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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27 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

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