Paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is almost always due to somatic mutations in phosphatidylinositol glycan class A (PIGA), a gene involved in the first step of GPI anchor biosynthesis; however, alternative mutations that cause PNH have recently been discovered. In addition, hypomorphic germ-line PIGA mutations that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. Eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab.

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

“…Therefore, proteins anchored by GPI are missing. Two of those missing proteins are complement regulatory proteins (CD55 and CD59) on red cells [28]. Acidifying normal human serum activates the alternative pathway of complement and leads to specific lysis of PNH erythrocytes secondary to increased vulnerability to the activated complement in acidified serum, as shown in Figure 1A.…”

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia

“…One patient who presented with a large PNH clone at diagnosis, developed symptomatic PNH with hemolysis requiring treatment with eculizumab 7 years after her initial treatment. 34 Two patients who achieved a CR experienced late relapses of SAA after 38 and 57 months. One responded to retreatment with a second course of high-dose cyclophosphamide, transiently reaching CR but ultimately having a variable platelet count of 70–100 × 10 9 /L that is sustained over 6 years.…”

Recurrent cerebral ischaemic events in the setting of paroxysmal nocturnal haemoglobinuria

“…Allogeneic bone marrow transplantation (BMT) is the only potentially curative therapy available for PNH 2. It is usually reserved for patients who are severely hypoplastic, refractory to other forms of treatment, or if eculizumab is not available, as transplant-related morbidity and mortality are not negligible.…”

“…Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired disorder of haematopoietic stem cells, characterised by haemolytic anaemia, pancytopenia and thrombotic events 2. Reported incidence of clinically significant disease is in the range of 1–10 cases per million, although this may be an underestimate 3.…”