Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Lamia Lamrani, Catherine Lacout, Veronique Ollivier, Cecile V Denis, Elizabeth Ellen Gardiner, Benoit Ho Tin Noe, William Vainchenker, Jean-Luc Villeval, Martine Jandrot-Perrus

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21 Citations (Scopus)

Abstract

Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2V617F, the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2 V617F knock-in mice with constitutive and inducible expression of JAK2V617F in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80 decrease in platelet-covered surface, when JAK2V617F blood was perfused at arterial shear over collagen. JAK2V617F platelets presented only amoderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2V617F expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2V617F expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. ? 2014 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)1136 - 1145
Number of pages10
JournalBlood
Volume124
Issue number7
DOIs
Publication statusPublished - 2014

Cite this

Lamrani, L., Lacout, C., Ollivier, V., Denis, C. V., Gardiner, E. E., Ho Tin Noe, B., ... Jandrot-Perrus, M. (2014). Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. Blood, 124(7), 1136 - 1145. https://doi.org/10.1182/blood-2013-10-530832
Lamrani, Lamia ; Lacout, Catherine ; Ollivier, Veronique ; Denis, Cecile V ; Gardiner, Elizabeth Ellen ; Ho Tin Noe, Benoit ; Vainchenker, William ; Villeval, Jean-Luc ; Jandrot-Perrus, Martine. / Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. In: Blood. 2014 ; Vol. 124, No. 7. pp. 1136 - 1145.
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title = "Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm",
abstract = "Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2V617F, the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2 V617F knock-in mice with constitutive and inducible expression of JAK2V617F in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80 decrease in platelet-covered surface, when JAK2V617F blood was perfused at arterial shear over collagen. JAK2V617F platelets presented only amoderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2V617F expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2V617F expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. ? 2014 by The American Society of Hematology.",
author = "Lamia Lamrani and Catherine Lacout and Veronique Ollivier and Denis, {Cecile V} and Gardiner, {Elizabeth Ellen} and {Ho Tin Noe}, Benoit and William Vainchenker and Jean-Luc Villeval and Martine Jandrot-Perrus",
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Lamrani, L, Lacout, C, Ollivier, V, Denis, CV, Gardiner, EE, Ho Tin Noe, B, Vainchenker, W, Villeval, J-L & Jandrot-Perrus, M 2014, 'Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm', Blood, vol. 124, no. 7, pp. 1136 - 1145. https://doi.org/10.1182/blood-2013-10-530832

Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. / Lamrani, Lamia; Lacout, Catherine; Ollivier, Veronique; Denis, Cecile V; Gardiner, Elizabeth Ellen; Ho Tin Noe, Benoit; Vainchenker, William; Villeval, Jean-Luc; Jandrot-Perrus, Martine.

In: Blood, Vol. 124, No. 7, 2014, p. 1136 - 1145.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

AU - Lamrani, Lamia

AU - Lacout, Catherine

AU - Ollivier, Veronique

AU - Denis, Cecile V

AU - Gardiner, Elizabeth Ellen

AU - Ho Tin Noe, Benoit

AU - Vainchenker, William

AU - Villeval, Jean-Luc

AU - Jandrot-Perrus, Martine

PY - 2014

Y1 - 2014

N2 - Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2V617F, the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2 V617F knock-in mice with constitutive and inducible expression of JAK2V617F in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80 decrease in platelet-covered surface, when JAK2V617F blood was perfused at arterial shear over collagen. JAK2V617F platelets presented only amoderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2V617F expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2V617F expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. ? 2014 by The American Society of Hematology.

AB - Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2V617F, the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2 V617F knock-in mice with constitutive and inducible expression of JAK2V617F in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80 decrease in platelet-covered surface, when JAK2V617F blood was perfused at arterial shear over collagen. JAK2V617F platelets presented only amoderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2V617F expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2V617F expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. ? 2014 by The American Society of Hematology.

UR - http://www.bloodjournal.org/content/bloodjournal/124/7/1136.full.pdf

U2 - 10.1182/blood-2013-10-530832

DO - 10.1182/blood-2013-10-530832

M3 - Article

VL - 124

SP - 1136

EP - 1145

JO - Blood

JF - Blood

SN - 0006-4971

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Lamrani L, Lacout C, Ollivier V, Denis CV, Gardiner EE, Ho Tin Noe B et al. Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. Blood. 2014;124(7):1136 - 1145. https://doi.org/10.1182/blood-2013-10-530832