+ Author Affiliations
- Correspondence to Steven E. McKenzie, MD, PhD, Cardeza Foundation for Hematologic Research, Departments of Medicine and Pediatrics, Thomas Jefferson University and Hospitals, Philadelphia, PA 19107. E-mail steven.mckenzie@jefferson.edu
Ischemic stroke is a major global
public health concern. Antiplatelet therapies are a mainstay of
treatment. There remains
a clinical need to prevent stroke when possible
and to minimize neurological damage with minimal bleeding when stroke
has
occurred. That is why it is particularly
exciting to see the work by van Eeuwijk et al1
from the group of Bernhard Nieswandt in this issue. Based on a
compelling rationale of the role of nonreceptor protein tyrosine
kinase Syk in platelet activation, van Eeuwijk
et al report the use of a novel oral Syk inhibitor BI1002494 for
prevention
and treatment of ischemic stroke in a
well-established mouse model.
See accompanying article on page 1247
Platelet activation at the sites of
ruptured atherosclerotic plaques results from adhesion that triggers
generation or secretion
of vasoactive and inflammatory mediators,
aggregation, and formation of a procoagulant surface. If activation
exceeds natural
or pharmacological inhibition, then an occlusive
thrombus results. Syk is a major signaling node for collagen receptor
GPVI
(glycoprotein VI), which couples to the FcRγ
chain and its immunoreceptor tyrosine activation motif to initiate
platelet activation.
Syk is also essential in platelets for signaling
via FcγRIIa and CLEC-2 and for outside-in signaling through activated
integrin
αIIbβ3. In contrast, Syk has no, or perhaps a
limited, role in response to G-protein coupled receptors, such as those
for
thrombin, thromboxane A2, and ADP (adenosine
diphosphate). These are the targets of conventional antiplatelet
therapies, which
have limitations in efficacy and safety. So the
promise of Syk inhibitors …
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