findings are in keeping with D-Dimer’s well-documented role as a biomarker in other inflammatory and ischemia-related disorders including coronary, cerebrovascular and peripheral arterial ischemic states. This report expands our knowledge regarding the protective effects of HbF against endothelial and hemostatic activation, and suggests a role for D-Dimer as a prothrombotic and proinflammatory marker in sickle cell anemia.