Elevated Circulating Angiogenic Progenitors and White Blood Cells Are Associated with Hypoxia-Inducible Angiogenic Growth Factors in Children with Sickle Cell Disease

We studied the number and function of angiogenic progenitor cells and growth factors in children aged 5–18 years without acute illness, 43 with Hemoglobin SS and 68 with normal hemoglobin. Hemoglobin SS subjects had at least twice as many mononuclear cell colonies and more circulating progenitor cell than Control subjects. Plasma concentrations of erythropoietin, angiopoietin-2, and stromal-derived growth factor (SDF)-1α were significantly higher in children with Hemoglobin SS compared to Control subjects. In a multivariate analysis model, SDF-1α concentration was found to be associated with both CPC number and total white blood cell count in the Hemoglobin SS group, suggesting that SDF-1α produced by ischemic tissues plays a role in mobilizing these cells in children with Hemoglobin SS. Despite having a higher number of angiogenic progenitor cells, children with Hemoglobin SS had slower migration of cultured mononuclear cells

Biologic Complexity in Sickle Cell Disease: Implications for Developing Targeted Therapeutics

Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstrated in vivo before investing in expensive and labor-intensive clinical trials

Effect of Chronic Blood Transfusion on Biomarkers of Coagulation Activation and Thrombin Generation in Sickle Cell Patients at Risk for Stroke.

Hypercoagulability in sickle cell disease (SCD) is associated with multiple SCD phenotypes, association with stroke risk has not been well described. We hypothesized that serum levels of biomarkers of coagulation activation correlate with high transcranial Doppler ultrasound velocity and decreases with blood transfusion therapy in SCD patients. Stored serum samples from subjects in the Stroke Prevention in Sickle Cell Anemia (STOP) trial were analyzed using ELISA and protein multiplexing techniques. 40 subjects from each treatment arm (Standard Care [SC] and Transfusion [Tx]) at three time points--baseline, study exit and one year post-trial and 10 each of age matched children with SCD but normal TCD (SNTCD) and with normal hemoglobin (HbAA) were analyzed. At baseline, median vWF, TAT and D-dimer levels were significantly higher among STOP subjects than either HbAA or SNTCD. At study exit, median hemoglobin level was significantly higher while median TCD velocity was significantly lower in Tx compared to SC subjects. Median vWF (409.6 vs. 542.9 μg/ml), TAT (24.8 vs. 40.0 ng/ml) and D-dimer (9.2 vs. 19.1 μg/ml) levels were also significantly lower in the Tx compared to the SC group at study exit. Blood levels of biomarkers coagulation activation/thrombin generation correlated positively with TCD velocity and negatively with number of blood transfusions. Biomarkers of coagulation activation/thrombin generation were significantly elevated in children with SCD, at high risk for stroke. Reduction in levels of these biomarkers correlated with reduction in stroke risk (lower TCD velocity), indicating a possible role for hypercoagulation in SCD associated stroke