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Dual endothelin‐1 receptor antagonism attenuates platelet‐mediated derangements of blood coagulation in Eisenmenger syndrome
Author(s): ,
B. Kevane
Affiliations:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. SPHERE Research Group, University College Dublin Conway Institute, Dublin, Ireland. Department of Haematology, Rotunda Hospital, Dublin, Ireland. Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland
,
S. Allen
Affiliations:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. SPHERE Research Group, University College Dublin Conway Institute, Dublin, Ireland
,
K. Walsh
Affiliations:
Department of Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland
,
K. Egan
Affiliations:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. SPHERE Research Group, University College Dublin Conway Institute, Dublin, Ireland
,
P. B. Maguire
Affiliations:
SPHERE Research Group, University College Dublin Conway Institute, Dublin, Ireland. Department of Biomolecular and Biomedical Sciences, University College Dublin, Dublin, Ireland
,
M. C. Galligan
Affiliations:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
,
D. Kenny
Affiliations:
Department of Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland
,
R. Savage
Affiliations:
Department of Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland
,
E. Doran
Affiliations:
Department of Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland
,
Á. Lennon
Affiliations:
Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland
,
E. Neary
Affiliations:
Department of Neonatology, Rotunda Hospital, Dublin, Ireland
F. Ní Áinle
Affiliations:
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. SPHERE Research Group, University College Dublin Conway Institute, Dublin, Ireland. Department of Haematology, Rotunda Hospital, Dublin, Ireland. Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland
Correspondence: Fionnuala Ní Áinle, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland|Tel.: +353 1803 4429|E‐mail: fniainle@mater.ie
ISTH Academy. Ni Ainle F. Aug 2, 2018; 227433
Fionnuala Ni Ainle
Fionnuala Ni Ainle

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Aims
The mechanisms underlying the competing thrombotic and hemorrhagic risks in Eisenmenger syndrome are poorly understood. We aimed to characterize derangements of blood coagulation and to assess the effect of dual endothelin‐1 receptor antagonism in modulating hemostasis in this rare disorder.
Methods
In a 10‐month recruitment period at a tertiary cardiology referral center, during which time there were over 14 000 outpatient consultations, consecutive subjects with Eisenmenger syndrome being considered for macitentan therapy (n = 9) and healthy volunteers (n = 9) were recruited. Plasma thrombin generation in platelet‐rich and platelet‐poor plasma was assessed by calibrated automated thrombography prior to and following therapy.
Results
Median peak plasma thrombin generation was higher in platelet‐rich plasma obtained from Eisenmenger syndrome subjects relative to controls (median peak thrombin [25th–75th percentile]: 228.3 [206.5–258.6] nm vs. 169.9 [164.3–215.8] nm), suggesting a critical mechanistic role for platelets in supporting abnormal hypercoagulability in Eisenmenger syndrome. Abnormal enhanced sensitivity to the anticoagulant activity of activated protein C was also observed in platelet‐rich plasma in Eisenmenger syndrome, suggesting that derangements of platelet activity may influence the activity of anticoagulant pathways in a manner that might promote bleeding in this disease state. Following 6 months of macitentan therapy, attenuations in the derangements in both procoagulant and anticoagulant pathways were observed.
Conclusions
Abnormal platelet activity contributes to derangements in procoagulant and anticoagulant pathways in Eisenmenger syndrome. Therapies targeting the underlying vascular pathology appear to ameliorate these derangements and may represent a novel strategy for the management of the competing prothrombotic and hemorrhagic tendencies in this disorder.
Keyword(s)
activated protein C resistance, endothelin‐1, heart defects, congenital, platelets, thrombosis
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