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Paroxysmal Nocturnal Hemoglobinuria (PNH)

By Evan M. Braunstein, MD, PhD, Instructor of Medicine, Johns Hopkins School of Medicine

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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 supportive and with eculizumab, a terminal complement inhibitor.

PNH 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

PNH 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 RBCs.

Pathophysiology

Both arterial and venous thrombosis can occur, including thrombosis of less common sites such as portal veins and cerebral venous sinuses. Protracted urinary hemoglobin loss may result in iron deficiency. PNH is associated with bone marrow dysfunction, 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, iron use, 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 are discussed elsewhere in The Manual.

Diagnosis

  • Flow cytometry

PNH 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 WBC 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 may contain hemosiderin.

Treatment

  • Supportive measures

  • Eculizumab

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

Supportive measures include oral iron and folate supplementation and sometimes transfusions. Corticosteroids (eg, prednisone 20 to 40 mg po once/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 thromboses but should be used cautiously.

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 d before starting eculizumab.

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