Increased Inflammatory Markers and Their Correlations To Clinical Complications In Hemoglobin SC Disease

Hemoglobin SC (HbSC) disease is the second most prevalent hemoglobinopathy after sickle cell anemia (SCA – homozygous HbSS). Despite its high prevalence, most of the knowledge about the pathophysiology of HbSC is inferred from studies focused primarily on SCA. In general, HbSC is considered a milder form of SCA. Chronic inflammatory activity is clearly seen in SCA, but not much is known about the inflammation present in HbSC. In the present study we aimed to evaluate inflammatory markers in HbSC patients and their associations with clinical and laboratory characteristics of the disease. This was a cross-sectional study performed on a cohort of 56 HbSC patients (mean age of 41 years), 39 SCA patients (mean age of 34 years), and 24 healthy age-matched controls. All of the patients were in steady state, with no history of painful crisis, hospitalization or transfusions during the preceding 3 months. None of the patients were in use of hydroxyurea. We evaluated the inflammatory markers, tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL8). Levels of inflammatory markers were correlated with hemolysis markers, blood counts, coagulation markers (tissue factor expression [TF], thrombin-antithrombin complex [TAT], d-dimer [DD]) and endothelial activation marker (soluble thrombomodulin [sTM]). TNF-α, IL8, TAT, DD and sTM were all measured by ELISA. Leukocyte TF mRNA expression was analyzed by real time quantitative PCR. Statistical analyses were performed by Mann-Whitney’s U test and Spearman’s rank correlation test. HbSC patients presented higher TNF-α levels than those of controls (2.72 vs. 0 pg/mL; P <0.0001), which were similar to the levels seen in SCA patients (2.72 vs. 2.74 pg/mL; P = 1.0). IL8 levels were similar between HbSC patients and controls (2.54 vs. 2.29 pg/mL; P = 0.16) and also similar between HbSC and SCA patients (2.54 vs. 2.82 pg/mL; P = 0.45). In the analyses of the HbSC cohort, IL8 levels presented significant positive correlations with: leukocyte (r=0.4; P=0.02), monocyte (r=0.5; P=0.001), and platelet counts (r=0.6; P=0.0002); and hemolysis markers: indirect bilirubin (r=0.4; P=0.04) and lactate dehydrogenase levels (r=0.4, P=0.04). TNF-α levels presented no significant correlations with laboratory markers. We also evaluated associations between IL8 and TNF-α levels and clinical complications; stroke, pulmonary arterial hypertension, acute thoracic syndrome, retinopathy, osteonecrosis, leg ulcers and autosplenectomy. HbSC patients with osteonecrosis had significantly higher IL8 levels (3.8 vs. 2.4; P=0.01) when compared with patients without this complication. IL8 levels were also higher in patients with autosplenectomy (3.8 vs. 2.0; P=0.0003). Our results indicate that HbSC disease patients present elevation of inflammation markers, similar to alterations seen in SCA. In our cohort, patients with higher peripheral blood counts and a more intense hemolytic activity, such as patients with autoesplenectomy, have higher levels of inflammatory markers. Our data suggest that inflammation may be a factor contributing to the pathophysiology of a very prevalent chronic complication of HbSC disease, osteonecrosis. Studies focusing on the pathophysiology of HbSC disease are lacking, and in view of the high prevalence of this disease we believe it should be the focus of future studies.