The intriguing role of platelets as custodians of brain-derived neurotrophic factor

A State of the Art lecture titled "Platelets and neurotrophins" was presented at the ISTH congress in 2023. Neurotrophins, a family of neuronal growth factors known to support cognitive function, are increasingly recognized as important players in vascular health. Indeed, along with their canonical receptors, neurotrophins are expressed in peripheral tissues, particularly in the vasculature. The better characterized neurotrophin in vascular biology is the Brain-Derived Neurotrophic Factor (BDNF). Its largest extracerebral pool resides within platelets, partly inherited from megakaryocytes and also likely internalized from circulation. Activation of platelets releases vast amounts of BDNF into their milieu, and interestingly leads to platelet aggregation through binding of its receptor, the Tropomyosin-related Kinase B (TrkB), on the platelet surface. As BDNF is readily available in plasma, a mechanism to preclude excessive platelet activation and aggregation appears critical. As such, binding of BDNF to α2-macroglobulin hinders its ability to bind its receptor, and limits its platelet-activating effects to the site of vascular injury. Altogether, addition of BDNF to a forming clot facilitates paracrine platelet activation, but also binds to fibrinogen, rendering the resulting clot more porous and plasma-permeable. Importantly, release of BDNF into circulation also appears to be protective against adverse cardiovascular and cerebrovascular outcomes, which has been reported in both animal models and epidemiological studies. This opens an avenue for platelet-based strategies to deliver BDNF to vascular lesions and facilitate wound healing through its regenerative properties. Finally, we summarize relevant new data on this topic presented during the 2023 ISTH Congress.