Full Length ArticleProthrombotic mechanisms in patients with congenital p.Cys89Tyr mutation in CD59
Introduction
Hemostasis is achieved via a balance of pro- and antithrombotic forces, is maintained by coagulation and fibrinolysis, and is influenced by blood physiology and plasma factors as well as factors derived from vessel walls and blood cells. Thrombosis is the prognostic factor with the greatest effect on survival in paroxysmal nocturnal hemoglobinuria (PNH) patients [1, 2]. Data from several retrospective studies in the pre-eculizumab era showed that the cause of death was related to thrombosis in 22.2–37.2% of PNH patients. The extremely high incidence of thrombosis in PNH, and its major impact on morbidity and mortality, underlines its clinical importance. The cumulative 10-year incidence of thrombosis in a retrospective study of 460 PNH patients with larger clones was 31–39% [1, 3, 4].
CD59 deficiency is a common finding in adult patients with PNH, which is characterized by clonal expansion of hematopoietic stem cells that have acquired a mutation in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A). PIGA encodes a GPI biosynthesis protein, phosphatidylinositol N-acetylglucosaminyltransferase subunit A [5, 6], and erythrocytes deficient in GPI-anchored membrane proteins, including CD59, undergo complement-mediated hemolysis.
We have originally described a primary homozygous Cys89Tyr CD59 mutation in Jewish patients of Sephardic ethnicity, that resulted in the amino acid substitution p.Cys89Tyr and thus a failure of CD59 protein function [7]. The Cys89Tyr mutation in CD59 was initially described with manifestation in infancy by chronic hemolysis and relapsing peripheral demyelinating disease resembling recurrent Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). More recently, we have described two infants carrying the mutation who manifested with recurrent strokes [8], establishing the concept that primary Cys89Tyr mutation in CD59 leads to a thrombophilic state. In this work, we have tried to examine the possible thrombophilic mechanisms in primary CD59 Cys89Tyr mutation.
Section snippets
Ethical Committee approval
The study design was approved by the Institutional Review Board (Helsinki Committee) at the Hadassah-Hebrew University Medical Center, and by the National Review Board, as part of the clinical study (ClinicalTrials.gov, NCT01579838) that was recently published [9]. The parents of all patients provided their signed informed consent.
Settings, locations, and recruitment
Samples were collected from 2014. Patients were selected following identification of their specific mutation. All patients known to have the mutation were included.
Complement activation
Patients
Following the original observation of five patients with primary Cys89Tyr mutation in CD59, we were able to identify and genetically diagnose two additional patients, both of whom had died from recurrent strokes [8]. Since recurrent stroke in 2/7 infants is evidence of a significant thrombophilic state in a pediatric population, we decided to further investigate the mechanisms that may lead to hypercoagulability in these patients. Four patients (all known patients) with the same mutation and
Discussion
Several factors were identified as pro-thrombotic mechanisms in CD59 deficiency. Intravascular hemolysis is one thrombophilic mechanisms in PNH (reviewed by Hill et al. [14]). High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. Administration of heme in healthy volunteers caused thrombophlebitis, demonstrating that it can cause vascular
Funding
This research was supported by the Israel Science Foundation.
Acknowledgements
This research was supported by the Legacy Heritage Bio-Medical Program (ISF) of the Israel Science Foundation (grant No. 1070/15 TO DM).
The authors thank Shifra Fraifeld, a medical editor in our Medical Center, for her editorial support during manuscript preparation.
References (47)
- et al.
Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories
Blood
(2008) - et al.
Stroke in paroxysmal nocturnal haemoglobinuria: patterns of disease and outcome
Thromb. Haemost.
(2007) - et al.
Natural history of paroxysmal nocturnal hemoglobinuria
N. Engl. J. Med.
(1995) - et al.
Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria
J. Thromb. Haemost.
(2012) - et al.
The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis
Science
(1993) - et al.
Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria
Cell
(1993) - et al.
CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy
Blood
(2013) - et al.
Devastating recurrent brain ischemic infarctions and retinal disease in pediatric patients with CD59 deficiency
Eur. J. Paediatr. Neurol.
(2015) - et al.
Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation
Ann. Neurol.
(2016) - et al.
The absolute counting of red cell-derived microparticles with red cell bead by flow rate based assay
Cytometry B Clin. Cytom.
(2009)
Alterations in markers of coagulation and fibrinolysis in patients with paroxysmal nocturnal hemoglobinuria before and during treatment with eculizumab
Thromb. Res.
Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop
J. Thromb. Haemost.
Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins
Blood
Thrombosis in paroxysmal nocturnal hemoglobinuria
Blood
Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa
J. Thromb. Haemost.
The role of monocytes in thrombotic disorders. Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms
Thromb. Haemost.
Monocytes circulate in constant reversible interaction with platelets in a [Ca2+]-dependent manner
Platelets
Thrombophlebitis and disturbed hemostasis following administration of intravenous hematin in normal volunteers
Am. J. Med.
Enhancement of platelet deposition by cross-linked hemoglobin in a rat carotid endarterectomy model
Circulation
Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin
Blood
The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity
J. Exp. Med.
Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase
Blood
Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells
Thromb. Haemost.
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Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.