Impact of Severe Pain on Outcomes in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder that renders affected red blood cells sensitive to complement-mediated lysis resulting in the release of hemoglobin. Excessive and persistent complement activation leads to chronic red cell hemolysis and direct activation of platelets and macrophages, causing inflammation, hemostatic activation, thromboembolism, ischemia, and, ultimately organ damage. Cell-free plasma hemoglobin in patients with PNH has been shown to deplete nitric oxide (NO), leading to smooth muscle constriction. The combination of thrombosis and vasoconstriction can lead to symptoms of end organ damage such as abdominal pain, chest pain and dyspnea. The relation of pain to severe morbidities and mortality has not been previously examined in PNH patients.

To determine whether severe pain in PNH patients is predictive of mortality, thrombosis or life-disabling morbidities, we retrospectively analyzed medical charts of 301 PNH patients from a national data registry in South Korea over the last 41 years. Patients with severe pain, defined as patients receiving opioids and/or NSAIDs for pain management, were compared to patients with no history of pain medication. We compared life-threatening morbidities and mortality between patients using pain medication (n=83) and patients with no pain medication (n=214).

Twenty-eight percent (83/297) of patients reported the use of opioid or NSAIDs. There was no significant difference between patients with severe pain and patients with no pain medication with respect to age at diagnosis (38 vs 40 years, P=0.412), granulocyte clone size (54% vs 48%, P=0.223) and LDH fold above normal at diagnosis (6.2 vs 5.3 fold, P=0.279). Thrombosis was recorded in 43% of patients with severe pain in contrast to 8% in patients with no pain medication (P<0.001). Patients with severe pain had an 8.4-fold greater risk for thrombosis compared to patients with no pain management (OR=8.4, 95% CI [4.15–17.08]; P<0.001). Twenty-five of the 83 patients with pain medication (30%) died during the follow up period of observation, a significantly higher rate of mortality compared to patients with no pain medication (8%; P<0.001). Patients with severe pain are roughly 5 times at greater risk for early mortality compared to patients with no pain medication (OR=4.8, 95% CI [2.44–9.38]; P<0.001).

These data demonstrated that PNH patients with severe pain experience an increased risk of thrombosis and early mortality. Almost 1 in 3 PNH patients experienced severe pain requiring pain medication during their disease. Patients with severe pain had an increased risk of thrombosis, which may support the idea that ischemia or microthrombi of small vessels, in addition to smooth muscle dystonia due to NO depletion, drives the severe pain in these patients. Our data also suggests that symptoms of consistent pain, including abdominal pain, chest pain and flank pain, may represent a continued progression and manifestation of complement activation and progressive organ damage that leads to early mortality and poor quality of life. Along with thrombosis and renal impairment as the major risk factors affecting survival, severe pain should be considered as a predictive factor of mortality. These results suggest that early signs of pain in PNH should be managed at the root cause (uncontrolled hemolysis), and that pain is a risk factor of poor outcomes in patients with PNH.

Lee:Novartis: Honoraria; Alexion: Honoraria. Chung:Novartis: Research Funding.