Aplastic anemia is a form of bone marrow failure that presents with pancytopenia and bone marrow aplasia. Etiologies of aplastic anemia are broad with the majority of cases classified as idiopathic. Aplastic anemia is defined by the loss of hematopoietic stem cells (HSCs) which is thought to be primarily autoimmune mediated via cytotoxic lymphocyte destruction of HSCs. There is a close relationship between aplastic anemia and clonal disorders like Paroxysmal Nocturnal Hemoglobinuria (PNH). In PNH, acquired mutations of the PIG-A gene result in absence of CD59 on RBCs which results in complement-mediated destruction. Here we discuss a case of aplastic anemia transformed to PNH that highlights the complexity of these two pathologies.

29-year old male with past medical history relevant for patent foramen ovale and epilepsy initially presented to an outside hospital with mucosal bleeding, weakness, and pancytopenia. Bone marrow biopsy at this time revealed a markedly hypocellular bone marrow (less than 5%), and a diagnosis of aplastic anemia was made. Following this, patient was intermittently followed and treated with Nplate, EPO, and prednisone. Three years following initial diagnosis, patient presented to our hospital with nausea, vomiting, weakness, and fatigue, and mucosal bleeding. Physical exam was unremarkable. On CBC, the patient was found to have pancytopenia with WBC 1.9, platelets of 1 and hemoglobin of 2.4. The differential diagnoses included aplastic crisis, MDS/AML, PNH, and infectious etiologies. To establish a diagnosis, a repeat BM biopsy was performed and revealed a normo- to hyper-cellular marrow with 1% blasts. Chromosomal analysis was negative for Fanconi-related chromosome breakage. Marrow sequencing revealed two variants of uncertain significance in the CTC1 and RMRP genes. Flow cytometry showed presence of GPI anchor deficient cells in 98.18% of granulocytes and 99.36% of monocytes, consistent with a diagnosis of PNH. Infectious workup was unremarkable.

Following these results, a final diagnosis of PNH was made. A confirmatory BM biopsy was requested but the patient refused additional testing. Patient’s treatment course has been limited by various social factors. However, the patient was recently started on treatment with Ravulizumab and will continue on this therapy until the confirmatory biopsy is performed.

References and Resources

1. Brodsky, R. (2022). Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria. In J. A. Melin (Ed.), UpToDate. Retrieved July 7, 2023, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-paroxysmal-nocturnal-hemoglobinuria?search=pnh&source=search_result&selectedTitle=1~90&usage_type=default&display_rank=1
2. Brodsky R. A. (2009). How I treat paroxysmal nocturnal hemoglobinuria. Blood, 113(26), 6522–6527. https://doi.org/10.1182/blood-2009-03-195966