Abstract
Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell disorder characterized by somatic mutations in the PIGA gene, resulting in a deficiency of glycosylphosphatidylinositol (GPI)-anchored surface proteins such as CD55 and CD59. This deficiency renders hematopoietic cells vulnerable to complement-mediated lysis, leading to intravascular hemolysis, bone marrow failure, and life-threatening thromboses. While classic manifestations include hemolytic anemia and thrombotic events, PNH can present with nonspecific cytopenias, particularly in patients with overlapping autoimmune disorders. We describe a diagnostically challenging case of PNH initially misattributed to refractory immune thrombocytopenia (ITP), highlighting the importance of clinical vigilance in older adults.
Case Description: An 82-year-old woman with a history of Sjögren's syndrome and autoimmune hypothyroidism presented with progressive fatigue, mucosal bleeding, and worsening thrombocytopenia (platelets 9 x 10⁹/L) unresponsive to corticosteroids, IVIG, and weekly romiplostim over two months. Initial evaluation revealed normocytic anemia (Hb 9.2 g/dL), elevated LDH (420 U/L), undetectable haptoglobin, indirect hyperbilirubinemia (T. bili 2.1 mg/dL, I. bili 1.7 mg/dL), and negative direct antiglobulin test (DAT). Reticulocyte count was mildly elevated (3.1%). A peripheral smear showed occasional schistocytes, anisopoikilocytosis, and borderline leukopenia. Prior diagnoses included ITP and iron deficiency, though iron studies and inflammatory markers were unremarkable.
Due to her lack of response to ITP-directed therapies and subtle evidence of hemolysis, further evaluation was pursued. Bone marrow biopsy demonstrated normocellular marrow with preserved trilineage hematopoiesis, mild erythroid hyperplasia, and no dysplasia or fibrosis. Flow cytometry of peripheral blood revealed a PNH clone with 60% GPI-deficient granulocytes, 45% monocytes, and 15% erythrocytes. Testing for B12, folate, TSH, ANA, anti-dsDNA, and antiphospholipid antibodies were unremarkable. CT angiography of the abdomen and pelvis showed no evidence of thrombosis or organomegaly.
She was diagnosed with classic hemolytic PNH and began treatment with ravulizumab following meningococcal and pneumococcal vaccination. Within three weeks, her platelet count improved to 42 x 10⁹/L, LDH levels normalized, and transfusion independence was achieved. Notably, romiplostim was discontinued without recurrence of severe thrombocytopenia. She reported marked improvement in energy and physical function, with sustained hematologic response at six-month follow-up.
Discussion: This case underscores the diagnostic complexity of PNH in older adults, particularly in the setting of autoimmune comorbidities and isolated cytopenias. While thrombocytopenia in elderly patients is commonly attributed to ITP or myelodysplasia, persistent transfusion requirements, Coombs-negative hemolysis, and therapeutic nonresponse should prompt reevaluation. Our patient's initial misdiagnosis delayed appropriate treatment, reinforcing the need for high clinical suspicion in cytopenias refractory to standard immunosuppressive regimens.
PNH may present insidiously or overlap with autoimmune marrow suppression. Flow cytometry remains the gold standard for diagnosis and should be pursued in patients with unexplained cytopenias, particularly when bone marrow is normocellular and lab findings suggest intravascular hemolysis. Complement inhibition with ravulizumab or eculizumab can transform the disease course by reducing hemolysis, thrombosis, and transfusion dependence.
In conclusion, this case illustrates that classic hemolytic PNH may present as isolated thrombocytopenia in patients with autoimmune backgrounds. Early recognition and targeted therapy can significantly improve patient outcomes and quality of life, even in the elderly.
