Sickle cell disease (SCD) is a hypercoagulable state, leading to increased rates of thrombotic complications such as stroke and venous thromboembolism (VTE). We have previously demonstrated an increased risk of non-catheter-related VTE among patients with sickle cell variant syndromes compared to those with sickle cell anemia (SS/Sβ0) genotypes. Variations in baseline laboratory values, including hemoglobin and hemolytic rate, have been shown to modify the risk of developing complications such as acute chest syndrome and retinopathy in SCD patients. In addition, splenectomy has been identified as a risk factor for VTE in patients with other hemoglobinopathies such as β-thalassemia intermedia. Therefore, we sought to determine the hematologic and clinical risk factors associated with VTE among our cohort of patients with SC and Sβ+thalassemia genotypes.
We conducted a retrospective cohort study of all patients with hemoglobin SC or Sβ+thalassemia genotypes cared for at the Sickle Cell Center for Adults at Johns Hopkins between August 2008 and July 2012. Baseline hematologic parameters were recorded for all patients and were defined as steady-state outpatient laboratory values that were taken at least 1 month after a hospitalization and at least 3 months after a transfusion. Clinical data such as SCD-specific comorbidities and history of surgical splenectomy were also collected for all patients. A history of VTE was confirmed by radiography in the majority of cases. In cases where radiology was not available, only patients with a verified history of anticoagulation were included. Patients with a history of catheter-related VTE only were excluded (n=2).
Ninety-five patients with sickle variant genotypes had complete data and were included for analysis. The median age at follow-up was 42 years (range 21–72 years), and 55.8% of patients were female. Twenty-six (27.4%) patients had a history of VTE, 28.6% (8/28) with Sβ+thalassemia genotype and 26.9% (18/67) with SC genotype. Patients with a history of VTE had higher baseline hemoglobin levels compared to those without history of clot (11.6 g/dL vs. 10.8 g/dL, p<0.001). Additional laboratory parameters, including baseline WBC, platelet levels, and reticulocyte counts, did not significantly correlate to a history of VTE. A history of splenectomy was noted in 26.9% (7/26) of patients with VTE, 4 of whom developed a pulmonary embolism (PE) only, 2 of whom had a history of both deep venous thrombosis (DVT) and PE, and 1 of whom experienced an abdominal vein thrombosis. Splenectomy was significantly correlated to VTE on bivariate analysis (p=0.001), whereas other prevalent comorbidities such as avascular necrosis and retinopathy did not appear to be associated with VTE. On multivariate analysis controlling for demographics and genotype, older age (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01–1.10, p=0.015), hemoglobin level (OR 3.82, CI 1.83–7.98, p<0.001) and history of splenectomy (OR 4.93, CI 1.10–22.14, p=0.038) were found to be independent risk factors for VTE in our cohort. On subgroup analysis by VTE type, increased hemoglobin level persisted as a risk factor for both DVT (OR 5.69, CI 2.04–15.83, p=0.001) and PE (OR 3.55, CI 1.65–7.68, p=0.001), but splenectomy was statistically correlated to PE only (OR 4.79, CI 1.05–21.78, p=0.043).
In patients with SC and Sβ+ thalassemia genotypes, VTE is common complication and is associated with higher baseline hemoglobin levels. In addition, splenectomy appears to be a risk factor for VTE, and specifically PE, in this population. These findings suggest that increased whole blood viscosity and surgical splenectomy may play a role in the development of venous thrombosis in SCD. Further studies will be needed to determine if functional asplenia is also associated with VTE in patients with sickle cell variant genotypes, and whether laboratory parameters can be used to predict VTE risk in SCD.
Naik:NHLBI (K12): Research Funding. Streiff:sanofi-aventis: Consultancy, Honoraria; BristolMyersSquibb: Research Funding; Eisai: Consultancy; Janssen Healthcare: Consultancy; Daiichi-Sankyo: Consultancy. Lanzkron:Hemaquest: Membership on an entity's Board of Directors or advisory committees; NHLBI: Research Funding.
Asterisk with author names denotes non-ASH members.
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