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Z. Zhao et al.
ed platelets”, which are defined as a subpopulation (12- 30%) of platelets that express procoagulant activity upon stimulation by collagen and thrombin.25,42 This procoagu- lant activity was also detected in exMT-treated platelets (Figure 5).
Third, the metabolic viability of exMT also suggests a potential role of ROS in the development of this interme- diate platelet phenotype because ROS are known to acti- vate platelets.15-17 We have shown that ROS from exMT activated platelets (Figure 3) and induced platelet microvesiculation (Figure 4) in an oxidant-dependent manner. A physical contact between exMT and platelets appears to be required for the ROS-induced platelet secre- tion because ROS primarily affect exMT-bound platelets. This direct exMT-platelet interaction may concentrate ROS activity on exMT-bound cells or protect the oxidants from plasma antioxidants.
In summary, we have shown that exMT-bound platelets develop an intermediate phenotype using ROS as media- tors. This intermediate phenotype is characterized by α- granule secretion, procoagulant activity and poor aggrega- tion (Figure 6F). As a result, these procoagulant platelets
remain in the circulation to promote non-focal coagula- tion, similar to the consumptive coagulopathy found in TBI patients43,44 and mouse models.9 While previous stud- ies have found protective effects of exMT on target cells,10,12,13 our study demonstrates that these exMT could also have detrimental effects by making platelets procoag- ulant and prothrombotic. The findings from this study could have much broader implications regarding exMT in other pathologies in which hypercoagulable and inflam- matory states develop, such as severe infections, autoim- mune diseases, and cancer.
Funding
This study was supported by NIH grants NS087296 and HL71895 (JFD), National Natural Science Foundation of China State Key Program grant 81330029 (JNZ), National Natural Science Foundation of China Major International Joint Research Project 81720108015 (JNZ), National Natural Science Foundation of China Research grants 81271361, 81271359 (JNZ) and 81601068 (ZLZ), Natural Science Foundation of Tianjin 17JCQNJC12100 (ZLZ) and a regional scientific grant 16PTSTJC00180 (JNZ).
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