الفهرس 
SICKLE CELL DISEASEOnly 14 pages are availabe for public view
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Abstract
Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Soluble fms-like tyrosine kinase-1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. By adhering to and inhibiting VEGF and placenta growth factor, it induces endothelial dysfunction with a possible role in the pathogenesis of SCD-associated nephropathy and pulmonary hypertension. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily and has been recently investigated as a marker of ineffective erythropoiesis in several anemias. Aim: To determine the levels of sFLT-l and GDF-15 in 35 young SCD patients compared with 35 age- and sex-matched healthy controls, assess their relation to markers of hemolysis and iron overload, and evaluate their role as potential markers for hemolysis associated complications. Methods: Patients were studied stressing on transfusion history, hydroxyurea therapy, hematological profile and serum ferritin. sFLT-l and GDF-15 were measured by enzyme linked immunosorbent assay (ELISA). All patients were in steady state and followed-up during the study period stressing on the occurrence of sickling crisis. Results: sFLT-1 and GDF-15 were significantly higher in SCD patients compared with control group (p<0.001). sFLT-1 was significantly higher in patients with history of thrombosis or pulmonary hypertension had significantly higher levels than those without (p<0.05). Patients who experienced sickling crisis during the study period had also higher sFLT-1 levels than those who were in steady state (p<0.001). SCD patients with serum ferritin ≥2500 µg/L showed higher sFLT-1 levels than those with lower ferritin levels (p=0.046). Hydroxyurea-treated patients had lower sFLT-1 levels than untreated patients (p=0.005). As regards GDF-15, significantly higher levels were found in patients who had history of thrombosis, splenectomy or serum ferritin ≥2500 µg/L showed higher GDF-15 levels (p<0.05). Both sFLT-1 and GDF-15 were positively correlated in SCD patients and significant positive relations were observed between sFLT-1 and transfusion index, WBC count, markers of hemolysis and serum ferritin. Also, significant positive correlations were shown between GDF-15 and transfusion index, markers of hemolysis and serum ferritin while both sFLT-1 and GDF-15 negatively correlated to hemoglobin and HbF (p<0.05). Multiple regression analysis showed that sickling crisis, pulmonary hypertension, HbF and indirect bilirubin were independently related to sFLT-1 while transfusion index, LDH and serum ferritin were independently related to GDF-15 in SCD patients. The cutoff value of sFLT-1 at 132.5 pg/mL could predict the occurrence of sickling crisis with 100% sensitivity and specificity of 100%. Also, sFLT-1 cutoff 127.5 pg/mL could differentiate patients with and without pulmonary hypertension with a sensitivity of 100% and specificity of 74%. Conclusion: sFLT-1 and GDF-15 may be considered a potential biological marker for vascular dysfunction and disease severity in SCD. Their levels are closely related to markers of hemolysis and iron overload and may provide utility for identifying patients who are at increased risk of thrombotic events. sFLT-1 levels may contribute to the pathogenesis of SCD-associated pulmonary hypertension and would help in early crisis prediction as well as monitoring the response to hydroxyurea therapy. Further longitudinal studies are needed to verify the practical utility of sFLT-1 and GDF-15 measurement and their potential to reflect the severity of the clinical course in SCD patients.