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Paroxysmal Nocturnal Hemoglobinuria (PNH)

By

Evan M. Braunstein

, MD, PhD, Johns Hopkins School of Medicine

Last full review/revision Sep 2020| Content last modified Sep 2020
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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder characterized by intravascular hemolysis and hemoglobinuria. Leukopenia, thrombocytopenia, arterial and venous thromboses, and episodic crises are common. Diagnosis requires flow cytometry. Treatment is with a terminal complement inhibitor such as eculizumab.

Paroxysmal nocturnal hemoglobinuria is most common among men in their 20s, but it occurs in both sexes and at any age. Hemolysis occurs throughout the day not just at night-time.

Etiology

Paroxysmal nocturnal hemoglobinuria is a clonal disorder caused by an acquired mutation in the PIGA gene of hematopoietic stem cells. PIGA, located on the X chromosome, encodes a protein that is integral for formation of the glycosylphosphatidylinositol (GPI) anchor for membrane proteins. Mutations in PIGA result in loss of all GPI-anchored proteins, including CD59, an important complement-regulating protein, on the surface of blood cells. As a consequence, cells are susceptible to complement activation, leading to ongoing intravascular hemolysis of red blood cells (RBCs).

Pathophysiology

Both arterial and venous thrombosis can occur in the extremities as well as in less common sites such as portal veins and cerebral venous sinuses. Thrombosis is a result of increased complement activation and hemolysis.

Protracted urinary hemoglobin loss may result in iron deficiency.

Paroxysmal nocturnal hemoglobinuria is associated with bone marrow dysfunction, likely due to immunologic attack on hematopoietic stem cells, often leading to leukopenia and thrombocytopenia. About 20% of patients with severe aplastic anemia, another clonal hematopoietic disorder, have a detectable PNH clone.

Symptoms

Crises are usually precipitated by a "trigger," such as infection, transfusion, vaccination, or menstruation. Abdominal, chest, and lumbar pain and symptoms of severe anemia may occur; gross hemoglobinuria and splenomegaly are common. Manifestations of vascular thrombosis depend on the affected vessel and can cause symptoms such as abdominal pain or headache, in addition to leg or arm swelling.

Diagnosis

  • Flow cytometry

Paroxysmal nocturnal hemoglobinuria is suspected in patients who have typical symptoms of anemia (eg, pallor, fatigue, dizziness, possible hypotension) or unexplained normocytic anemia with intravascular hemolysis, particularly if leukopenia or thrombocytopenia and/or thrombotic events are present.

Historically, if PNH was suspected, the acid hemolysis (Ham test) or sugar-water test was usually the first test done. These tests relied on activation of complement via acidification of serum or high-concentration sucrose solutions.

Currently, diagnosis of PNH is with flow cytometry, which is used to determine the absence of specific RBC or white blood cell cell surface proteins (CD59 and CD55). This test is highly sensitive and specific.

Bone marrow examination is not necessary but, if done to exclude other disorders, usually shows erythroid hyperplasia.

Gross hemoglobinuria is common during crises, and the urine will contain hemosiderin constantly.

Treatment

  • Complement inhibitors (eg, eculizumab)

  • Supportive measures

Patients with small clones (ie, < 10% by flow cytometry) who are largely asymptomatic generally do not need treatment. Indications for treatment include

  • Symptomatic hemolysis requiring transfusions

  • Thrombosis

  • Other cytopenias

Eculizumab, a monoclonal antibody that binds to C5 and acts as a terminal complement inhibitor, has remarkably changed the course of the disorder. It is given to all patients who require treatment. Eculizumab reduces transfusion requirements, thromboembolism risk, and symptoms and improves quality of life. However, eculizumab increases the risk of infection with Neisseria meningitidis, so patients should receive the meningococcal vaccine at least 14 days before starting eculizumab.

Supportive measures include oral iron and folic acid supplementation and sometimes transfusions. Corticosteroids (eg, prednisone 20 to 40 mg orally once a day) can control symptoms and stabilize RBC values in > 50% of patients and can be used when eculizumab is unavailable. However, due to the adverse effects of long-term use, corticosteroids should be avoided for chronic treatment.

Generally, transfusions are reserved for crises. Transfusions containing plasma (and thus C3) should be avoided. Washing RBCs with saline before transfusion is no longer necessary. Heparin followed by warfarin or other anticoagulants may be required for acute thrombosis but is not usually required long term once complement inhibitor therapy is initiated..

Key Points

  • Paroxysmal nocturnal hemoglobinuria (PNH) can cause hemolysis at any time of day not only at night.

  • Common clinical features include hemoglobinuria, pancytopenia and arterial and venous thromboses.

  • Venous thromboses occur in unusual locations eg in hepatic veins.

  • Treat symptomatic patients with complement inhibitors.

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