Nitric Oxide Consumption and Pulmonary Hypertension in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Pulmonary hypertension (PHT) is an emerging common complication of hereditary hemolytic anemias. It has been mechanistically and epidemiologically linked to intravascular hemolysis and decreased nitric oxide (NO) bioavailability. While this complication has been described in approximately 30% of adult patients with sickle cell disease and thalassemia, the prevalence of PHT in patients with paroxysmal nocturnal hemoglobinuria (PNH), an acquired disease with the highest levels of intravascular hemolysis observed, has never been determined. PNH patients frequently have symptoms consistent with both hemolysis and PHT including severe fatigue and dyspnea on exertion. Therefore, we examined for the presence of PHT in PNH and explored potential mechanisms associated with its development by measuring the ability of plasma to instantaneously consume NO using ozone-based chemiluminescence. Doppler echocardiography was performed in 24 hemolytic PNH patients to estimate pulmonary artery systolic pressures. Systolic PHT was defined by a tricuspid regurgitant jet velocity (TRV) ≥ 2.5m/s at rest. Eleven (46%) patients had elevated pulmonary artery systolic pressures (mean TRV 2.7m/s ± 0.08) and one (4%) had severely elevated pressures (TRV 3.5m/s). Plasma from PNH patients (n=28) consumed 32.26 ± 8.74μM NO while normal subjects (n=9) consumed 2.42 ± 0.77μM NO (p=0.03). LDH levels correlated with NO consumption (p<0.001). Of the 24 patients evaluated for pulmonary pressure, there was no significant correlation between PHT and severity of NO consumption. In a separate analysis, 4 patients treated with eculizumab in the initial pilot study demonstrated a lower NO consumption at 7.34 ± 5.68μM NO at a median of 3.1 (2.3 – 3.1) years after starting eculizumab. Interestingly, 8 of 12 patients not on primary warfarin prophylaxis had PHT whereas only 3 of 12 patients on warfarin had PHT (p=0.04). In addition, warfarin therapy correlated inversely with TRV (R=−0.54; P=0.007). In summary, 1) PHT appears to be extremely common in patients with PNH, adding an additional hemolytic anemia to the growing list of human hemolytic diseases associated with PHT, 2) patients with PNH demonstrate high levels of NO consumption that are highly correlated to intravascular hemolysis (LDH) in these patients, 3) warfarin therapy is associated with lower rates of pulmonary hypertension supporting a strong rationale for primary prophylaxis with warfarin, and 4) eculizumab therapy is associated with reduced levels of NO consumption. Since NO consumption is associated with increased risk of thrombosis, it is possible that NO consumption contributes to thrombosis in PNH patients with PHT. Thus, inhibition of intravascular hemolysis and subsequent NO consumption may be a reasonable approach to reducing thrombotic risk and potentially the incidence of PHT in PNH. Additional studies are required to determine the contributions of chronic pulmonary thromboembolic disease, intravascular hemolysis and reduced NO bioavailability to the pathogenesis of pulmonary hypertension in PNH.