Pulmonary Hypertension and Hemoglobin F Values in Patients with Sickle Cell Disease

Introduction

Sickle cell disease is associated with various complications, including pulmonary hypertension. This complication affects approximately 10% of all individuals with sickle cell disease (SCD) (Ordeuk et al; 2015). Many theories surrounding its mechanism in patients with SCD exist, some including hemolytic anemia-related chronic organ injury, breakdown of erythrocytes releasing pro-inflammatory molecules, upregulation of placental growth factor, loss of peroxisome proliferator-activated receptor ɣ, hyperhomocysteinemia, decreased nitric oxide availability, and alterations in intracellular erythrocyte redox environment. All proposed mechanisms are thought to contribute to vascular endothelial dysfunction (Wood, 2020). Interestingly, there are higher rates of death from pulmonary hypertension reported in patients with SCD who were non-compliant with hydroxyurea compared to patients who were (Steinberg, 2010). This begs the question, does hydroxyurea, and potentially higher levels of hemoglobin F, serve as protective factors for patients against acquiring pulmonary complications such as pulmonary hypertension. Our study analyzed the incidence of pulmonary hypertension and hemoglobin F levels in 496 patients with SCD. We aimed to determine if hemoglobin F is a protective factor against pulmonary hypertension in patients with SCD.

Methods

This study used a descriptive cross-sectional, secondary analysis to analyze the medical records of 496 patients at the Center for Blood Disorders in Augusta, Georgia. Data obtained from the secondary review of patients' charts included thrombotic events (TE), HbF values closest to the TE, and the presence of SCD clinical complications, including pulmonary hypertension. A diagnosis of pulmonary hypertension was confirmed using documented echocardiograms with right ventricular systolic pressure greater than 40. A two-sample t-test was used to compare mean HbF values. All analyses were performed using R version 4.2.3.

Results

One hundred and nine of the 496 patients (21%) in our study had a diagnosis of pulmonary hypertension. Patients diagnosed with pulmonary hypertension had a mean hemoglobin F level of 8.8% with a standard deviation of 11.2. Patients without a diagnosis of pulmonary hypertension had a mean hemoglobin F level of 9.41% with a standard deviation of 9.87. There was no statistical significance between the levels of hemoglobin F in patients with and without pulmonary hypertension (p = 0.6174). Additionally, when controlled for age and hemoglobin F, there was no significant difference in the diagnosis of pulmonary hypertension based on the patient's sex (p = 0.219). The results demonstrated that as a patient's age increases, the incidence of pulmonary hypertension increases (p = 2.00 E-05). The average age of patients with a diagnosis of pulmonary hypertension in our study was 39.8. The average age of diagnosis of pulmonary hypertension for the general population is 51.7 (Krowl, 2023).

Conclusion

Current literature estimates that 10% of sickle cell patients are diagnosed with pulmonary hypertension (Gordeuk et al., 2015). However, this figure may be underestimated. In our study, approximately 21% of patients with SCD had a diagnosis of pulmonary hypertension. Additionally, a previous study analyzed the autopsies of patients with SCD. Researchers found evidence of anatomical changes suggestive of pulmonary hypertension in 75% of the patients with SCD (Wood, 2020). Our cohort showed no significant association between hemoglobin F levels and the incidence of pulmonary hypertension in patients with SCD. This indicates that hemoglobin F does not protect against the development of pulmonary hypertension in patients with SCD. Future studies should be conducted on newer treatment options to determine their effectiveness in preventing complications such as pulmonary hypertension in patients with SCD. Our results did demonstrate an association between age and the incidence of pulmonary hypertension. When controlled for age and hemoglobin F levels, as a patient's age increased, the incidence of pulmonary hypertension increased. Additionally, the average age of patients with pulmonary hypertension in our study was 39.8, and the average age for the general population was 51.7. This demonstrates that patients with SCD have an earlier onset of pulmonary hypertension compared to other causes of pulmonary hypertension.

Kutlar:blue bird bio: Consultancy, Other: DMC; Vertex: Consultancy, Other: Evebt adjudication committee; Akira Bio: Consultancy, Research Funding; NIH/NHLBI: Other: Sickle cell disease Implementation Consortium; REACH and PUSH-UP Studies: Other: DSMB MEMBER (NHLBI); Global Blood Therapeutics/ Pfizer: Other: EAC Member; Novo-Nordisk: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.