Pulmonary endarterectomy as treatment for chronic thromboembolic pulmonary hypertension in sickle cell disease
Authors: Ashley T. Freeman, Kenneth I. Ataga
Journal: American Journal of Hematology (2015)

Pulmonary hypertension (PHT) is defined as a resting mean pulmonary arterial pressure (PAP) ≥ 25 mmHg by right heart catheterization (RHC). It is a common complication of sickle cell disease (SCD), with an estimated prevalence of 6–11% 1. The pathogenesis of PHT in SCD is multifactorial with contributions from hemolysis, inflammation, endothelial dysfunction, hypercoagulability, and thrombosis. Effective strategies for the treatment of SCD-associated PHT have not yet been determined. Here, we report the successful treatment of two cases of chronic thromboembolic pulmonary hypertension (CTEPH) in SCD with pulmonary endarterectomy. A 26-year-old male with HbSS complicated by frequent pain episodes, acute chest syndrome, and recurrent pulmonary thrombosis developed progressive dyspnea on exertion with NYHA class IV symptoms by age 25. Pre-operative echocardiography showed a tricuspid regurgitant jet velocity (TRV) of 3.9 m/sec. Six-minute walk distance (6MWD) was 373 m (47% predicted). Ventilation-perfusion (V/Q) scan revealed multiple, bilateral wedge-shaped perfusion defects. A pulmonary angiogram showed bilateral hypoperfusion in the upper lobes and basal segments, and chronic occlusive changes (Fig. 1). RHC showed a mean PAP of 41 mmHg and pulmonary artery occlusion pressure of 13 mmHg. The patient had a RBC exchange transfusion followed by bilateral pulmonary endarterectomy without complications. Nine months after surgery, a repeat echocardiogram showed a decreased TRV of 2.2 m/sec and his 6MWD improved to 461 m (58% predicted). One year after surgery, his symptoms have improved to NYHA Class II. Pulmonary angiogram demonstrating generalized hypoperfusion of the bilateral upper lobes and lateral basal segments with central vessel truncation (e.g., left lateral basal lobe branch indicated by red arrow) and filling defects (e.g., right upper lobe branch indicated by green arrow). A 38-year-old female with HbSS complicated by frequent pain episodes, acute chest syndrome, and recurrent pulmonary thrombosis developed progressive shortness of breath with NYHA class IV symptoms despite chronic anticoagulation. Pre-operative echocardiography showed a TRV of 4.3 m/sec. Her 6MWD was 263 m (43% predicted) and a V/Q scan showed multiple, bilateral perfusion defects. A RHC revealed a mean PAP of 40 mmHg, with a pulmonary artery occlusion pressure of 11 mmHg. The patient underwent RBC exchange transfusion pre-operatively followed by bilateral pulmonary endarterectomy without complication. Two months after the procedure a repeat echocardiogram showed an improved TRV of 2.5 m/s. Repeat V/Q scan also showed improvement in all old perfusion defects. However, the scan also showed a new defect in the right upper lobe, likely representing a new subacute thrombosis, despite the presence of an IVC filter. Her symptoms improved, from NYHA Class IV to Class III, 6 months post-operatively. Multiple studies in SCD patients show that nearly every aspect of hemostasis is altered in the direction of a procoagulant phenotype. Although an area of ongoing research, several factors, including hemolysis, ischemia-reperfusion injury, and RBC phosphatidylserine exposure are reported to play a role in the pathogenesis of coagulation activation in SCD. Heme, an inflammatory mediator and a product of intravascular hemolysis, induces tissue factor (TF) expression in cultured macrovascular and microvascular endothelial cells in a concentration-dependent manner 2. In addition, increased bioavailability of nitric oxide (NO) by pharmacologic and genetic techniques has been shown to reduce endothelial TF expression in mouse models of SCD 3. While the contribution of coagulation activation to SCD-related complications has not been extensively studied, pulmonary thrombosis may be a major risk factor for PHT in patients with SCD. No significant associations were observed between plasma markers of coagulation activation and echocardiography-derived TRV 4. However, autopsy studies have demonstrated an increased incidence of pulmonary thrombosis in patients with SCD. National and statewide hospital discharge data have also shown an increased incidence of pulmonary embolism amongst SCD patients, but interestingly not an increased incidence of deep vein thrombosis suggesting a high rate of in situ pulmonary thrombosis. More recently, retrospective studies have confirmed the increased risk of venous thromboembolism (VTE) in SCD, with a higher mortality observed in patients with VTE compared to those without this complication 5. There are few studies specifically addressing treatment of PHT in SCD. Current strategies include optimizing SCD therapy and identifying potentially modifiable etiologies such as obstructive sleep apnea, pulmonary thrombosis, and left ventricular dysfunction. Hydroxyurea, approved for treatment of severe anemia and frequent vaso-occlusive episodes, has the potential benefit of being an NO donor. Endothelin receptor antagonists and prostaglandin therapy are approved for treatment of pulmonary arterial hypertension and have been recommended for select SCD patients with marked elevation of pulmonary vascular resistance and normal pulmonary artery occlusion pressure on RHC, and related symptoms 1. Phosphodiesterase-5 inhibitor therapy is presently not recommended as first-line treatment for RHC-confirmed PHT due to the association of sildenafil with increased hospitalizations for pain crises. Riociguat, a soluble guanylate cyclase stimulator, is a vasodilator that bypasses the NO pathway. It has shown promise in CTEPH and PAH, but has not yet been studied in SCD. Although a study of the low molecular weight heparin, tinzaparin showed a reduction in the duration of pain crisis and hospitalization 6, most studies of anticoagulants in SCD have been small and poorly controlled. Treatment with the factor Xa inhibitor, rivaroxaban, as well as PAR-2 or IL-6 deficiency have been reported to attenuate PHT in animal models 7. A study of rivaroxaban in SCD is ongoing to assess its pharmacodynamics effects (www.clinical trials.gov. identifier NCT02072668). Finally, pulmonary endarterectomy is standard for non-SCD patients with CTEPH, but the experience in SCD is limited, possibly due to concerns for a high risk of perioperative complications. Pulmonary endarterectomy requires cardiopulmonary bypass, hypothermia, and periods of circulatory arrest, which will likely increase the risk of sickling. These two cases, along with the previously published reports of four patients who underwent pulmonary endarterectomy 8-10, demonstrate that patients can undergo this procedure safely, with symptomatic and hemodynamic benefit. In summary, SCD patients with CTEPH, should be considered for pulmonary endarterectomy. Authors thank Ertan Pamuklar, MD for help with the figure. Ashley T. Freeman Kenneth I. Ataga* Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina