Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million. It is characterized by hemolysis, bone marrow dysfunction with peripheral blood cytopenia, hypercoagulability, thrombosis, renal impairment and arterial and pulmonary hypertension. Hemolysis and subsequent hemosiderin accumulation in tubular epithelium cells induce tubular atrophy and interstitial fibrosis. The origin of PNH is the somatic mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene located on Xp22: this condition leads to the production of clonal blood cells with a deficiency in those surface proteins that protect against the lytic action of the activated complement system. Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, until the introduction of the C5 complement blockade agent Eculizumab. A second generation of anti-complement agents is currently under investigation, representing future promising therapeutic strategies for patients affected by PNH. In the case of chronic hemolysis and renal iron deposition, a multidisciplinary approach should be considered to avoid or treat acute tubular injury or acute kidney injury (AKI). New promising perspectives derive from complement inhibitors and iron chelators, as well as more invasive treatments such as immunoadsorption or the use of dedicated hemodialysis filters in the presence of AKI.
Highlights
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million [1].The name of this disease is due to the characteristic severe hemolytic anemia giving episodes of hemoglobin in the urine, evident in overnight urine concentrations, but that happen all day long.The main features of PNH are represented by hemolysis, bone marrow dysfunction, hypercoagulability, thrombosis and smooth muscle dystonia, all signs and symptoms that can cause severe complications such as renal failure and arterial and pulmonary hypertension [2,3]
The cause of PNH is a somatic mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene on Xp22 [10], coding for one of the several enzymes involved in the generation of glycosyl phosphatidylinositol (GPI) anchors in the endoplasmic reticulum
PNH is characterized by a plethora of insidious symptoms and damage mechanisms such as hemolysis, peripheral cytopenia, bone marrow dysfunction, thrombosis, arterial and pulmonary hypertension
Summary
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million [1]. Eculizumab [5] has represented, during the past few years, the main agent directed against this disease, but recently, a growing number of complement inhibitors has been under investigation, such as Ravulizumab [6], new generations of C5 inhibitor, Coversin [7], Compstatin analogs and C3 Inhibitors [8] or Factor D inhibitors [9]. This second generation of anti-complement agents represents future promising therapeutic strategies for patients affected by PNH
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