Paroxysmal Nocturnal Hemoglobinuria


Revisiting the Distinct Phenotypic Categories of Paroxysmal Nocturnal Hemoglobinuria

conference reporter by Jaroslaw P. Maciejewski, MD, PhD, FACP

The phenotypic characterization of paroxysmal nocturnal hemoglobinuria (PNH) is evolving. Researchers at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition presented data proposing the recognition of a unique phenotype of PNH that is distinct from the existing phenotypic categories that are recognized by the International PNH Interest Group (IPIG).


Following this presentation, featured expert Jaroslaw P. Maciejewski, MD, PhD, FACP, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Maciejewski’s clinical perspectives on these findings are presented here.

“There was an abstract presented at ASH 2023 describing a unique subset of patients who do not have hemolysis, yet the red blood cell clone is small. . . . Normally, the red blood cell clones are small because most of them are being lysed.”
— Jaroslaw P. Maciejewski, MD, PhD, FACP

PNH phenotypes were previously classified by IPIG as being classic PNH, PNH in the setting of another bone marrow disorder, or subclinical PNH. People now think of PNH phenotypes differently. For example, there is aplastic anemia with a tiny PNH clone, aplastic anemia with a sufficiently large clone that could produce PNH symptoms, and hemolytic PNH. Hemolytic PNH is divided into primary hemolytic PNH or secondary hemolytic PNH based on the patient’s history. There is no other bone marrow failure syndrome that is associated with PNH, so the presence of a PNH clone is almost confirmatory for immune-mediated bone marrow failure, namely aplastic anemia. Clinically significant PNH does not arise in patients with myelodysplastic syndrome (MDS), congenital bone marrow failure, or chemotherapy- or other drug-induced bone marrow failure.


Some patients who are diagnosed with MDS, likely due to the presence of erythroid dysplasia, are later found to have a PNH clone. Indeed, their PNH may have been misdiagnosed. Such patients had PNH to begin with, and their doctors just could not diagnose it. The only PNH/MDS that exists is the MDS that evolves from PNH. In this case, the question is: Does the patient have a PNH clone and an MDS clone and the MDS clone takes over (usually displacing the PNH clone), or did the MDS clone evolve from within the PNH clone? In my opinion, the latter is much less common. In general, the presence of a PNH clone has been found to be exceedingly rare and should prompt investigations of PNH.


There was an abstract presented at ASH 2023 describing a unique subset of patients who do not have hemolysis, yet the red blood cell clone is small (abstract 1352). Normally, the red blood cell clones are small because most of them are being lysed. So, the only explanation for it, in my mind, is to assume that the PIGA mutation affects more myeloid precursor cells than erythroid precursor cells, whereas, in normal cases, the mutation is present prior to the commitment to differentiate between erythroid and myeloid precursor cells. With PNH, like any disease, there are nuances, including the propensity to develop extravascular hemolysis, thrombotic complications, and PNH diversity due to the position of the mutation within the PIGA gene and whether there are more type II or III PNH cells.


Remissions sometimes occur, and I have experienced a few of them. The question then becomes: Is this a true remission or a replacement of the PNH clone by an MDS clone that is not a PNH mutant? If an MDS clone evolves as a PNH subclone by the acquisition of additional mutations, then all the cells would be a PNH phenotype. But sometimes you see a decline in PNH clone size because the other clone contains another mutation that has a survival advantage over the PNH cells.


In terms of the phenotype, I think that you have to clinically distinguish between patients with hemolytic PNH (who have chronic, high-level hemolysis) and patients with chronic, low-level baseline hemolysis (whose PNH comes in attacks and who have hemolytic crisis once or twice per year but are otherwise fine). Patients in the latter group usually have a greater number of type II PNH cells, and they are relatively asymptomatic until something hits them, such as another disease or infection, and they end up in the Emergency Department with a hemolytic crisis. Whereas, day-to-day, patients in the former group are in a state of constant crisis.


Babushok DV. When does a PNH clone have clinical significance? Hematology Am Soc Hematol Educ Program. 2021;2021(1):143-152. doi:10.1182/hematology.2021000245


Korkama E-S, Armstrong A-E, Jarva H, Meri S. Spontaneous remission in paroxysmal nocturnal hemoglobinuria—return to health or transition into malignancy? Front Immunol. 2018;9:1749. doi:10.3389/fimmu.2018.01749


Lian Y, Shi J, Nie N, et al. Evolution patterns of paroxysmal nocturnal hemoglobinuria clone and clinical implications in acquired bone marrow failure. Exp Hematol. 2019;77:41-50. doi:10.1016/j.exphem.2019.08.005


Nakao S. Diagnostic problems in acquired bone marrow failure syndromes. Int J Hematol. 2016;104(2):151-152. doi:10.1007/s12185-016-2057-4


Parker C, Omine M, Richards S, et al; International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106(12):3699-3709. doi:10.1182/blood-2005-04-1717


Sun L, Babushok DV. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2020;136(1):36-49. doi:10.1182/blood.2019000940


Tombul Z, Bahaj W, Ozturk M, et al. Ahemolytic PNH: clinical features of a distinct phenotype of paroxysmal nocturnal hemoglobinuria [abstract 1352]. Abstract presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA.



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Jaroslaw P. Maciejewski, MD, PhD, FACP

Chairman, Department of Translational Hematology and Oncology Research
Taussig Cancer Institute
Cleveland Clinic
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University School of Medicine
Cleveland, OH