Venous thromboembolism in blood or marrow transplant recipients

Cancer is a well-recognized risk factor for venous thromboembolism (VTE) and several risk prediction models have been developed to identify patients at high risk. However, the majority of patients included in these studies had solid tumors, and blood or marrow transplant (BMT) recipients were excluded. BMT recipients comprise a unique group of cancer patients who are prone to VTE due to endothelial damage from high intensity chemotherapy and radiation, requirement for central venous catheters, prolonged hospitalizations, concomitant infections, and the presence of graft versus host disease (GvHD) in allogeneic transplant recipients requiring immunosuppressive therapy for prevention and treatment. BMT recipients are also excluded from clinical trials evaluating the efficacy and safety of anticoagulants, leading to a knowledge gap in the treatment of VTE in this population.

Previous studies reporting the risk of VTE in BMT recipients were limited by small sample sizes and a short follow up period. In a study of 431 allogeneic BMT recipients with a median follow-up time of 20 months, the median time until the first bleeding episode was 60 days, whereas the median time from BMT to diagnosis of VTE was 211 days, suggesting that thrombotic complications occur later in the transplant course compared to bleeding^[1]. The presence of thrombocytopenia and bleeding complications preclude the use of thromboprophylaxis in the immediate post-transplant period. In another study, the incidence of VTE was 4.6% at 180 days after BMT^[2] In a retrospective analysis of allogenic transplant recipients followed for a median of 4 years, the incidence of VTE was 5.5% and 7.1% at 1 year and 2 years, respectively^[3]. A recent meta-analysis reported a 5% incidence of VTE after BMT, with similar incidences in autologous and allogeneic BMT recipients of 4%^[4]. Median follow-up time in the majority of the studies included in this analysis was 3-4 years, and there was considerable heterogeneity among the studies. The risk factors predisposing to VTE are likely different in autologous compared to allogeneic BMT recipients, due to the pathophysiology of the underlying diseases, treatment regimens used, and presence of chronic GvHD in allogeneic transplant recipients which causes increased risk of VTE due to underlying inflammation. Previous studies have demonstrated a high incidence of VTE in patients with GvHD (45% with acute and 35% with chronic GvHD)^[4]. Since GvHD also increases the risk of bleeding, it is difficult to propose thromboprophylaxis, and prospective studies in this sub-group of BMT patients would be helpful.

BMT is increasingly being utilized for treatment of aggressive/refractory hematologic malignancies. With improved transplantation techniques and reduced intensity conditioning regimens, the age limit for BMT has also liberalized. Long-term survival is now an expected outcome after BMT similar to other malignancies, resulting in a growing number of BMT survivors, expected to exceed 500,000 by 2030 in the United States alone^[5]. Hence, it is important to understand the health complications faced by BMT survivors and their impact on survival and health care utilization. Long term BMT survivors have an increased risk of new onset co-morbidities such as diabetes, hypertension and dyslipidemia and risk of developing atherosclerosis and arterial vascular events^[6]. The long term risk of VTE in BMT survivors remains unstudied, and a comprehensive evaluation of comorbidities and the role of GvHD in VTE risk would be helpful in defining the high risk population. Multi-institutional collaboration for studies evaluating the role of thromboprophylaxis in patients with GvHD and other high risk features is needed to address the knowledge gaps in this area.

VTE patients experience inferior survival compared to age-, sex- and race-matched individuals without VTE in the general population; the mortality risk is highest in the first year after VTE, but can remain elevated up to 30 years^[7]. In a retrospective analysis of 2,276 allogenic transplant recipients with a median follow up of 50 months, VTE was associated with increased non-relapse mortality, but not with relapse, progression-free survival or overall survival^[3]. Since bleeding complications are also high in the BMT setting due to prolonged periods of thrombocytopenia and ongoing complications from GvHD, continued risk assessment to identify high-risk populations is important for optimizing the benefit of thromboprophylaxis. The high risk of VTE and associated mortality necessitates the need for guidelines for prevention and treatment of VTE in BMT recipients.

 

References

1. Labrador J, Lopez-Anglada L, Perez-Lopez E, et al. Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients. Haematologica. 2013;98: 437-443.
2. Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB. The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. Blood. 2008;112: 504-510.
3. Kekre N, Kim HT, Ho VT, et al. Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Haematologica. 2017;102: 1185-1191.
4. Zahid MF, Murad MH, Litzow MR, et al. Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis. Ann Hematol. 2016;95: 1457-1464.
5. Majhail NS, Tao L, Bredeson C, et al. Prevalence of Hematopoietic Cell Transplant Survivors in the United States. Biol Blood Marrow Transplant. 2013;19: 1498-1501.
6. Bhatia S. Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Rev Hematol. 2011;4: 437-452; quiz 453-434.
7. Sogaard KK, Schmidt M, Pedersen L, Horvath-Puho E, Sorensen HT. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation. 2014;130: 829-836.