Platelet-mimicking procoagulant nanoparticles augment hemostasis in animal models of bleeding

Abstract

Treatment of bleeding disorders using transfusion of donor-derived platelets faces logistical challenges due to their limited availability, high risk of contamination, and short (5 to 7 days) shelf life. These challenges could be potentially addressed by designing platelet mimetics that emulate the adhesion, aggregation, and procoagulant functions of platelets. To this end, we created liposome-based platelet-mimicking procoagulant nanoparticles (PPNs) that can expose the phospholipid phosphatidylserine on their surface in response to plasmin. First, we tested PPNs in vitro using human plasma and demonstrated plasmin-triggered exposure of phosphatidylserine and the resultant assembly of coagulation factors on the PPN surface. We also showed that this phosphatidylserine exposed on the PPN surface could restore and enhance thrombin generation and fibrin formation in human plasma depleted of platelets. In human plasma and whole blood in vitro, PPNs improved fibrin stability and clot robustness in a fibrinolytic environment. We then tested PPNs in vivo in a mouse model of thrombocytopenia where treatment with PPNs reduced blood loss in a manner comparable to treatment with syngeneic platelets. Furthermore, in rat and mouse models of traumatic hemorrhage, treatment with PPNs substantially reduced bleeding and improved survival. No sign of systemic or off-target thrombotic risks was observed in the animal studies. These findings demonstrate the potential of PPNs as a platelet surrogate that should be further investigated for the management of bleeding.

Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis

“…Platelet-mimicking procoagulant nanoparticles (PPNs), containing PS on their surface, can resist clot lysis and increase clot stability, leading to reduced bleeding and improved survival in rodent models of thrombocytopenia and traumatic hemorrhage. The design of PPNs able to amplify thrombin and fibrin generation at injured sites and enhance homeostatic clot formation emphasizes the multiple therapeutic applications of engineered EVs [ 340 ].…”

Platelet‐inspired nanomedicine in hemostasis thrombosis and thromboinflammation

“…phosphatidylserine, PS) on the surface of SynthoPlate nanoparticles in an injury site-selective manner, inspired by the platelet procoagulant function. 76 Here, the PS remained masked by a polyethylene glycol (PEG) brush conjugated on the particle surface, which could be cleaved by the action of plasmin predominantly at the injury site for targeted augmentation of hemostasis. This new design could significantly enhance hemostasis, even when endogenous platelet activity was impaired.…”

“…In another recent approach, we have explored the exposure of anionic phospholipids (e.g. phosphatidylserine, PS) on the surface of SynthoPlate nanoparticles in an injury site‐selective manner, inspired by the platelet procoagulant function 76 . Here, the PS remained masked by a polyethylene glycol (PEG) brush conjugated on the particle surface, which could be cleaved by the action of plasmin predominantly at the injury site for targeted augmentation of hemostasis.…”

Treatment of inherited thrombocytopenias

“…On the other hand, 'synthetic platelet' nanoparticles have already been manufactured and have been proved capable of supporting hemostasis in animal models. 91 …”