Venous Thromboembolism Is Associated with Right-Sided Cardiac Dysfunction and Increased Mortality in Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a hypercoagulable state. Approximately 11-12% of patients with SCD have a venous thromboembolism (VTE) by age 40 which portends a nearly three-fold increased mortality risk compared to those without VTE. Additionally, echocardiographic findings of right-sided cardiac dysfunction and pulmonary hypertension (PH) are also independent mortality predictors in SCD. In the general population, VTE is a risk factor for PH; however, the association in SCD is uncertain. We hypothesized that patients with SCD and VTE have a greater frequency of right-sided cardiac dysfunction by transthoracic echocardiogram (TTE) and associated mortality risk compared to those without VTE.

Methods: We performed a retrospective chart review of 402 consecutive SCD patients who received care at our institution between 2003 and 2021. VTE was defined as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) by diagnostic imaging. Demographics, clinical and laboratory data, VTE diagnostic imaging, and TTE results were obtained from each subject. For those with VTE, we recorded data pre-VTE and 5 years post-VTE. For those without VTE, we recorded data at entry into the database and 5 years later. The atrial and ventricular size, right and left ventricular function, valvular function, and tricuspid regurgitant jet velocity (TRV) were collected from each echocardiogram. Data were analyzed using Fisher's exact, Sign-ranked and McNemar's tests.

Results: In our cohort, 251 subjects (62%) were HbSS/HbSβ⁰ and 227 (56%) were female. VTE occurred in 75 individuals (19%) with deep vein thrombosis in 35 (47%), pulmonary embolism in 50 (67%), and both observed in 9 (12%). Prior history of acute chest syndrome, avascular necrosis, stroke, and surgical splenectomy was associated with VTE (p<0.01 for all). History of VTE was associated with an increased mortality rate during our study period compared to those without VTE (13% vs 6%, p=0.04). Within our cohort, 183 patients had initial and follow-up echocardiography (77% of VTE group, 38% of non-VTE group). In the VTE group, there was a higher frequency of right atrial enlargement five years post-VTE compared to pre-VTE (p=0.03). There was a non-significant trend towards decreased right ventricular function over five years in the VTE group (p=0.08) Neither of these findings occurred in the non-VTE group. There was no significant change in TRV after five years of follow-up in either group; however, only 45% of echocardiograms had TRV ascertained.

Conclusions: Sickle cell disease patients who sustained a VTE had an increased risk of prior complications and subsequent mortality compared to those without a VTE. The presence of increased right atrial size and a trend towards right ventricular dysfunction five years post-VTE suggest development of pulmonary hypertension despite lack of change in the TRV. These findings need to be explored by a deeper analysis of the echocardiography, and in the future, a prospective study.

Klings:Bayer Health Care Pharmaceuticals: Current Employment, Research Funding; United Therapeutics Corporation: Current Employment, Research Funding; Reata Pharmaceuticals: Current Employment, Research Funding; Arena Pharmaceuticals: Ended employment in the past 24 months, Research Funding; Actelion Pharmaceuticals: Ended employment in the past 24 months, Research Funding.