The Association between Tricuspid Regurgitation Velocity and Pulmonary Embolism in Sickle Cell Disease: A Retrospective Cohort Analysis

Background: Sickle cell disease (SCD) is a hypercoagulable state associated with an increased risk for pulmonary embolism (PE). While tricuspid regurgitation jet velocity (TRJV) is a well-established risk factor for death in adults with SCD, its relationship with PE is less well-defined. Evidence suggests that TRJV activates platelets through shear stress, creating a prothrombotic state in the lungs. Thus, an elevated TRJV may be associated with a higher incidence of PE, potentially identifying a high-risk group for morbidity and mortality. We tested the hypothesis that increased TRJV levels are associated with a diagnosis of PE in a population of individuals with SCD.

Methods: Based on a previously constructed electronic cohort of children and adults with SCD (Cronin et al.), we conducted an observational retrospective cohort study of individuals with SCD at Vanderbilt University Medical Center (VUMC). We extracted demographic information, vital signs, laboratory results, and data on disease-modifying therapies, including hydroxyurea, chronic transfusion, and hematopoietic stem cell transplant. TRJV was evaluated with Doppler echocardiography. PE diagnosis was identified using ICD-9 codes (415.X) and ICD-10 codes (126.X). Only the first PE diagnosis and all preceding TRJV measurements were considered to determine if elevated TRJV predicts PE. TRJV was categorized into < 2.5 m/sec, ≥ 2.5 to < 2.7 m/sec, ≥ 2.7 to < 3.0 m/sec, and ≥ 3.0 m/sec, based on their biological plausibility for complications as indicated in the literature. Multivariable Cox regression analysis was conducted using Stata, with TRJV as coded above, adjusting for confounding variables, including age, at first echocardiogram, sex at birth, hemoglobin level and platelet count at each TRJV, and time-varying treatment covariates for hydroxyurea and chronic transfusion. Observations were censored if a patient received a hematopoietic stem cell transplant. Statistical significance was defined as p < 0.05

Results: Data was extracted from the charts of 461 SCD patients who had undergone echocardiography between 2004 and 2024. TRJV was reported and extracted from 1375 echocardiograms, encompassing all 461 patients. For patients with a PE diagnosis, we used only TRJV measurements taken before that diagnosis. Additionally, we restricted the cases to those with at least 0.5 years between the first TRJV measurement and the last encounter or PE. The final data consisted of 363 patients with 1,294 echocardiograms. The cohort consisted of 47.9% males with a median age of 27.6 years (IQR 21.3 – 36.9). PE was diagnosed in 53 patients (14.6%) with an increased odds of death compared to those without a PE diagnosis (Odd ratio 2.32, 95% CI 1.18-4.57; p=0.014).In the multivariable Cox regression, only patients with TRJV ≥ to 3.0 m/sec had an increased risk of PE compared to TRJV < 2.5 m/sec (hazard ratio 3.64, 95% CI: 1.62 – 8.18; p=0.002). Additionally, compared to no treatment, using hydroxyurea (hazard ratio 4.69, 95% CI: 1.95 – 11.26; p=0.001) or receiving chronic transfusion (hazard ratio 4.27, 95% CI: 1.51 – 12.10; p=0.006) were associated with a greater risk of PE. Our analysis was limited by missing or incomplete patient data for SCD genotype and mean platelet volume, leading to the exclusion of these variables from the Cox regression analysis. This may have limited the inclusion of all relevant variables that could have influenced the results.

Conclusion: Individuals with SCD and a TRJV ≥ 3.0 m/sec have more than three and a half times higher risk for developing PE than those with a lower TRJV. Individuals with PE are at increased risk of death. PE is also associated with hydroxyurea or regular blood transfusion therapy, although the biological basis for disease-modifying therapies and PE is unknown and requires additional evaluation.