Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria is a clonal disorder caused by an acquired mutation in the PIGA gene in 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).

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 Iron Deficiency Iron (Fe) is a component of hemoglobin, myoglobin, and many enzymes in the body. Heme iron is contained mainly in animal products. It is absorbed much better than nonheme iron (eg, in plants... read more .

Paroxysmal nocturnal hemoglobinuria is associated with bone marrow dysfunction, likely due to immunologic attack on hematopoietic stem cells, often leading to leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (⁹/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more and thrombocytopenia Thrombocytopenia Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more . About 20% of patients with severe aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more , another clonal hematopoietic disorder, have a detectable PNH clone.

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.

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 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.

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

Monoclonal antibodies that bind to C5 and act as terminal complement inhibitors (eg, eculizumab) have changed the course of the disorder. They are given to all patients who require treatment. Complement inhibition reduces transfusion requirements, thromboembolism risk, and symptoms and improves quality of life. However, this therapy also increases the risk of infection with Neisseria meningitidis, so patients should receive the meningococcal vaccine Meningococcal Vaccine The meningococcal serogroups that most often cause meningococcal disease in the United States are serogroups B, C, and Y. Serogroups A and W cause disease outside the United States. Current... read more or initiate prophylactic antibiotic treatment at least 14 days before starting therapy .

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 complement inhibition is unavailable. However, due to the adverse effects of long-term use, corticosteroids should be avoided for long-term treatment.

Generally, transfusions Technique of Transfusion CAUTION: Before transfusion is started, consent should be obtained, and the patient’s wristband, blood unit label, and compatibility test report must be checked at the bedside to ensure that... read more are reserved for crises. Washing RBCs with saline before transfusion is no longer necessary. Heparin followed by warfarin or other anticoagulants is given for acute thrombosis but is not usually required long term once complement inhibitor therapy is initiated..