For decades, clinicians have suspected that children and adults with sickle cell disease (SCD) were at increased risk for venous thromboembolism (VTE). The evidence for increased prevalence of VTE in SCD has been primarily based on limited case series, case-control studies, or administrative data sets. There are limited data indicating the association between SCD and VTE, often confounded by risk factors in the general population such as prolonged hospital stay and comorbidities. Acute and long-term implications of, and risk factors for thrombophilia in children and adults with SCD are currently being identified. Clear evidence of increased risk for VTE in an individual with SCD and acute chest syndrome (ACS) will have an impact on the management of ACS.
Using a population-based data set from state of California, Dr. Ann Brunson and colleagues carefully described the prevalence of VTE and VTE sequelae in 6,237 individuals with SCD. Approximately 11 percent of the cohort developed incident VTE, of whom 52 percent had pulmonary emboli and deep vein thrombosis (DVT); 26 percent had only lower-extremity DVT; and 23 percent developed only upper-extremity DVT. Significant risk factors for VTE included female sex since female patients had a higher hazard ratio (HR, 1.22; 95% CI, 1.05-1.43) and severe SCD (defined as ≥ 3 admissions or emergency department visits combined per year; HR, 2.86; 95% CI, 2.42-3.37). Individuals in the cohort with a VTE had an approximately threefold increased risk of death compared to individuals without incident VTE (HR, 2.88; 95% CI, 2.35-3.52). However, recurrent VTE was not associated with a higher risk of death when compared to those with only a single episode VTE (HR, 0.97; 95% CI, 0.69-1.38).
The most novel finding in the study was an estimate of the recurrence rate for VTE. The study provides additional evidence to address the lingering question of whether long-term anticoagulation should be offered to individuals with SCD and VTE. With a median follow-up period of 15 years, the five-year VTE recurrence rate in adults with severe SCD was at least one in three. Taken together, these data support a plausible approach for prolonged anticoagulation after VTE in adults with severe SCD. Perhaps even more importantly, there is now equipoise as to the optimal strategies (limited-duration anticoagulation vs. prolonged anticoagulation) to prevent VTE recurrence in this high-risk population and potentially premature death. Only a carefully completed clinical trial will address the questions of primary and secondary prevention for VTE in SCD.
In Brief
As is the case in all administrative data sets, the results cannot be evaluated in isolation. Reassurance of the significance of these findings is based on a natural history cohort from the Cooperative Study from Sickle Cell Disease demonstrating a high cumulative rate of VTE in individuals with SCD younger than 40 years1 and similarity to the current study’s cumulative rate of 12.5 percent. Comparable to other administrative data sets, particularly for rare diseases, several noteworthy limitations are present in this study. These include lack of information regarding the type of treatment, degree of adherence to anticoagulation therapy during the observation period, and absence of laboratory confirmation of SCD diagnosis. The authors attempted to limit misclassification of SCD bias; however, disease misclassification may have still occurred. Dr. Christopher Bean and colleagues have demonstrated that genetic sequencing of the β-globin gene was only confirmed in approximately 6 percent of the African-American adults who self-reported having SCD. The majority of individuals were mislabeled as having SCD, had sickle cell trait (63%), or no hemoglobinopathy at all.2 Despite this limitation, the results of the current study, coupled with evidence from other similar studies,1,3 should now prompt consideration for carefully designed randomized clinical trials to identify the optimal primary and secondary prevention strategies for VTE in this high-risk population.
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Competing Interests
Dr. DeBaun indicated no relevant conflicts of interest.
