Paroxysmal Nocturnal Hemoglobinuria PDF
An Introduction to Paroxysmal Nocturnal Hemoglobinuria (PNH) Ultimate guide 2015, Full illustrated
Paroxysmal nocturnal hemoglobinuria (PNH) was first described as a distinct and life-threatening entity in 1882. The clinical hallmark of PNH, nocturnal hemoglobinuria, has fascinated generations of physicians and led to the discovery of the alternative complement pathway, identification of the membrane proteins that regulate complement and attachment mechanisms for cell surface proteins, and the genetic basis of the disease (Parker, 2008). PNH has traditionally been associated with significant morbidity and poor prognosis. However, approval of the anti-complement protein 5 (C5) antibody eculizumab for treatment in 2007 has significantly changed the natural history of PNH.
Molecular genetics of PNH
PNH is an X-linked, non-malignant, chronic, and hematological disorder that is associated with hemolytic anemia, bone marrow failure, thrombosis, and poor quality of life (QoL) (Schrezenmeier et al., 2014). PNH arises from acquired mutations in the PIG-A gene. Affected individuals have hematopoietic stem cells (HPSC) that are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-AP), such as CD55 and CD59, both of which are critical for regulation of the complement cascade in innate immunity (Hill et al., 2007). Clonal expansion of GPI-AP-deficient HPSC results in blood cell progeny (erythrocytes, leukocytes, and platelets) that are also GPI-AP deficient, and as a result, are susceptible to complement and hemolysis (Figure 1.1). The complement cascade is an innate host defense mechanism in which complement proteins identify and target non-self cells for neutralization or destruction via opsonization, phagocytosis, or a membrane attack complex (MAC) that perforates target cell membranes and causes lysis.
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