Aplastic Anemia and PNH: Current Clinical Perspectives

Aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are distinct but interrelated hematologic disorders that often present together, complicating diagnosis and management. AA is marked by bone marrow failure leading to pancytopenia, while PNH results from clonal expansion of hematopoietic stem cells with a genetic mutation affecting red blood cell stability. Their coexistence suggests shared underlying mechanisms, particularly immune dysregulation.

Recognizing this overlap is crucial for timely diagnosis and effective treatment. Advances in understanding their pathophysiology have led to improved diagnostic tools and targeted therapies.

Immune Dysregulation In Bone Marrow

In AA, immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs) alters the bone marrow environment. Cytotoxic CD8+ T cells play a central role by releasing pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which induce apoptosis and suppress proliferation by disrupting key signaling pathways, including STAT1 and JAK-STAT. The resulting marrow hypoplasia leads to pancytopenia.

Diminished regulatory T cells (Tregs) further exacerbate marrow failure. Normally, Tregs maintain immune tolerance, but in AA, their reduced numbers and impaired function allow autoreactive T cells to persist, perpetuating hematopoietic destruction. Studies show a lower Treg-to-effector T cell ratio in severe AA, correlating with disease severity and response to immunosuppressive therapy.

Beyond T cell dysfunction, aberrant antigen presentation by dendritic cells and monocytes amplifies the immune attack. Increased human leukocyte antigen (HLA) class II expression on these cells enhances autoreactive T cell activation, fueling inflammation. Elevated soluble immune mediators such as interleukin-2 (IL-2) and IL-17 sustain this pro-inflammatory environment, reinforcing marrow suppression.

PNH Clones In Aplastic Anemia

A significant proportion of AA patients harbor PNH clones, which arise from somatic mutations in the PIGA gene. This mutation disrupts glycosylphosphatidylinositol (GPI) anchor biosynthesis, leading to a loss of complement regulatory proteins CD55 and CD59, making red blood cells susceptible to complement-mediated lysis.

The bone marrow failure in AA creates conditions favoring PNH clone survival. Suppressed normal hematopoiesis gives PIGA-mutant clones a selective advantage, as they may be more resistant to immune-mediated destruction. Longitudinal studies show these clones can persist for years, sometimes expanding to clinically significant levels with hemolysis, hemoglobinuria, or thrombosis. However, many remain small and asymptomatic, complicating treatment decisions.

Flow cytometry is the gold standard for detecting PNH clones, allowing identification of even minor GPI-deficient populations. Studies suggest small PNH clones in AA correlate with better responses to immunosuppressive therapy (IST), particularly with antithymocyte globulin (ATG) and cyclosporine. This supports the idea that PNH clones serve as a biomarker of immune-mediated hematopoiesis. However, their clinical significance remains uncertain, and ongoing research aims to clarify their role in disease progression and treatment outcomes.

Laboratory Investigations

Accurate laboratory evaluation is essential for distinguishing AA from PNH and assessing their coexistence. A complete blood count (CBC) typically reveals pancytopenia in AA, while PNH may present with hemolytic anemia, reticulocytosis, and variable white blood cell and platelet counts. The mean corpuscular volume (MCV) is often elevated in AA due to stress erythropoiesis, whereas schistocytes or polychromasia on a peripheral smear suggest hemolysis in PNH.

Bone marrow examination helps differentiate the two conditions. AA is characterized by hypocellularity, reduced hematopoietic precursors, and increased fat content without significant dysplasia or fibrosis. PNH lacks defining marrow pathology but may coexist with AA, necessitating additional testing for GPI-anchor deficient cells. Flow cytometry remains the gold standard for detecting PNH clones, assessing CD55 and CD59 expression on blood cells. A PNH clone size exceeding 10% is typically associated with clinical symptoms, but even smaller clones may hold prognostic value.

Biochemical markers further aid diagnosis. Elevated lactate dehydrogenase (LDH) and low haptoglobin indicate intravascular hemolysis, a hallmark of PNH, whereas AA alone does not typically present with these findings. Elevated serum erythropoietin suggests a compensatory response to anemia, while iron studies assess secondary complications such as transfusion-related iron overload. Urine hemosiderin and hemoglobinuria testing support PNH diagnosis, particularly in cases with episodic nocturnal hemolysis.

Clinical Presentations

Patients with AA and PNH exhibit diverse symptoms, influenced by bone marrow failure and hemolysis severity. In AA, pancytopenia leads to fatigue from anemia, recurrent infections due to neutropenia, and mucocutaneous bleeding caused by thrombocytopenia. Symptoms develop gradually, with progressive weakness, pallor, and petechiae. Severe cases risk life-threatening complications such as sepsis or major bleeding.

PNH presents differently, primarily driven by intravascular hemolysis and thrombosis. Hemoglobinuria, often most pronounced in the morning due to nocturnal complement activation, is a classic but not universal symptom. Patients may experience dark-colored urine, jaundice, and abdominal pain, likely due to nitric oxide depletion from free hemoglobin scavenging. Thrombosis, particularly in atypical sites like the hepatic, mesenteric, or cerebral veins, is a major cause of morbidity and mortality. Unlike AA, where infections and bleeding dominate, PNH-related thrombosis can be sudden and severe, requiring urgent intervention.