Sickle cell anemia (SCA) patients present an elevated rate of thrombotic complications and increased biological markers of hemostatic activation. Hemoglobin SC disease (HbSC) is the second most prevalent hemoglobinopathy after SCA (homozygous HbSS), has specific clinical and pathological characteristics that may differ from SCA, and viscosity appears to be a hallmark of the disease. Studies have shown an increase in thrombotic events in HbSC patients, especially pulmonary embolism, however, not much is known about the coagulation activation in this population. We herein aimed to evaluate the hypercoagulability markers in HbSC disease and their associations with patients' clinical and laboratory characteristics.
This was a cross-sectional study performed on a cohort of 41 adult HbSC (mean age of 43 years) and 58 adult HbSS patients (mean age of 36 years), all in steady-state, and 25 healthy age-matched controls. We evaluated the expression of tissue factor (TF), the physiological initiator of coagulation, and thrombin-antithrombin complex (TAT), a final marker of coagulation activation. Leukocyte TFmRNA expression was analyzed by real time quantitative PCR and TAT plasma levels were measured by ELISA. Comparisons between the two patient groups and controls were performed using Kruskal-Wallis test followed by Dunn's Multiple Comparisons test. Fisher's exact test and Mann-Whitney's U test were used to compare patients' clinical complications and laboratory characteristics. Spearman's rank test was used for correlations analysis.
Relative TF mRNA expression was significantly up-regulated in HbSC patients when compared to controls (2.6 vs. 1.2), however levels of TF were lower in HbSC than HbSS patients (2.6 vs. 3.3) (P<0.0001). Confirming the biological relevance of TF expression, TAT plasma levels were also higher in HbSC patients in comparison to controls (4.2 vs. 2.4), and lower in HbSC than HbSS patients (4.2 vs. 7.3); (P<0.0001). In the analyses of the HbSC cohort, TAT levels presented significant positive correlations with inflammation markers: leukocyte (r=0.5; P=0.001), monocyte (r=0.4; P=0.01), and platelet counts (r=0.5; P=0.002); and hemolysis markers: reticulocyte counts (r=0.4; P=0.01) and lactate dehydrogenase levels (r=0.6, P=0.0001). We also evaluated associations between TAT levels and clinical complications: stroke, pulmonary arterial hypertension, acute thoracic syndrome, retinopathy, osteonecrosis, leg ulcers, autosplenectomy and microalbuminuria. HbSC patients with retinopathy had significantly higher TAT levels (4.7 vs. 3.9; P=0.03) when compared with patients without this complication. TAT levels were also higher in patients with autosplenectomy (4.8 vs. 3.8; P=0.004), and in patients with osteonecrosis, although this had borderline statistical significance (4.6 vs. 3.9; P=0.06). TF expression significantly correlated with monocyte counts (r=0.6; P=0.01).
Our results indicate that HbSC disease patients present elevated coagulation activation markers when compared to controls, although not as intense as seen in SCA. Thrombotic complications in HbSC patients have been mainly linked to the hyperviscosity present in this disease. Our data suggest that inflammation and hemolysis are also important factors contributing to hemostatic activation, which may participate in the pathophysiology of very prevalent chronic complications of HbSC disease: retinopathy and osteonecrosis. Interestingly, in our cohort, patients with autosplenectomy had higher levels of pro-coagulant markers, possibly due to a higher intravascular hemolytic rate and elevated peripheral blood counts. Although HbSC disease is considered a milder form of SCA, autopsy studies have shown that mortality by pulmonary embolism is more frequent in HbSC disease than in SCA, being the second cause of mortality in these patients (Manci et al, 2003). Studies addressing the pathophysiology of coagulation activation in HbSC disease are lacking. Low numbers of cases of HbSC disease are usually included in studies focusing mainly in SCA, and the results are very variable, probably due to the small numbers of patients. In view of the high prevalence and morbimortalilty of thrombotic complications in this population, we believe that future studies should focus on a better understanding of hypercoagulability in HbSC disease.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.