Association Between Elevated Hemolysis at Diagnosis and Early Mortality and Risk of Thrombosis In Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients with Cytopenia

PNH is a rare, progressive and life threatening disease driven by chronic hemolysis leading to thrombosis, renal impairment, pain, severe fatigue, poor quality of life and premature death. Thrombosis is the leading cause of death (accounting for 40–67% of PNH-related deaths) and was recently identified as a significant risk factor for mortality in Asian PNH patients. Abdominal pain is a common and distressing symptom in PNH and has also been found to be risk factor for thrombosis and mortality in PNH patients. In PNH patients with concomitant aplasia/cytopenias (PNH-cytopenia), the symptoms associated with hemolytic PNH (i.e., severe fatigue and anemia) may be attributed to a hypocellular marrow, potentially masking the life threatening risk of hemolysis-mediated thrombosis and abdominal pain. Here we evaluate the correlation of clinical risk factors with hemolytic symptoms in cytopenic PNH patients.

We retrospectively analyzed medical charts of 286 PNH patients from the National Data Registry in South Korea to identify aplastic PNH patients with evidence of hemolytic symptoms at the time of diagnosis. We defined PNH-cytopenia patients with evidence of at least 2 of the following hematological values at diagnosis: Hgb <10 g/dL; ANC <1.5×10⁹/L; thrombocytopenia <100×10⁹/L. Hemolysis was defined as LDH °Ã1.5 fold above the upper limit of normal (ULN).

The median patient age was 37 years (range: 8 to 88 years) and median PNH duration was 7.8 years. At diagnosis, median PNH granulocyte clone was 49% and LDH was 3.9-fold above ULN. Median platelet count was 99×10⁹/L and median ANC was 1.2×10⁹/L, 21% with ANC <1.0×10⁹/L. PNH-cytopenia was identified at diagnosis in 42% of PNH patients. PNH-cytopenic patients experienced a similar prevalence of hemolytic symptoms and mortality compared to PNH patients with no evidence of cytopenia (PNH) (see table below). Thrombosis was equally prevalent in PNH-cytopenia compared to PNH (12% vs18%; P=0.175). Abdominal pain was equally prevalent in PNH-cytopenia and PNH (52% vs 42%; P=0.112) and there was similar mortality between the 2 groups (13% vs 11%; P=0.631). There was a significantly higher prevalence of mortality (14% vs 4%; p=0.048), thrombosis (22% vs 4%; p=0.003) and abdominal pain (53% vs 32%; p=0.007) in patients with elevated hemolysis (°Ã LDH 1.5 above ULN) compared to patients without hemolysis. We found that 69% of PNH-cytopenia patients demonstrated elevated hemolysis at diagnosis. Thrombosis was identified in 17% of PNH-cytopenia patients with elevated hemolysis compared to 3% with no evidence of elevated LDH (p=0.051); abdominal pain (59% vs 32%; p= 0.012) and death (16% vs 3%; p=0.070) were higher in PNH-cytopenia patients with hemolysis compared to PNH-cytopenia patients without hemolysis.

CONCULSION: These data demonstrate that the presence of hemolysis at diagnosis is associated with of life-threatening thrombosis, poor quality of life, and mortality in PNH patients. Despite the evidence of hypoplasia, PNH-cytopenia patients with hemolysis demonstrate a higher risk of life-threatening thrombosis, pain, and mortality. These data indicate that hemolysis is a potential risk factor for life- threatening complications independent of the presence of cytopenia in patients with PNH. Treatment for PNH patients with cytopenias should focus on both controlling hemolysis as well as improving hypoplasia.

No relevant conflicts of interest to declare.