Narrative Review: Paroxysmal Nocturnal Hemoglobinuria: The Physiology of Complement-Related Hemolytic Anemia

@article{Brodsky2008NarrativeRP,
  title={Narrative Review: Paroxysmal Nocturnal Hemoglobinuria: The Physiology of Complement-Related Hemolytic Anemia},
  author={Robert A. Brodsky},
  journal={Annals of Internal Medicine},
  year={2008},
  volume={148},
  pages={587-595}
}
  • R. Brodsky
  • Published 2008
  • Medicine
  • Annals of Internal Medicine
Clinical Principles Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem-cell disorder caused by a somatic mutation in a gene known as phosphatidylinositol glycan class A (PIGA). It may arise de novo or in the setting of acquired aplastic anemia. Clinical presentation can include hemolytic anemia, hemoglobinuria, thrombosis, severe fatigue, abdominal pain, and esophageal spasm. Thrombosis, the leading cause of death from PNH, most commonly occurs in abdominal and cerebral… Expand
Paroxysmal nocturnal hemoglobinuria and the age of therapeutic complement inhibition
TLDR
Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life (QoL) of patients. Expand
Paroxysmal nocturnal hemoglobinuria.
TLDR
Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement. Expand
Paroxysmal Nocturnal Hemoglobinuria from Bench to Bedside
TLDR
Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH and has led to the development of a highly effective targeted therapy. Expand
The Presence of Paroxysmal Nocturnal Hemoglobinuria in Patients with Idiopathic Chronic Renal Failure
Paroxysmal nocturnal hemoglobinuria is a rare hematopoietic stem cell disease resulting from a somatic mutation in the PIG-A gene (phosphatidylinositol glycan-complementation class A gene) andExpand
Paroxysmal nocturnal hemoglobinuria: stem cells and clonality.
  • R. Brodsky
  • Biology, Medicine
  • Hematology. American Society of Hematology. Education Program
  • 2008
TLDR
The leading hypotheses to explain clonal outgrowth in PNH are: 1) PNH cells evade immune attack possibly, because of an absent cell surface GPI-AP that is the target of the immune attack; 2) The PIG-A mutation confers an intrinsic resistance to apoptosis that becomes more conspicuous when the marrow is under immune attack'; and 3) A second mutation occurs in the PNH clone to give it an intrinsic survival advantage. Expand
How do PIG-A mutant paroxysmal nocturnal hemoglobinuria stem cells achieve clonal dominance?
TLDR
Treatment with a monoclonal antibody (eculizumab) that inhibits terminal complement activation is now available for PNH patients and helps reduce the morbidity and mortality of the disease. Expand
Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria
TLDR
The diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients are reviewed, as well as the early recognition of its systemic complications, based on the best available evidence and international guidelines. Expand
BONE MARROW FAILURE Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder thatmanifests with hemolytic anemia, bone marrow failure, and thrombosis. One of the earliest descriptions ofExpand
How I treat paroxysmal nocturnal hemoglobinuria.
TLDR
Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored. Expand
Postpartum thrombotic complication in a patient with paroxysmal nocturnal hemoglobinuria
TLDR
After delivery, the patient presented severe complications: development of pleural and peritoneal effusion, pulmonary embolism, bilateral upper limbs thrombophlebitis, and a possible abdominal angina with a transient paralytic ileus and now the baby is healthy and the mother has returned to the usual therapeutic regimen. Expand
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References

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A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins.
TLDR
The results demonstrate that on the basis of PIG-AP expression, the proportion of AA patients who show features of typical AA along with a PNH phenotype is substantially higher than previously recognized. Expand
Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome.
TLDR
The presence of a minor population of P NH-type cells suggests a benign type of bone marrow failure, probably caused by an immunologic mechanism, and peripheral blood should be tested using sensitive flow cytometry for the presence of PNH- type cells in all patients withBone marrow failure before treatment. Expand
Paroxysmal nocturnal hemoglobinuria.
TLDR
A 30 years old male patient presented with 5 years history of transfusion dependent anemia with intermittent episodes of passing dark colored urine in the morning, confirming the diagnosis of paroxysmal nocturnal hemoglobinuria. Expand
Natural history of paroxysmal nocturnal hemoglobinuria.
TLDR
PNH is a chronic disorder that curtails life, and a spontaneous long-term remission can occur, which must be taken into account when considering potentially dangerous treatments, such as bone marrow transplantation. Expand
Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.
TLDR
Using flow cytometric analysis of granulocytes, it is identified cells that have the PNH phenotype, and PNH red blood cells also were identified, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH. Expand
Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.
TLDR
This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH. Expand
Resistance of paroxysmal nocturnal hemoglobinuria cells to the glycosylphosphatidylinositol-binding toxin aerolysin.
TLDR
It is found that PNH blood cells (erythrocytes, lymphocytes, and granulocytes), but not blood cells from normals or other hematologic disorders, are resistant to the cytotoxic effects of aerolysin. Expand
Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).
TLDR
It is suggested that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow. Expand
Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays
TLDR
Large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence, and a correlation of PNH clone size to more symptomatic PNH is suggested. Expand
The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria.
TLDR
It is proposed that lack of u-PAR expression on the surface of peripheral blood leukocytes may be causally related to the high incidence of venous thrombosis observed in PNH patients. Expand
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