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In Vitro Effects of BCR-ABL Tyrosine Kinase Inhibitors on Endothelial Cells Survival and Functions

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RESEARCH OUTPUTS / RÉSULTATS DE RECHERCHE

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University of Namur

In Vitro Effects of BCR-ABL Tyrosine Kinase Inhibitors on Endothelial Cells Survival

and Functions

Haguet, Hélène; Douxfils, Jonathan; Chatelain, Christian; GRAUX, Carlos; Mullier, François;

Dogne, Jean-Michel

Published in:

Special Issue: Abstracts of the 64th Annual Meeting of the Scientific Standardization Committee of the

International Society on Thrombosis and Haemostasis, July 18–21, 2018

Publication date:

2018

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Publisher's PDF, also known as Version of record

Link to publication

Citation for pulished version (HARVARD):

Haguet, H, Douxfils, J, Chatelain, C, GRAUX, C, Mullier, F & Dogne, J-M 2018, In Vitro Effects of BCR-ABL

Tyrosine Kinase Inhibitors on Endothelial Cells Survival and Functions. in Special Issue: Abstracts of the 64th

Annual Meeting of the Scientific Standardization Committee of the International Society on Thrombosis and

Haemostasis, July 18–21, 2018., PB497, Research and Practice in Thrombosis and Haemostasis, no. S1, vol. 2,

pp. 242, 64 th Annual International Society on Thrombosis and Haemostasis SSC meeting, Dublin, Ireland,

18/07/18. <https://onlinelibrary.wiley.com/doi/epdf/10.1002/rth2.12125>

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Thirty five of them have acquired risk factors (arterial hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, obstructive sleep apnea, smoking, oral contraceptives, family history) and hyperhomo-cysteinemia. The prevalence of acquired risk factors for stroke are significantly higher in ischemic stroke patients without thrombosis and clinically significant stenosis.

Conclusions: We found that thrombophilia could be a risk factor for

thrombosis or severe stenosis in young patients with stroke.

PB497 

| In Vitro Effects of BCR- ABL Tyrosine

Kinase Inhibitors on Endothelial Cells Survival

and Functions

H. Haguet1,2; J. Douxfils1; C. Graux3; C. Chatelain1; F.

Mullier2; J.-M. Dogné1

1University of Namur, Department of Pharmacy, Namur, Belgium; 2CHU UCL

Namur, Hematology Laboratory, Yvoir, Belgium; 3CHU UCL Namur, Department

of Hematology, Yvoir, Belgium

Background: BCR- ABL tyrosine kinase inhibitors (TKIs) are the

main-stay of the treatment for chronic myeloid leukemia (CML). New gen-eration TKIs (dasatinib, nilotinib, bosutinib and ponatinib) increase the risk of arterial thromboembolism in patients with CML. Clinical data suggest that new generation TKIs might accelerate atherogenesis.

Aims: This research aims to determine the effect of BCR- ABL TKIs

on endothelial cell survival and major functions using an in vitro model (i.e. HUVEC).

Methods: Viability was assessed using MTS and LDH assays

fol-lowing standard protocols. Expression of 3 adhesion molecules (i.e. ICAM- 1, VCAM- 1 and E- selectin) was quantified by on- cell ELISA after 4- hour TNF- α activation. Endothelial cell migration was evalu-ated by scratch assays (i.e. monitoring of wound closure of a scratch on confluent monolayer).

Results: At high concentration, dasatinib, nilotinib and ponatinib

reduce cell metabolism. Additionally, high- dose ponatinib induces necrosis as demonstrated by increased LDH release. On- cell ELISA demonstrates decreased expression of 3 adhesion molecules (i.e. ICAM- 1, VCAM- 1 and E- selectin) by dasatinib, nilotinib and ponatinib at high concentration. This diminution correlates with the decreased viability of endothelial cell with these 3 treatments. Imatinib and bosutinib have no or little impact on adhesion mol-ecule expression. Finally, scratch assays indicate that high- dose dasatinib inhibits endothelial cell migration whereas other TKIs do not have any impact.

Conclusions: Over the 5 commercialized BCR- ABL TKIs, dasatinib,

nilotinib and ponatinib possess the most impact on endothelial cells and possibly promote atherosclerosis development through im-paired endothelium permeability, enabling migration and trapping of lipoprotein into the intima. Determination of mechanism(s) by which TKIs promote cardiovascular events is required to implement appro-priate risk minimization measures and select patients to whom the prescription of these drugs should be avoided.

PB498 

| Impaired Fibrinolytic Activity in

Nigerian Myocardial Infarction Patients

O.I. Ajayi; F.S. Ozimede

University of Benin, Physiology, Benin City, Nigeria

Background: Myocardial infarction (MI) is referred to as the changes

that occur in cardiac muscle and the sudden deprivation of circulat-ing blood leadcirculat-ing to necrosis of myocardial tissue. The pathogen-esis has been well documented in countries with advanced medical technologies while in developing countries such as Nigeria, MI as an unfolding major cardiovascular events leading to sudden death in most cases.

Aims: This study was designed to ascertain the fibrinolytic patterns

in acute MI events with a view to indicate their possible role in diag-nosis and management.

Methods: A total of 10 acute myocardial infarction (AMI) patients

together with 20 age and sex - matched apparently healthy subjects as controls were studied. Blood samples were taken at the point of admission (Day 0), on the 4th and 7th day respectively after treat-ment has commenced. Fibrinolytic indices such D- dimer concentra-tion (DDC) and Euglobulin lysis time test (ELT) were measured with standard laboratory methods.

Results: We observed a significantly increase in Euglobin lysis

time as well as in increased D- dimer levels AMI patients on admis-sion compared with controls (P<0.05, respectively). DDC became significantly lowered from the 4th day of admission while all the ELT remained significantly high until the 7th day of admission and treatment (P<0.05, respectively). On the other hand lipids such as Cholesterol and HDL remained relatively unchanged from admission and throughout the duration of the study.

Conclusions: Conclusively, impaired fibrinolytic activity could be a

major associated risk of thrombosis in Nigerians with AMI. The role of lipids in AMI pathogenesis in Nigerians seem to be unpronounced.

PB499 

| Shear Enhances Fibrin- induced GPVI

Shedding and Platelet ADAM10 Function

S.J. Montague1,2; S. Hicks1,3; P.Y. Choi3,4; C.S.-M. Lee1; X.

He2; R.K. Andrews5; W.M. Lee1,2; E.E. Gardiner1,3

1The Australian National University, ACRF Department of Cancer Biology and

Therapeutics, Canberra, Australia; 2The Australian National University, Research

School of Engineering, College of Engineering and Computer Science, Canberra, Australia; 3National Platelet Research and Referral Centre, Canberra, Australia; 4Canberra Hospital, Canberra, Australia; 5Monash University, Australian Centre

for Blood Diseases, Melbourne, Australia

Background: Fibrin, shear stress and active Factor X (FXa) induce

glycoprotein (GP) VI shedding independent of direct thrombin ac-tivity. A Disintegrin And Metalloproteinase (ADAM) 10 is the main sheddase releasing human platelet soluble GPVI ectodomain.

Aims: To assess molecular links between these agonists and

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