Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

Keiichi Enjyoji; Jean Sévigny; Yuan Lin; Paul S. Frenette; Patricia D. Christie; Jan Schulte Am Esch; Masato Imai; Jay M. Edelberg; Helen Rayburn; Miroslaw Lech; David L. Beeler; Eva Csizmadia; Denisa D. Wagner; Simon C. Robson; Robert D. Rosenberg

doi:10.1038/12447

Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

Keiichi Enjyoji, Jean Sévigny, Yuan Lin, Paul S. Frenette, Patricia D. Christie, Jan Schulte Am Esch, Masato Imai, Jay M. Edelberg, Helen Rayburn, Miroslaw Lech, David L. Beeler, Eva Csizmadia, Denisa D. Wagner, Simon C. Robson, Robert D. Rosenberg

Research output: Contribution to journal › Article › peer-review

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Abstract

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39- deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

Original language	English (US)
Pages (from-to)	1010-1017
Number of pages	8
Journal	Nature Medicine
Volume	5
Issue number	9
DOIs	https://doi.org/10.1038/12447
State	Published - Sep 1999
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Enjyoji, K., Sévigny, J., Lin, Y., Frenette, P. S., Christie, P. D., Am Esch, J. S., Imai, M., Edelberg, J. M., Rayburn, H., Lech, M., Beeler, D. L., Csizmadia, E., Wagner, D. D., Robson, S. C., & Rosenberg, R. D. (1999). Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nature Medicine, 5(9), 1010-1017. https://doi.org/10.1038/12447

Enjyoji, K, Sévigny, J, Lin, Y, Frenette, PS, Christie, PD, Am Esch, JS, Imai, M, Edelberg, JM, Rayburn, H, Lech, M, Beeler, DL, Csizmadia, E, Wagner, DD, Robson, SC & Rosenberg, RD 1999, 'Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation', Nature Medicine, vol. 5, no. 9, pp. 1010-1017. https://doi.org/10.1038/12447

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title = "Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation",

abstract = "CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39- deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.",

author = "Keiichi Enjyoji and Jean S{\'e}vigny and Yuan Lin and Frenette, {Paul S.} and Christie, {Patricia D.} and {Am Esch}, {Jan Schulte} and Masato Imai and Edelberg, {Jay M.} and Helen Rayburn and Miroslaw Lech and Beeler, {David L.} and Eva Csizmadia and Wagner, {Denisa D.} and Robson, {Simon C.} and Rosenberg, {Robert D.}",

note = "Funding Information: Acknowledgments We thank K. Koziak and E. Kaczmarek for expert assistance; F.H. Bach for advice; B. Talbot (Sherbrooke University, Qu{\'e}bec, Canada) for his expertise in antibody production, and J.G. Lively (Cancer Research Institute, Massachusetts Institute of Technology) for technical advice regarding murine endothelial cell cultures. K.E. is a recipient of a Health Science Research Grant from the Japan Foundation for Aging and Health. J.S. is a recipient of fellowships from the Heart and Stroke Foundation of Canada and from “Fonds pour la Formation de Chercheurs et l{\textquoteright}Aide {\`a} la Recherche du Qu{\'e}bec”. S.C.R. received support from Medical Research Council, University of Cape Town Liver Center, Cape Town, South Africa. This work was supported in part by National Institutes of Health grants HL57307 (S.C.R.), PO1-41484 (R.D.R.) and HL41002 (D.W.).",

year = "1999",

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doi = "10.1038/12447",

language = "English (US)",

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T1 - Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

AU - Enjyoji, Keiichi

AU - Sévigny, Jean

AU - Lin, Yuan

AU - Frenette, Paul S.

AU - Christie, Patricia D.

AU - Am Esch, Jan Schulte

AU - Imai, Masato

AU - Edelberg, Jay M.

AU - Rayburn, Helen

AU - Lech, Miroslaw

AU - Beeler, David L.

AU - Csizmadia, Eva

AU - Wagner, Denisa D.

AU - Robson, Simon C.

AU - Rosenberg, Robert D.

N1 - Funding Information: Acknowledgments We thank K. Koziak and E. Kaczmarek for expert assistance; F.H. Bach for advice; B. Talbot (Sherbrooke University, Québec, Canada) for his expertise in antibody production, and J.G. Lively (Cancer Research Institute, Massachusetts Institute of Technology) for technical advice regarding murine endothelial cell cultures. K.E. is a recipient of a Health Science Research Grant from the Japan Foundation for Aging and Health. J.S. is a recipient of fellowships from the Heart and Stroke Foundation of Canada and from “Fonds pour la Formation de Chercheurs et l’Aide à la Recherche du Québec”. S.C.R. received support from Medical Research Council, University of Cape Town Liver Center, Cape Town, South Africa. This work was supported in part by National Institutes of Health grants HL57307 (S.C.R.), PO1-41484 (R.D.R.) and HL41002 (D.W.).

PY - 1999/9

Y1 - 1999/9

N2 - CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39- deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

AB - CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39- deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

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Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

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