Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic condition affecting hematopoietic stem cells that is characterized by the premature destruction of erythrocytes.1 Patients with PNH present with several notable clinical features, particularly hemolytic anemia, bone marrow failure, smooth muscle dystonia, and thrombosis.2

Hematologic Features

Intravascular hemolysis caused by the clonal expansion of PIGA-mutated hematopoietic stem cells results in abnormal laboratory tests that show increased levels of lactate dehydrogenase  (LDH), reticulocytes, and indirect bilirubin, along with low levels of haptoglobin. While premature erythrocyte destruction occurs constantly in PNH, periods of stress, trauma, or infection may exacerbate intravascular hemolysis.1,3 

Hemolysis in PNH leads to acquired hemolytic anemia, which can present with a number of clinical symptoms, including2,3:

  • Extreme fatigue
  • Increased need for sleep
  • Tachycardia
  • Headache
  • Dizziness or lightheadedness
  • Weakness
  • Acute or chronic renal dysfunction
  • Smooth muscle dystonia
  • Dyspnea, especially on exertion 
  • Chest pain
  • Jaundice
  • Pallor

High serum LDH levels may indicate increased erythrocyte destruction. Urinalysis may reveal the presence of hemoglobin or excess iron deposits.4 

A minority of patients with classic PNH report hemoglobinuria, which is most apparent as reddish, brownish, or cola-colored urine in the morning after hemoglobin collects overnight in the bladder before excretion. Most patients with PNH demonstrate no visible hemoglobinuria or experience hemoglobinuria intermittently without relation to time of day.2

Read more about PNH signs and symptoms

Bone Marrow Dysfunction

All patients with PNH have some form of bone marrow dysfunction. Those with mild bone marrow dysfunction often are asymptomatic or present with only mild symptoms, while those with severe bone marrow dysfunction may exhibit pancytopenia: the triad of anemia, leukopenia, and thrombocytopenia.3 

In addition to the signs and symptoms of anemia, patients with leukopenia have an increased risk of developing bacterial and fungal infections, while those with thrombocytopenia have an increased risk of excessive bleeding or bruising, especially of the gums and nose. Women with PNH and thrombocytopenia may experience menorrhagia.3 

Patients with PNH may have comorbid aplastic anemia or myelodysplastic syndrome, which are also conditions related to bone marrow failure. The cause of myelodysplastic syndrome in PNH patients is unknown, although clinical studies show that the majority of the patients have acquired somatic genetic abnormalities in bone marrow cells. PNH rarely transforms into acute leukemia.3

Read more about PNH comorbidities

Smooth Muscle Dystonia

Hemolysis of erythrocytes leads to increased levels of free hemoglobin circulating in the blood. Excess free hemoglobin in the blood scavenges nitric oxide, which regulates smooth muscle tone and platelet activation.5 

In PNH, the reduction of nitric oxide plasma levels due to free hemoglobin scavenging results in smooth muscle dystonias, such as hypertension, gastrointestinal contractions, and erectile dysfunction. Lower nitric oxide plasma levels may also contribute to clot formation.5 Clinically, patients with PNH and smooth muscle dystonia may present with pulmonary hypertension, abdominal pain, dysphagia, and erectile dysfunction.6

Read more about PNH diagnosis

Renal Impairments

In PNH, renal dysfunction may present as either acute or chronic renal disease. Up to 65% of patients with PNH have comorbid chronic renal disease, while 21% present with renal insufficiency.7

Several pathophysiological mechanisms contribute to renal injury in patients with PNH. These mechanisms include7:

  • Renal ischemia or hypovolemia
  • Toxicity of free hemoglobin, which directly affects tubular cells in the kidneys
  • Glomerular deposition of fibrin
  • Obstruction of renal tubules by uric acid crystals or hemoglobin urinary casts

Read more about PNH pathophysiology

Thrombotic Features

Up to 30% of patients with PNH experience thrombosis, especially deep vein thrombosis in unusual veins, such as the hepatic, abdominal, cerebral, and subdermal veins. It is the most common cause of mortality among patients with PNH.3,8

Hepatic vein thrombosis, also known as Budd-Chiari syndrome, can progress slowly in PNH or have an abrupt onset of symptoms. It is characterized by rapidly progressing splenomegaly, ascites, abdominal pain, and jaundice. This may progress to hepatic failure, vascular collapse, and/or death.8

Thrombotic events in the abdominal vessels may cause abdominal pain lasting 1 to 6 days and potentially bowel infarction if severe.8

Cerebral vein thrombosis may present as a mild to severe headache.8

Dermal vein thrombosis may cause raised, painful, red skin nodules affecting large regions. These lesions often resolve within a few weeks, typically without necrosis. If necrosis occurs, the patient may require skin grafting.8  

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Inflammatory Manifestations

Free circulating plasma hemoglobin and heme — the byproducts of hemoglobin metabolism — activate endothelial cells and coagulation. They are also proinflammatory, potentially due to their consumption of nitric oxide. Inflammatory biomarkers may be elevated on serological testing.5

Read more about PNH testing

References 

  1. Paroxysmal nocturnal hemoglobinuria. MedlinePlus. Updated February 24, 2022. Accessed November 22, 2022. 
  2. Brodsky R. Paroxysmal nocturnal hemoglobinuria: what every physician needs to know. Cancer Therapy Advisor. Accessed November 22, 2022.
  3. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders (NORD). Accessed November 22, 2022.
  4. Paroxysmal nocturnal hemoglobinuria. Cleveland Clinic. Accessed November 22, 2022.
  5. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. doi:10.1001/jama.293.13.1653
  6. Brodsky RA. Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria. UpToDate. Updated June 10, 2022. Accessed November 22, 2022.
  7. Kokoris SI, Gavriilaki E, Miari A, et al. Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment. Hematology. 2018;23(8):558-566. doi:10.1080/10245332.2018.1444563
  8. Besa EC. Paroxysmal nocturnal hemoglobinuria clinical presentation. Medscape. Updated May 20, 2021. Accessed November 22, 2022.

Reviewed by Debjyoti Talukdar, MD, on 11/29/2022.

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