<p>Individuals with paroxysmal nocturnal hemoglobinuria (PNH) often present with nonspecific symptoms, making diagnosis challenging. A delayed diagnosis can lead to suboptimal treatment and increased morbidity. The early and accurate diagnosis of PNH is crucial to ensure timely treatment and improve patient quality of life.</p>

PNH is variable and nonspecific in its presentation, which can make it difficult to recognize. Fatigue is the most commonly reported symptom related to hemolytic anemia. The classic triad for PNH is unexplained hemolytic anemia, some degree of cytopenias or bone marrow failure, and thrombosis, especially at unusual sites, such as the intra-abdominal veins. Patients with PNH may report symptoms related to smooth muscle dystonias, such as abdominal pain, dysphagia, and/or erectile dysfunction.

<br>

Patients may initially see a urologist if they have dark urine, or they might seek care with their primary care physician or gastroenterologist for an evaluation of abdominal pain. These providers will likely be considering more common causes of these symptoms, and then, once common etiologies are ruled out, they would refer the patient elsewhere for a broader evaluation.

<br>

PNH is included in the long differential diagnosis of a direct antiglobulin test (DAT)–negative hemolytic anemia. This, combined with the presence of other components of the triad (eg, cytopenias or thrombosis), would raise the clinical suspicion for PNH. Other causes of DAT-negative hemolytic anemia may be distinguished from PNH based on the clinical history and laboratory findings.

<br>

Once PNH is considered, the diagnostic test is fairly straightforward. This is a specific type of flow cytometry to detect the loss of GPI-anchored proteins on blood cells. It is important to look at both red and white blood cell lineages because testing red blood cells alone might lead to an underestimation of the PNH population due to ongoing hemolysis. In patients who have significant leukopenia or thrombocytopenia, a bone marrow biopsy should be done to look for a bone marrow failure syndrome contributing to cytopenias, such as aplastic anemia. It is also important to note that patients with aplastic anemia should be checked for the presence of a PNH clone at initial diagnosis and followed over time, since hemolytic PNH can arise from an aplastic background.

<br>

The key to a PNH diagnosis is to think about it. It is important to recognize that PNH has a variable and nonspecific presentation, and that many patients often lack the full classic triad of unexplained hemolytic anemia, thrombosis (particularly at unusual sites), and some degree of cytopenias or bone marrow failure.