Risk of Thromboembolism in Patients with Paroxysmal Nocturnal Hemoglobinuria Presenting with Both Clinical Symptoms and Elevated Hemolysis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disorder characterized by chronic complement-mediated hemolysis. Chronic hemolysis is associated with an increased risk of thromboembolism (TE), the major cause of end organ damage and early mortality in PNH. Patients with PNH frequently experience clinical symptoms such as abdominal pain, chest pain, dyspnea, and hemoglobinuria. Pain and dyspnea are a likely consequence of vasoconstriction due to sequestering of nitric oxide by free hemoglobin released during hemolysis. These symptoms not only cause patient distress but may be indicative of advanced disease and an increased risk of TE.

To evaluate if the risk of TE is increased in PNH patients with increased hemolysis, measured by lactate dehydrogenase (LDH) serum levels ≥1.5-fold higher than the upper limit of normal (LDH ≥1.5×ULN), plus any of the four clinical symptoms of abdominal pain, chest pain, dyspnea, or hemoglobinuria during the course of the disease, compared with patients who had an individual clinical symptom or LDH ≥1.5×ULN alone.

This study included 224 PNH patients from the South Korean national PNH registry. In patients with LDH ≥1.5×ULN at diagnosis, associations between the presence of the four individual clinical symptoms and the incidence of TE were analyzed using logistic regression. The effect of multiple symptoms including LDH ≥1.5×ULN on the TE rate was assessed using odds ratios (OR) and associated 95% confidence intervals (CIs).

The results of the analyses between clinical symptoms, LDH ≥1.5×ULN, and the incidence of TEs are tabulated below. The risk of TE was significantly increased in patients with LDH ≥1.5×ULN (OR: 8.57; P<0.001) or who had abdominal pain, chest pain or dyspnea (OR: range 2.74–2.86; P≤0.022) during the course of the disease compared with patients without these individual symptoms. The risk of TE was further increased in patients with both LDH ≥1.5×ULN and at least one of the four symptoms compared with patients with LDH ≥1.5×ULN alone (OR: 9.20; P=0.032). Individual symptom analyses showed that patients with each symptom and LDH ≥1.5×ULN had a significantly increased risk of TE compared with patients without the symptom and LDH <1.5×ULN. This was particularly evident for abdominal pain and chest pain (OR: 17.79 and 19.04, respectively; P≤0.006) but also seen in patients with dyspnea or hemoglobinuria (OR: 10.28 and 10.35, respectively; P≤0.025). These results suggest that the combination of LDH ≥1.5×ULN and one or more of these clinical symptoms poses a much greater risk of a TE than any of the individual factors alone.

These data confirm that hemolysis, identified by LDH ≥1.5×ULN, is a significant risk factor for TE in PNH patients. Importantly, the risk of TE was further increased in patients with both elevated hemolysis and symptoms of abdominal pain, chest pain, dyspnea or hemoglobinuria compared with patients with elevated hemolysis alone. These results suggest that early intervention is important for PNH patients with both elevated hemolysis and clinical symptoms, and also highlight the need for careful monitoring of clinical symptoms that signal an elevated clinical risk for TE.

Lee:Alexion Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jang:Alexion Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees.