Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by chronic intravascular hemolysis, which is brought about by the continual activation of alternative pathways of the complement system—an integral part of the innate immune system.

This disease is notoriously invasive, and the rate of correct diagnosis upon first encounter is low. Nevertheless, the past few years have seen progress in terms of how this disease is diagnosed and the therapeutic options available to treat it.

A key reason PNH is so difficult to diagnose is the heterogeneity in its presentation. Symptoms vary and may include signs of bone marrow failure, thrombophilia, fatigue, abdominal pain, renal failure, and pulmonary hypertension. 

PNH Occurring With Headaches and Dyspnea 

The case study of an 18-year-old woman diagnosed with PNH after presenting at the emergency department with headaches and shortness of breath was detailed by Fattizzo and colleagues in the Journal of Clinical Medicine. The headaches were described as being “disabling” in nature.

Read more about PNH etiology 

History-talking revealed that she had asthma during childhood and had started taking birth control medication 3 months earlier. Upon physical examination, the patient appeared to be pale and tachycardic and had scleral jaundice.

Laboratory investigations showed an increase in D-dimer levels, as well as severe hemolytic anemia (hemoglobin: 7.8 g/dL; lactate dehydrogenase: 7 times the upper limit of normal). She had normal anticoagulation times, fibrinogen, platelet, and white cell count. Reticulocyte levels were high (220 x 109/L). 

Direct antiglobulin test was negative. A cytometry assay demonstrated PNH clone levels of 88% granulocytes, 90% monocytes, and 38% erythrocytes. 

Combined, these investigations were enough for the patient’s physicians to diagnose her with PNH. 

A Case of Smoldering and Insidious PNH 

Another case study, also presented by Fattizzo and colleagues, details a 62-year-old woman who presented with abdominal and bone pain, as well as persistent fatigue.

She had a long history of chronic macrocytic anemia and was known to have fibromyalgia and obesity. In the last decade or so, she had been seen by several clinicians under a working diagnosis of anemia of chronic inflammation. A previous course of steroids did not elicit a notable response. 

A closer look at her medical history revealed she was positive for a superficial thrombophlebitis of the left basilic vein. In addition, she had mild chronic kidney disease with a glomerular filtration rate of 50 mL/min. 

When the patient was admitted, she complained of “recurrent urinary tract infections”, which were found to be dark urine episodes during upper respiratory tract infections. Laboratory investigations revealed normocytic anemia with increased red cell distribution width; this was consistent with increasing levels of reticulocytes and iron deficiency (ferritin: 8 ng/mL). Her lactate dehydrogenase levels were 3 times the upper limits of normal, and her unconjugated bilirubin was also increased. 

Direct antiglobulin test was negative. Flow cytometry studies revealed 38% PNH clone size on granulocytes, 43% on monocytes, and 30% on reticulocytes. Combined, these investigations confirmed the diagnosis of classic hemolytic PNH. 

“This case shows how PNH clinical presentation may be smoldering and insidious so that clinical suspicion and careful anamnesis are fundamental,” Fattizzo and colleagues wrote.

Arriving at a Diagnosis 

Schrezenmeier and colleagues reported in the Annals of Hematology on the characteristics of a cohort of patients on the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry

“Substantial proportions of patients had a history of physician-reported PNH-related symptoms at baseline,” including fatigue (80.9%), dyspnea (45.3%), hemoglobinuria (45.0%), abdominal pain (35.2%), dysphagia (16.5%), and erectile dysfunction (24.2%), they wrote

Read more about PNH diagnosis 

In the case studies described by Fattizzo et al, careful laboratory investigations were crucial in helping physicians arrive at the PNH diagnosis. According to the study team, the investigations most pertinent in establishing the diagnosis included whole blood count, hemolytic markers (such as lactate dehydrogenase, bilirubin, and absolute reticulocyte count), urine analysis, and iron/vitamin B12/folate status, as well as hepatic and renal function tests. A direct antiglobulin test is usually negative. 

The presenting symptoms in both cases could easily be attributed to other more common medical causes. Hence, a willingness to investigate the cause of the illnesses by following the evidence is crucial in helping physicians arrive at a correct diagnosis and save lives. This is the only way to beat what has been termed “the great impersonator.” 

“The disease has to be recognized quickly, as its morbidity and mortality can be dramatically reduced with early and proper intervention (monitoring, anticoagulation, complement inhibitors) and with patient education,” Fattizzo et al wrote. 

The good news is that advancements in PNH mean patients have a better shot at living relatively normal lives, provided their disease is correctly diagnosed at the first opportunity. For this to be achieved, physicians must be thoroughly familiar with the contours of the disease and order the right investigations to arrive at an irrefutable conclusion. 


Fattizzo B, Serpenti F, Giannotta JA, Barcellini W. Difficult cases of paroxysmal nocturnal hemoglobinuria: diagnosis and therapeutic noveltiesJ Clin Med. 2021;10(5):948 doi:10.3390/jcm10050948

Schrezenmeier H, Röth A, Araten DJ, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH RegistryAnn Hematol. 2020;99(7):1505-1514. doi:10.1007/s00277-020-04052-z