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

Nature Medicine volume 5, pages 1010–1017 (1999)Cite this article

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.

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Figure 1: Generation of cd39-deficient mice.
Figure 2: Analysis of mouse cd39/ATPDase.
Figure 3: Thromboregulation.
Figure 4: Platelet accumulation in mesenteric arterioles injured with ferric chloride.
Figure 5: Platelet function in vitro.
Figure 6: Immunopathology of transplanted hearts from cd39+/+ and cd39–/– mouse donors.
Figure 7: Tissue factor activity in EC cultures of mutant and wild-type mice.

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Acknowledgements

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.).

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Author notes

  1. Simon C. Robson and Robert D. Rosenberg: SCR & RDR are joint senior authors

Authors and Affiliations

  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Keiichi Enjyoji, Patricia D. Christie, Jay M. Edelberg, Helen Rayburn, Miroslaw Lech, David L. Beeler & Robert D. Rosenberg

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Jean Sévigny, Yuan Lin, Jan Schulte Am Esch II, Masato Imai, Eva Csizmadia & Simon C. Robson

  3. Department of Pathology, Center for Blood Research, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Paul S. Frenette & Denisa D. Wagner

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Correspondence to Robert D. Rosenberg.

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Enjyoji, K., Sévigny, J., Lin, Y. et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 5, 1010–1017 (1999). https://doi.org/10.1038/12447

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