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Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician's guide.

ABSTRACT: Paroxysmal nocturnal haemoglobinuria (PNH), an ultra-orphan disease with a prevalence of 15.9 per million in Europe, is a life-threatening disorder, characterized by haemolysis, bone marrow failure and thrombosis. Patients with PNH prior to the availability of eculizumab had a median survival of between 10 and 22 years, with thrombosis accounting for 22-67% of deaths. 29-44% of patients had at least one thrombosis. This paper provides a clinician's guide to the diagnosis, management and complications of PNH, with an emphasis on thrombosis.

SUBMITTER: Griffin M

PROVIDER: S-EPMC5305005 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician's guide.

Griffin Morag M Munir Talha T

Therapeutic advances in hematology 20161221 3

Paroxysmal nocturnal haemoglobinuria (PNH), an ultra-orphan disease with a prevalence of 15.9 per million in Europe, is a life-threatening disorder, characterized by haemolysis, bone marrow failure and thrombosis. Patients with PNH prior to the availability of eculizumab had a median survival of between 10 and 22 years, with thrombosis accounting for 22-67% of deaths. 29-44% of patients had at least one thrombosis. This paper provides a clinician's guide to the diagnosis, management and complica ...[more]

PMID: 28246555

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Project description:Thrombosis is one of the most common causes of mortality in Paroxysmal nocturnal hemoglobinuria (PNH), but the predisposing factors for thrombosis are yet to be defined. In this study, we outline the clinical characters and the susceptible genes which lead to thrombotic formation in 104 patients with PNH. The results displayed that the genotypes with minor alleles of rs495828 or rs2519093 in the ABO gene were associated with high risk to thrombus formation (OR 5.95, 95% CI 1.90-18.65 and OR 6.3, 95% CI 2.01-19.79, respectively). Further, the TT haplotype was associated with a significant increased risk of thrombosis (OR=3.25, 95%CI 1.42-7.39). Multivariate regression analysis showed larger PNH clone and genotypes with rs495828/rs2519093 minor allele as independent risk factors for thrombosis in PNH. Some patients who came back for follow-up were tested for the plasma levels of vWF and factor VIII. Patients carrying the rs495828/rs2519093 minor allele had a significant higher level of vWF and factor VIII compared with those carrying the major allele. Therefore, we found for the first time that the rs495828/rs2519093 polymorphism represent an independent prognostic factor in PNH patients for thrombus formation, probably by increasing the vWF and factor VIII.

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Project description:The clinical management of paroxysmal nocturnal hemoglobinuria (PNH), a rare but life-threatening hematologic disease, has fundamentally improved with the introduction of a therapeutic that prevents complement-mediated intravascular hemolysis. However, a considerable fraction of PNH patients show insufficient treatment response and remain transfusion dependent. Because the current treatment only prevents C5-induced lysis but not upstream C3 activation, it has been speculated that ongoing opsonization with C3 fragments leads to recognition and phagocytosis of PNH erythrocytes by immune cells. Here, for the first time, we provide experimental evidence for such extravascular hemolysis and demonstrate that PNH erythrocytes from anti-C5-treated patients are phagocytosed by activated monocytes in vitro. Importantly, we show that this uptake can be mediated by the end-stage opsonin C3dg, which is not traditionally considered a phagocytic marker, via interaction with complement receptor 3 (CR3). Interaction studies confirmed that C3dg itself can act as a ligand for the binding domain of CR3. The degree of C3dg-mediated erythrophagocytosis in samples from different PNH patients correlated well with the individual level of C3dg opsonization. This finding may guide future treatment options for PNH but also has potential implications for the description and management of other complement-mediated diseases.

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