Mechanism of intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH)

Nakakuma, Hideki

doi:10.1002/(sici)1096-8652(199609)53:1<22::aid-ajh5>3.0.co;2-7

Cited by 25 publications

(2 citation statements)

References 68 publications

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“…This defect in PIG-A reduces surface expression of the glycosylphosphatidylinositol (GPI)–anchored complement regulatory proteins CD55 and CD59 on hematopoietic cells (ie, erythrocytes, platelets, and leukocytes) and leads to terminal complement–mediated intravascular hemolysis and increased risk of thrombosis [ 5 , 6 ]. Patients with PNH present with diverse clinical manifestations, the most common being chronic intravascular hemolysis, fatigue, and dyspnea [ 7 – 9 ]. Thromboembolic events (TEs) are the leading cause of death in patients with PNH, accounting for 40% to 67% of deaths before the complement inhibition era [ 10 – 12 ], with a 5‐year mortality rate of approximately 30% [ 13 ].…”

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confidence: 99%

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry

Höchsmann,

Peffault de Latour,

Hill

et al. 2023

Ann Hematol

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The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)–negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20–72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86–92.62]; without recent anticoagulation, 5.33 [0.26–109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54–45.32]; ≥ 50%, 1.97 [0.45–8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2–3 criteria, 3.18 [0.44–23.20]; ≥ 4 criteria, 3.60 [0.38–33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE.

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Section: Introductionmentioning

confidence: 99%

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry

Höchsmann,

Peffault de Latour,

Hill

et al. 2023

Ann Hematol

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“…In normal individuals, CD55 inhibits the formation of C3 and C5 convertases, and CD 59 blocks formation of the membrane attack complex. Patients with PNH who lack these two GPI‐anchored proteins and erythrocytes are vulnerable to complement‐mediated intravascular haemolysis (Nakakuma, ). Haemolysis can be chronic or acute, precipitated by triggers such as infections, drugs or trauma.…”

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Piperacillin‐tazobactam drug‐induced immune haemolysis in a case of paroxysmal nocturnal haemoglobinuria

McDonald

Brodie

Murphy

et al. 2019

Transfusion Medicine

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Dear Sir,Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematological disorder characterised by varying degrees of marrow failure (manifesting as hypoplasia, aplasia or dysplasia), complement-mediated haemolysis and a predisposition to thrombosis. The pathophysiology is related to a somatic mutation in haematopoietic progenitor cells in the phosphatidylinositol glycan class A gene, leading to the inability to synthesise the glycosyl-phosphatidylinositol (GPI) anchor that binds certain proteins to cell membranes. The two proteins that are pertinent to the pathophysiology of PNH are CD55 and CD59. Haemolysis in PNH is mediated by the constitutively activated alternative pathway of complement. In normal individuals, CD55 inhibits the formation of C3 and C5 convertases, and CD 59 blocks formation of the membrane attack complex. Patients with PNH who lack these two GPI-anchored proteins and erythrocytes are vulnerable to complement-mediated intravascular haemolysis (Nakakuma, 1996). Haemolysis can be chronic or acute, precipitated by triggers such as infections, drugs or trauma. Haemolysis is characteristically direct antiglobulin test (DAT) negative (Packman, 2015).We describe a patient with aplastic anaemia and PNH, who in the course of a complicated inpatient stay for Budd-Chiari Syndrome developed immune-mediated haemolysis secondary to the antimicrobial piperacillin-tazobactam.A 36-year-old man presented with acute liver failure secondary to Budd-Chiari Syndrome. He had a background of aplastic anaemia diagnosed 10 years previously, with subsequent development of a PNH clone. He was initially treated with anti-thymocyte globulin, followed by maintenance ciclosporin.He presented to the emergency department with abdominal pain secondary to hepatic vein thrombosis, and this was complicated by an ischaemic bowel. He underwent bowel resection and post-operatively developed an intra-abdominal collection. He then underwent a percutaneous liver biopsy to investigate the cause of his deteriorating liver function, and later that day, he was commenced on piperacillin-tazobactam to treat developing sepsis. Two hours following the liver biopsy, he developed severe lumbar back pain, and his haemoglobin dropped from 80 to 53 g/L. A further sample was sent for a group and antibody screen and cross match, although he had a previous negative antibody screen sample earlier that day. The repeat sample showed the presence of an 'autoantibody' in association with a positive DAT. Lactate dehydrogenase (LDH) was 316 μ/L earlier that day and rose to 2275 μ/L (Fig. 1). His liver function deteriorated as a result of this acute insult, he was transferred to the intensive care unit, and his antimicrobial treatment was escalated to meropenem.The diagnosis of drug-induced haemolysis was not immediately apparent due to a number of factors. A few hours prior to this episode, he had undergone percutaneous liver biopsy, and initially, post-procedure haemorrhage was felt the most likely reason for a drop in haemoglobin, especially as he wa...

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De novo “Classic” Paroxysmal Nocturnal Hemoglobinuria (PNH) (Marchiafava-Micheli Syndrome)

Pleyer

Greil

2010

Chronic Myeloid Neoplasias and Clonal Overlap Syndromes

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Mechanism of intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH)

Cited by 25 publications

References 68 publications

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry

Piperacillin‐tazobactam drug‐induced immune haemolysis in a case of paroxysmal nocturnal haemoglobinuria

De novo “Classic” Paroxysmal Nocturnal Hemoglobinuria (PNH) (Marchiafava-Micheli Syndrome)

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