Diagnostic delays and misdiagnosis patterns in paroxysmal nocturnal hemoglobinuria

Abstract

Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by complement-mediated hemolysis, cytopenias, and thrombosis. Its nonspecific clinical presentation frequently results in diagnostic confusion with common hematologic and systemic disorders, significantly delaying diagnosis and increasing patient morbidity. We conducted a systematic review to identify patterns and reasons behind diagnostic delays and misdiagnosis of PNH. Methods: In accordance with PRISMA guidelines, we systematically searched PubMed, Embase, and Google Scholar up to July 2025 for English-language case reports or series confirming PNH diagnosis (by flow cytometry or Ham test) with documented ≥12-month diagnostic delay or initial misdiagnosis explicitly reported. Two independent reviewers extracted patient demographics, clinical presentations, initial misdiagnoses, duration of diagnostic delay, triggers for correct diagnosis, and clinical outcomes. Results were compared to contemporary data from international PNH registries. Results: We included 68 patients and median age at symptom onset was 30 years (IQR 24–49), significantly younger than the reported international registry median (~45 years), highlighting potential under-recognition in younger adults.Females comprised 45.6% of cases, consistent with registry data. Median diagnostic delay was 24 months (IQR 12–60). Only 20.6% were diagnosed within one year of symptom onset; about half the registry-reported rate of (~40%), and 22.1% experienced delays over five years. Frequent initial misdiagnoses included iron-deficiency anemia, aplastic anemia/myelodysplastic syndrome, and autoimmune hemolytic anemia, collectively accounting for over one-third of misdiagnoses. Renal and gastrointestinal symptoms represented persistent diagnostic pitfalls, with median delays of approximately 34 months, indicating ongoing challenges differentiating hemolytic symptoms from more common renal or gastrointestinal complaints. Extreme delays (median ~11 years) were associated with initial misdiagnoses of autoimmune or inflammatory diseases. Conversely, unusual-site thromboses (hepatic, portal, cerebral veins) led to faster recognition (median delay: 3 months) Clinical triggers prompting definitive PNH testing were persistent unexplained hemolysis (46%), thrombotic events (37%), incidental findings from marrow biopsies or flow cytometry performed for unrelated cytopenias (29%), overt hemoglobinuria (26.5%), and unexplained refractory cytopenias (26.5%). Misinterpreting hemoglobinuria as infection or hematuria frequently contributed to delayed diagnosis. Notably, demographic characteristics, particularly race/ethnicity, were underreported (23.5% of cases). Conclusions: Significant diagnostic delays persist in recognizing Paroxysmal Nocturnal Hemoglobinuria (PNH), even in the era of accessible confirmatory testing. Diagnostic delays frequently arise due to significant clinical overlap between PNH and bone marrow failure syndromes such as aplastic anemia and myelodysplastic syndromes, prolonging diagnostic delays. Diagnostic delays are particularly pronounced when PNH presentations mimic autoimmune or systemic inflammatory diseases. Conversely, unusual-site thromboses were linked to earlier diagnoses, underscoring thrombosis as a critical diagnostic clue. The under-reporting of key demographic information, such as race and ethnicity, underscores the need for improved documentation to fully understand disparities and diagnostic challenges in PNH. Early recognition is essential; this systematic review highlights common diagnostic pitfalls that clinicians should appreciate to facilitate timely diagnosis and improve patient outcomes.