A Synthetic Short-Chain Polyphosphate Complexed With Silica Nanoparticle, Corrects Coagulopathy Under Hemodilute, Hypothermic, or Acidotic Conditions as Assessed by In Vitro Coagulation Assays.

INTRODUCTION

Noncompressible hemorrhage accounts for up to 90% of potentially survivable combat deaths. Hypothermia, acidosis, and resuscitative hemodilution ("the lethal triad") contribute significantly to coagulation dysfunction after trauma and are sequelae of trauma-induced coagulopathy. The polyphosphate (polyP)-silica nanoparticle (SNP) (polyP-SNP) complex is a synthetic biomimetic of platelet-length polyP. It is under development as a prohemostatic therapeutic for noncompressible hemorrhage. In this study, we assessed the polyP-SNP complex's ability to restore hemostasis under conditions mimicking the lethal triad in human-pooled normal plasma (hPNP).

MATERIALS AND

METHODS

Lethal triad conditions were simulated using hPNP by dilution with isotonic saline (hemodilution: 100-10% hPNP), chilling (hypothermia: 37-30 °C), or adding lactic acid (metabolic acidosis: 0-10 mM). Thrombin generation assay was performed in a 96-well fluorogenic assay format. The reaction was initiated by adding CaCl2/phospholipid to citrated hPNP with equal concentrations of the polyP-SNP complex or SNP (0.25 mg/mL). Thromboelastography (TEG) was performed using TEG5000 analyzer. The reactions were initiated by adding CaCl2 to hPNP with equal concentrations of the polyP-SNP complex or SNP. Lipidated tissue factor (0.5 ng/mL) was used as positive control for both assays.

RESULTS

The polyP-SNP complex improved thrombin generation at all diluted hPNP levels with Time-to-Peak ≤2 min at ≥33% hPNP. Lipidated tissue factor -control failed to generate thrombin at ≤33% PNP. PolyP-SNP improved thrombin generation assay Time-to-Peak by 10× under hypothermic conditions (32 °C) and 50% under conditions of severe acidosis, respectively. Across all conditions, polyP-SNP also improved TEG parameters.

CONCLUSIONS

The results demonstrate the potential of the polyP-SNP complex as a prohemostatic therapeutic for noncompressible hemorrhage, including under lethal triad conditions.