20 The dynamics of fibrin polymerization therefore play a central role in thrombosis and bleeding because thrombosis resulting from fibrin formation in the microcirculation, as in DIC, decreases blood flow, which causes tissue damage, whereas deficient fibrin polymerization is critical during hemostasis to prevent exsanguination. The coagulation cascade culminates in the formation of fibrin through the polymerization of fibrinogen that is initiated by the serine protease thrombin, forming an insoluble matrix. Together, these data demonstrate that a fibrinolytic agent loaded into fibrin-targeting nanogels could improve DIC outcomes. When incorporated with human DIC patient plasma, tPA-FSNs restored clot structure and clot growth under flow. In vivo, tPA-FSNs decreased the presentation of multiorgan microthrombi, recovered platelet counts, and improved bleeding outcomes in a DIC rodent model. We hypothesized that this dual action would simultaneously address bleeding and microthrombi with DIC to improve outcomes. FSNs enhance formation of actively polymerizing clots by crosslinking fibrin fibers, but they can also target preexisting microthrombi and, when loaded with tPA, facilitate targeted delivery to lyse the microthrombi.
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The objective of this study was to develop fibrin-specific core-shell nanogels (FSNs) loaded with tissue-type plasminogen activator (tPA) to treat the microcirculatory complications of DIC, which would facilitate targeted clot dissolution to manage microthrombi and the potential consumptive coagulopathy that causes bleeding. Treatments for thrombotic episodes or bleeding presentation in DIC oppose each other, thus creating therapeutic dilemmas in management. Different clinical events lead to DIC, including sepsis, trauma, and shock. In DIC, excessive thrombin generation causes symptoms from formation of microthrombi to multiorgan failure bleeding risks can also be a concern because of clotting factor consumption. Disseminated intravascular coagulation (DIC) is a pathological coagulopathy associated with infection that increases mortality.
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