Restoring Hemostasis Following Injury Using Polyphosphate‐Coated Silica Nanoparticles

According to the 2010 World Health Organization Global Burden of Disease study, injury accounts for over 5 million deaths per year, roughly 1 out of every 10 deaths worldwide. By 2030, injury is expected to become the 5th leading worldwide cause of death. Hemorrhage control is a major focus in treating critically injured patients. Uncontrolled blood loss accounts for 25–30% of civilian deaths and the vast majority of all battlefield deaths. Quick interventions are critical to prevent exsanguination. Rapid effectiveness is the key to saving lives and preventing morbidity. A major problem plaguing trauma treatment is the current trend of dividing patients into cohorts based on their pre‐injury medical condition. This is especially evident in anticoagulated patients, where reversal agents are only effective for specific anticoagulants. Varied treatment protocols require clinicians to know the patient's medical history for effective intervention. A universal procoagulant that can restore clotting function across a variety of hemorrhaging patients, is stable at ambient conditions, and does not promote unwanted thrombosis can mark a major breakthrough in the treatment of all injured patients. Novel hemostatic agents such as nanoparticles can bridge the critical time between injury and treatment to begin treatment quicker and improve the condition of trauma patients upon hospital arrival. One such potential solution is created by coating a silica nanoparticle (SNP) with a biomimetic short chain polyphosphate (polyP) polymer to form polyP‐SNP. In response to vessel injury, short‐chain polyP binds to thrombin at the injury site. After binding to thrombin, polyP enhances back‐activation of FXI and FV, ultimately leading to an increase in the production of thrombin, the integral factor for clotting ( Fig. 1). Additionally, by targeting FXI and FV, short chain polyP bypasses the anticoagulated pathways to act as a potent antidote for FXa inhibitors and direct thrombin inhibitors. Preliminary rat trials suggest that a 5 mg/kg dose of polyP‐SNPs after a tail cut reduced blood loss by roughly 33 % ( Fig. 2, p = 0.011) and led to 100 % survival. Ex vivo studies of polyP‐SNPs using blood drawn from an uninjured rat showed that polyP‐SNP had no effect on initiation of clotting, yet had a major effect on the acceleration of coagulation after clotting was initiated ( Fig. 3). In vitro studies using human blood specimens have shown that polyP and polyP‐SNP improve coagulation function in samples from patients prone to bleeding including anticoagulated and hemophiliac patients. PolyP‐SNPs quickly accelerate clot formation once the body has initiated clotting. The stability of polyP‐SNPs at ambient conditions enables quicker intervention to prevent conditions that develop as a result of injury. In vivo studies have shown that the use of polyP‐SNP after injury significantly reduces blood loss. This system has been shown to be effective at reducing blood loss in a traumatic injury without unwanted clotting. Furthermore, polyP‐SNP has been shown in vitro to correct bleeding abnormalities across multiple populations prone to bleeding after injury. PolyP‐SNPs have the potential to be at the vanguard of novel treatments that save lives by safely and effectively enabling prehospital treatment for all injured patients.Blood clotting is initiated by injury (purple) or a negatively‐charged surface such as silica (blue). After initiation, the main goal of the common pathway is the rapid production of thrombin (green) to accelerate coagulation. The thrombin burst is directly tied to creation of the physical clot (black) that plugs the injured vessel. Short chain polyphosphate (red) binds to thrombin and accelerates the common pathway to produce more FVa, thrombin, and increase clot strength.PolyP‐SNP reduce blood loss by 33 % post‐injury. A One‐way ANOVA was performed on blood loss after tail amputation followed by Tukey's post‐hoc test to compare groups; both 5 mg/kg and 10 mg/kg doses reduced total blood loss compared to placebo (F2‐22 = 5.02, p < 0.05).(A) PolyP‐SNP do not significantly reduce initial clot formation times (clot growth 0–2 mm, R value) using thromboelastography [One‐way ANOVA (F4, 114 = 23.76, p < 0.0001)]. (B) PolyP‐SNPs accelerate later‐stage clot growth (2–20 mm, K value) [One‐way ANOVA (F4, 121 = 7.87, p < 0.0001)]. (C) When added together, polyP‐SNPs hasten clot growth from 0 – 20 mm (R+K value) [One‐way ANOVA (F4, 123 = 19.21, p < 0.0001)].