Pulmonary Hypertension in Sickle Cell Disease: The Role of Activated Blood Coagulation and Inflammation.

Introduction: Pulmonary hypertension (PHT) is a common complication of sickle cell disease (SCD). The pathogenesis of PHT in this setting is likely multifactorial. There is an abundance of evidence to suggest that the coagulation system is activated in patients with SCD. In addition, autopsy series have shown that an in situ thrombotic arteriopathy is seen in the majority of SCD patients with PHT. The purpose of this study is to determine whether markers of thrombin generation, platelet activation and inflammation are associated with PHT in SCD patients.

Methods: This cross-sectional study was performed using a cohort of patients followed at the Sickle Cell Clinic at UNC-Chapel Hill. The pulmonary artery systolic pressure (PASP) was determined with a Doppler echocardiogram by applying the modified Bernoulli equation (PASP = 4V² + right atrial pressure). Pulmonary hypertension was defined using an age-, sex- and BMI-adjusted reference range. Laboratory studies, including a complete blood count, soluble CD40 ligand [sCD40L] (a marker of inflammation and platelet activation) and markers of thrombin generation (thrombin-anti-thrombin complex [TAT], prothrombin fragment 1+2 [F1+2], and D-dimers) were obtained on all SCD subjects and on six healthy, race-matched control subjects without SCD. Wilcoxon Rank Sum Tests were used to compare median values in SCD patients with and without PHT, as well as between SCD patients and the control individuals.

Results: Of the 76 subjects with SCD (SS = 56, SC = 9, Sβ⁰ = 4, Sβ⁺ = 7), PHT was found in 26 (34%). Compared with SCD patients without PHT, those with PHT had higher WBC counts (10.4 X 10³/μL vs. 8.7 X 10³/μL; p = 0.05). In addition, while PHT patients had consistently higher levels of such parameters as: D-dimers (1603 ng/mL [FEU] vs. 1233 ng/mL [FEU]; p = 0.3), TAT (7.05 μg/L vs. 5.7 μg/L; p = 0.8) and F1+2 (1.15 nmol/L vs. 0.9 nmol/L; p = 0.3), they failed to achieve statistical significance. On the other hand, the sCD40L level was lower (6.7 ng/mL vs. 7.6 ng/mL; p = 0.6) in the PHT group, although this difference was also not significant. In a second analysis, SCD patients had significantly higher levels of D-dimers (1251.5 ng/mL [FEU] vs. 318 ng/mL [FEU]; p = 0.02), sCD40L (7.3 ng/mL vs. 2.8 ng/mL; p = 0.0003), WBC count (9.2 X 10³/μL vs. 7.1 X 10³/μL; p = 0.02) and platelet count (399 X 10³/μL vs. 251 X 10³/μL; p = 0.002) when compared to control individuals. The TAT and F1+2 levels were also higher in SCD patients, although the differences were not significant.

Conclusion: Compared to controls, SCD patients have increased thrombin generation, platelet activation and inflammation. In our cohort, SCD patients with PHT have higher levels of various markers of thrombin generation compared to patients without PHT. The lack of statistical significance is likely a result of the baseline elevation of these markers in SCD patients in steady state and as such, much higher increases in the levels of these markers and/or much larger sample sizes would be required to reveal a significant difference between both groups. This evidence of further activation of coagulation in SCD patients with PHT provides a rationale for clinical trials exploring the use of anticoagulation therapy in these patients.