Stroke is a debilitating brain injury associated with high mortality and long-term disability worldwide.1-2 Ischemic strokes, caused by clots that restrict blood flow to downstream brain tissue, account for more than 80% of all strokes in the United States.1-2 While rapid removal of the clot, either via thrombectomy or thrombolysis, is beneficial, the majority of patients still experience substantial loss of function and persistent neurological deficits post-stroke.1-2 Recent evidence suggests that platelets may provide mechanistic insights into the effects of ischemia-reperfusion injury (IRI), a potential target for the treatment of stroke-related morbidity.1
In a review published in Blood Advances, Noor F. Shaik, MD/PhD candidate at Thomas Jefferson University in Pennsylvania, and coauthors summarized the potential mechanisms of ischemia-reperfusion (IR)-mediated platelet activation and how platelets may impair reperfusion injury after stroke.1
IR-Mediated Platelet Activation
The replenishment of oxygen and nutrients to damaged brain tissue during ischemic stroke is essential, but subsequent IRI can also propagate cell injury through production of reactive oxygen species (ROS). The brain is highly sensitive to ischemia as it is the most metabolically active per unit weight of any organ and has reduced levels of defensive antioxidant enzymes that help alleviate damage from ROS. Recent studies indicate that the eruption of ROS occurring post-IR lowers the bioavailability of nitric oxide, thereby reducing the threshold for thrombus propagation and platelet activation. Researchers are currently investigating potential agonists of platelet activation following ischemic stroke/reperfusion, which are summarized in Table 1.
|Table 1. List of agonists released following ischemic stroke/reperfusion that may activate platelets1|
|Abbreviations: ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin type 1 motif number 13; ADP, adenosine 59-diphosphate; HMGB1, high-mobility group box-1; S1P, sphingosine-1-phosphate; VWF, von Willebrand factor|
Role of von Willebrand Factor Axis in IRI
von Willebrand factor (VWF) is a glycoprotein released from IR-damaged endothelium that is thought to play a key role in the progression of IRI. After IR, activated platelets can enhance IRI by interacting with VWF, ultimately recruiting, and subsequently activating leukocytes that release platelet microparticles to enhance tissue death. A recent study showed that blockade of the VWF receptor glycoprotein Ib (GPIb) was able to lower the amount of occluded cerebral microvessels and thrombus burden in mice.3 These results suggest that platelet interactions with leukocytes, especially neutrophils, are a key factor in platelet-mediated IRI. When recruited to the site of IR, neutrophils augment IRI by releasing ROS as they remove cellular debris. Currently, researchers are investigating GPIb inhibition as a novel therapeutic target for the amelioration of IRI post-stroke.
Another promising target located in the GPIb-VWF–signaling axis is disintegrin-like and metalloprotease with thrombospondin type 1 motif number 13 (ADAMTS13). Mechanistically, the lack of ADAMTS13 worsens IRI by increasing leukocyte infiltration and also by increasing accumulation of platelet-VWF-leukocyte aggregates. A recent study showed that ADAMTS13 knockout mice also had elevated levels of high mobility group box-1 (HMGB1), which is a potential platelet agonist.4 These results suggest that ADAMTS13 infusion may protect from IRI without causing hemorrhage, an attractive feature of a novel therapy.
Several platelet-mediated activities, including platelet-secreted products, microparticle formation, phosphatidylserine exposure, and platelet integrin αIIb β3 may play important roles in tissue death following ischemic stroke and reperfusion. Many of these processes are being explored as potential therapeutic targets for IRI.
While a large body of literature supports the role of platelets as drivers of IRI post-stroke, there is a smaller body of research suggesting that platelet activity is essential to safeguard against IRI and aid in recovery after ischemic stroke. Since platelets store both antiangiogenic and proangiogenic factors, as well as release anti-inflammatory cytokines, such as interleukin 10, this hypothesis is plausible.
Expert Perspective: Identifying New Targets for Treating IRI
“Platelets can be a double-edged sword in the context of strokes,” commented study author Ulhas P. Naik, PhD, of the department of medicine at Thomas Jefferson University in an email interview. “The use of currently available anti-platelet drugs is limited since they cause bleeding (hemorrhagic transformation).”
“The practical next steps will be to identify a new target that will mitigate platelet activation and neutrophil interaction without compromising hemostasis – such targets are hard to find, but not impossible, and we hope to achieve this goal in the near future,” Dr. Naik said.
“We have recently identified several targets and are in the process of characterizing small-molecule inhibitors of these targets,” he further explained.
- Shaik NF, Regan RF, Naik UP. Platelets as drivers of ischemia/reperfusion injury after stroke. Blood Adv. 2021;5(5):1576-1584. doi:10.1182/bloodadvances.2020002888
- Roy-O’Reilly M, McCullough LD. Age and sex are critical factors in ischemic stroke pathology. Endocrinology. 2018;159(8):3120-3131. doi:10.1210/en.2018-00465
- Schuhmann MK, Guthmann J, Stoll G, Nieswandt B, Kraft P, Kleinschnitz C. Blocking of platelet glycoprotein receptor Ib reduces “thrombo-inflammation” in mice with acute ischemic stroke. J Neuroinflammation. 2017;14(1):18. doi:10.1186/s12974-017-0792-y
- Fujioka M, Nakano T, Hayakawa K, et al. ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury. Neurol Sci. 2012;33(5):1107-1115. doi:10.1007/s10072-011-0913-9