![]() ![]() 10 9 The growth phenotype is thought to be due to the observed upregulation of the early growth response factor 1 gene ( EGR-1) and ectopic expression of the high mobility transcription factor coding genes HMGA2 has been reported in a few cases. 9 PIG-A mutant cells have been demonstrated to be less sensitive to T lymphocytes and, along with leukemic cells with the same mutation, possess increased resistance to natural killer cells. ![]() Loss of ULBP1 may prevent their destruction by NKG2D lymphocytes allowing for immune-escape from ULBP-NKG2D engagement in the bone marrow. 8 The UL16 binding protein 1 (ULBP1), a stress-induced ligand for the NKG2D receptor, is a GPI-linked glycoprotein thought to be lost on PNH stem cells. Two mutually cooperative hypotheses exist to explain the clonal expansion of PNH cells one involves immune selection-mediated expansion and the second predicts that dominant PNH clones acquire a growth advantage. The process behind the clonal expansion of the PIG-A mutated stem cells in PNH patients is not fully understood. 7 This implies that the presence of the PIG-A mutation alone is not sufficient to allow the PNH clone to dominate. 1 Studies have shown the presence of a small number of GPI anchor deficient cells in the blood of healthy controls as well as in patients with PNH. 6 GPI, a glycolipid moiety, anchors numerous proteins to the cell surface, with more than 12 GPI-anchored proteins (GPI-APs) located on hemopoietic cells. The PIG-A gene codes for an enzyme involved in the formation of the N-acetylglucosaminyl phosphatidylinositol biosynthetic protein which is necessary for the first step in the biosynthesis of glycosylphosphatidyinositol (GPI) anchors. 5 PNH is caused by an acquired inactivating mutation of the PIG-A gene located on the X chromosome. The incidence of PNH is estimated at 0.1–0.2/100,000 persons per year. Paroxysmal nocturnal hemoglobinuria pathophysiology 4 3 The review herein will discuss changes to the hemostatic system in PNH, and highlight areas that require future research in the prothrombotic processes involved in PNH. 3 Multiple proposed mechanisms behind the increased incidence of thrombosis include a prothrombotic state in conjunction with platelet abnormalities and impaired fibrinolysis. 2 Despite such a large role in the burden of the disease, the mechanism behind the development of thrombosis is poorly understood, highlighting the importance of thrombosis management in PNH patients and elucidating more information regarding the nature of the thrombotic event. 1 Thromboembolic events are the most common cause of morbidity and mortality in PNH and account for 40–67% of deaths 40% of patients having suffered an event before diagnosis and 29–44% of patients suffering at least one event throughout the course of their disease. It is caused by an acquired mutation in the X-linked phosphatidylinositol glycan class A gene ( PIG-A), causing stem cell progeny (mature blood cells) to lack complement regulatory proteins and exposing them to complement attack. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder of multipotent hematopoietic stem cells. Further studies, including novel in vivo and in vitro thrombosis models, are required in order to define the role of the individual mechanisms contributing to thrombosis, impaired fibrinolysis and clarify other complement-driven prothrombotic mechanisms in paroxysmal nocturnal hemoglobinuria. While many factors may affect thrombosis in paroxysmal nocturnal hemoglobinuria, the relative contribution of each mechanism that has been implicated is difficult to quantify. Impaired fibrinolysis has also been observed and may be caused by several mechanisms involving interactions between complement activation, coagulation and fibrinolysis. ![]() Platelet and endothelial microparticles as well as oxidative stress may play a role. Paroxysmal nocturnal hemoglobinuria leads to a complex and multifaceted prothrombotic state due to the pathological effects of platelet activation, intravascular hemolysis and neutrophil/monocyte activation. This review article discusses the different factors that contribute to the increased risk of thrombosis in paroxysmal nocturnal hemoglobinuria. The increased incidence of thrombosis in paroxysmal nocturnal hemoglobinuria is still poorly understood, but unlike many other thrombotic disorders, predominantly involves complement-mediated mechanisms. Paroxysmal nocturnal hemoglobinuria is a rare acquired hematologic disorder, the most serious complication of which is thrombosis. ![]()
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