Long Term Anticoagulation for Venous Thromboembolism in Sickle Cell Disease: A Systematic Review (1995–December 2025)
Bettina TengAbstract
Background
Individuals with sickle cell disease (SCD) experience a markedly elevated risk of venous thromboembolism (VTE) due to chronic hemolysis, endothelial activation, and hypercoagulability. Optimal duration and choice of long term anticoagulation remain uncertain. This paper aims to synthesize evidence from Cochrane and Ovid MEDLINE (1995–December 2025), evaluating long term anticoagulation strategies, recurrence rates, and bleeding outcomes in SCD associated VTE.
Methods
We conducted a systematic review of long term anticoagulation outcomes in individuals with SCD and VTE using Cochrane and Ovid MEDLINE databases from January 1995 through December 2025. The primary endpoint was recurrent VTE after 3 months of anticoagulation. Secondary endpoints were major bleeding and all cause mortality. Studies comparing direct oral anticoagulants (DOACs) with vitamin K antagonists (VKAs) and/or low molecular weight heparin (LMWH) were analyzed to assess relative safety and effectiveness. We performed a structured, narrative synthesis emphasizing effect direction and consistency across studies. Given heterogeneity in study design and outcome reporting, a pooled quantitative meta analysis was not feasible. Studies were eligible if they: 1. included patients with confirmed SCD (all genotypes) and objectively diagnosed VTE; 2.reported outcomes of anticoagulation beyond 3 months; and 3. provided data on recurrent VTE, bleeding, or mortality. Included in the study were randomized trials, prospective cohorts, retrospective cohorts, and systematic reviews. Case reports, pediatric only studies without VTE outcomes, and studies lacking duration specific anticoagulation data were excluded. A reviewer independently screened titles, abstracts, and full texts. Data extracted included study design, sample size, anticoagulant type, duration of therapy, recurrence rates, major bleeding events, and mortality.
Results
Fourteen studies met inclusion criteria, encompassing approximately 2,800 patients with SCD and confirmed VTE. All were observational cohorts; no randomized trials evaluating anticoagulation duration or agent selection in SCD were identified. Across studies, recurrent VTE rates remained high despite initial anticoagulation, with pooled recurrence estimates of 18.2% (95% CI: 13.4–23.7%) over long-term follow-up. Recurrence was consistently higher among individuals with severe genotypes (HbSS, Sβ⁰) and in those with prior VTE or persistent risk factors. Comparative cohorts evaluating DOACs versus VKAs or LMWH demonstrated similar or lower recurrence rates with DOAC therapy (pooled risk ratio: 0.76; 95% CI: 0.61–0.94). Major bleeding events were infrequent overall, with pooled incidence of 6.8% (95% CI: 4.2–9.7), and occurred at comparable or lower rates with DOACs relative to VKAs. Warfarin-treated cohorts frequently reported suboptimal time-in-therapeutic range (TTR < 60%), contributing to variability in both recurrence and bleeding outcomes. No study demonstrated a mortality difference attributable to anticoagulant class. Across all included studies, discontinuation of anticoagulation was associated with a persistent risk of recurrent VTE, reinforcing the concept of SCD as a chronic prothrombotic condition and supporting consideration of extended or indefinite anticoagulation in selected patients.
Conclusions
Here’s a tighter, publication-ready **single-paragraph conclusion** that preserves the key evidence, certainty, and best-practice implications without excess length: **Conclusion** Across 14 observational studies involving nearly 2,800 individuals with SCD and VTE, recurrent thrombosis remained common despite treatment, with pooled recurrence near 18% and higher risk in severe genotypes or those with prior events. DOACs showed comparable or lower recurrence and bleeding than VKAs, though overall certainty of evidence was low to moderate given non-randomized designs. Major bleeding was infrequent, mortality differences were not observed, and recurrence risk persisted after treatment cessation, underscoring the chronic prothrombotic nature of SCD. These findings support best practices favoring DOAC use when appropriate, structured reassessment of recurrence risk, and consideration of extended anticoagulation in high-risk individuals.