Пароксизмальна нічна гемоглобінурія (ПНГ)

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 of membrane proteins. Mutations in PIGA result in loss of all GPI-anchored proteins, including CD55 and CD59, important complement-regulating proteins, 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.

Paroxysmal nocturnal hemoglobinuria is associated with bone marrow dysfunction, likely due to immunologic attack on hematopoietic stem cells, often leading to leukopenia and thrombocytopenia. Approximately 50% of patients with acquired aplastic anemia, an autoimmune bone marrow failure disorder, have a detectable PNH clone (1).

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.

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.

• 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.

Diagnosis of PNH is with flow cytometry, which is used to determine the absence of specific RBC or white blood cell surface proteins (CD59, CD55, and fluorescein-labeled proaerolysin [FLAER] on leukocytes. Flow cytometry 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.

Approximately one third of patients with PNH clones have classic PNH with features of hemolysis and thrombotic risk (1). PNH clones commonly occur in patients with bone marrow failure (acquired aplastic anemia) who do not have PNH-related symptoms. These patients typically have smaller (< 30%), subclinical PNH clones and do not benefit from complement inhibitors; instead, definitive therapy is directed at the aplastic anemia. However, classic PNH can evolve from aplastic anemia, and patients with aplastic anemia should be screened annually for the presence of a PNH clone. Conversely, patients presenting with classic PNH may experience progressive bone marrow failure and ultimately require treatment for aplastic anemia with immunosuppression or bone marrow transplant.

• 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 anemia or a transfusion requirement

• Thrombosis

Complement inhibition reduces transfusion requirements, thromboembolism risk, and symptoms and improves quality of life.

Monoclonal antibodies that bind to C5 and act as terminal complement inhibitors (eg, eculizumab) are often used. In a clinical trial, eculizumab reduced intravascular hemolysis and was effective therapy for PNH (1).

The proximal complement inhibitors pegcetacoplan (C3 inhibitor, given by subcutaneous infusion) and iptacopan (oral factor B inhibitor, given orally) block hemolysis through the alternative pathway. Proximal complement inhibitors have the potential to block both intravascular and extravascular hemolysis, which occurs as a consequence of C5 inhibition (2). Both terminal and proximal complement inhibition increases the risk of infection with Neisseria meningitidis, so patients should receive the meningococcal vaccine or initiate prophylactic antibiotic treatment at least 14 days before starting therapy.

If complement inhibition is unavailable, corticosteroids may increase hemoglobin and reduce hemolysis in some patients, but supportive evidence is lacking. However, due to the adverse effects of long-term use, corticosteroids should be avoided for long-term treatment. Complement inhibition does not treat concomitant bone marrow failure.

Supportive measures include oral iron and folic acid supplementation and sometimes transfusions.

Generally, transfusions are reserved for crises or symptomatic anemia. Heparin followed by warfarin or another anticoagulant is given for acute thrombosis but is not usually required long term once complement inhibitor therapy is initiated.