Perspective: Tyrosine Phosphatases As Novel Targets For Antiplatelet Therapy

Arterial thrombosis is the primary cause of most cases of myocardial infarction and
stroke, the leading causes of death in the developed world. Platelets, highly specialized
cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet
drugs, which prevent platelets from aggregating, have been very effective in reducing the
mortality and morbidity of these conditions. However, approved antiplatelet therapies
have adverse side effects, most notably the increased risk of bleeding. Moreover, there
remains a considerable incidence of arterial thrombosis in a subset of patients receiving
currently available drugs. Thus, there is a pressing medical need for novel antiplatelet
agents with a more favorable safety profile and less patient resistance. The discovery of
novel antiplatelet targets is the matter of intense ongoing research. Recent findings
demonstrate the potential of targeting key signaling molecules, including kinases and
phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives
to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major
class of enzymes in signal transduction. We give an overview of previously identified
PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also
introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet
biology and thrombosis. We review our data on genetic deletion as well as
pharmacological inhibition of VHR, providing proof-of-principle for a novel and
potentially safer VHR-based antiplatelet therapy.