During storage, platelets become gradually impaired in activation and signaling responses. In this issue of Blood, Canault and colleagues demonstrate that storage-induced shedding of platelet receptors GP1bα and GPV is mediated by p38 MAP kinase and inhibition of this pathway improves the function and posttransfusion recovery of stored platelets.1 

Therapeutically, platelet concentrates are crucial for transfusion into thrombocytopenic patients, particularly when bleeding. However, the efficacy of these transfusions is limited by the shelf life of the platelet concentrates and their diminishing function over time. Therefore, it is crucial to understand how to optimally store platelets to preserve their hemostatic function once transfused. In addition, it is important to maintain the suppression of platelet markers that could contribute to their clearance after transfusion.

Platelet storage lesion is a term that describes both the biochemical and structural changes that occur in platelets during storage. Morphologic and functional alterations have been characterized in stored platelets and include shape change, reduction in activation by agonists, secretion of platelet granules, blebbing, and exposure of surface phosphatidylserines. Less is known about the biochemical properties regulating these changes. Recently, inhibition of PI3-kinase–dependent Rap1 activation has been reported to reduce both αIIbβ3 activation and α-granule release, improving platelet survival during storage.2 

During storage, platelets shed adhesive surface glycoproteins. In this issue of Blood, Canault et al investigate another signaling pathway responsible for platelet receptor shedding that is known to alter platelet function.1  They examine the role of p38 MAP kinase in GPIbα and GPV shedding from the platelet surface through tumor necrosis factor-α–converting enzyme (TACE/ADAM17) and how this affects stored platelet function and survival. Using mice that express a nonfunctional form of TACE, they confirm that TACE is responsible for the cleavage of GP1bα and GPV, as previously reported.3-5  Canault et al show that inhibition of TACE is important in posttransfusion clearance of platelets.1  Shedding of both glycoproteins by TACE is not mediated through PKC, MEK/ERK, or caspases, as demonstrated by pharmacologic inhibitor work.1  Instead, inhibition of p38 MAPK significantly reduces the shedding of GPIbα and GPV from the platelet surface.1  Inhibition of p38 MAPK does not affect platelet function but does affect increased platelet recovery and improved platelet function after transfusion.1 

The work presented by Canault et al1  suggests that treating all stored platelets with a p38 MAPK inhibitor would increase the efficacy of platelet transfusions. However, questions arise over whether or not this is possible in humans. Posttransfusional function of platelets and survival of transfused mice suggest that the addition of a p38 MAPK inhibitor will not have any adverse effects. Importantly, this is inconsistent with previous data using human platelets in which inhibition of p38 MAPK resulted in the loss of platelet aggregation induced by collagen6,7  or by low-dose thrombin,7  although some recovery occurred at higher concentrations of the agonists.6,7  Is it possible that the differences can be attributed to the model being studied, that is, human platelets versus mouse platelets? Clearly, further experimentation is needed to clarify the clinical effects of long-term storage with a p38 MAPK inhibitor on platelet function, survival, and patient-specific platelet reactivity.

Another issue with this approach is that inhibition of MAP kinase as a means of preventing platelet storage disease is nonspecific. It is well established that this pathway regulates many parts of platelet activation (not just shedding) and many functions in the vasculature. Animal studies looking at the inhibition p38 MAPK in high-salt, high-fat diets have shown a reduction in blood pressure, and improved endothelial-dependent and -independent vasorelaxation.8  Hypoxia-induced endothelial dysfunction can be reversed with inhibition of p38 MAPK by improving vasorelaxation, increasing NO production, and reducing superoxide levels.9  Although these properties, that is, vasodilation, may be beneficial in the setting of elevated blood pressure, vessel dilation can be dangerous in the setting of hemorrhage. Clearly, the global effect of p38 MAP kinase inhibition on the vasculature relevant to bleeding would need to be examined.

Can MAP kinase inhibition be used to maintain the integrity and functionality of platelets stored for transfusion? Whereas this article presents some exciting mechanistic data, more questions are raised concerning the clinical relevance of this approach. As there are many other factors that can affect platelet function during storage, such as bacterial contamination and activation by plasma products, that are independent of p38 MAPK signaling, these interesting data stress the importance of taking a broad view of the problems involved with platelet transfusion.

Conflict-of-interest disclosure: The authors declare no competing financial interests. ■

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