PB1047 - CAY001, a synthetic short-chain polyphosphate (polyP) complexed with silica nanoparticle (SNP), corrects coagulopathy under hemodilute, hypothermic, or acidotic conditions

Background: Hypothermia, acidosis, and resuscitative hemodilution (“the lethal triad”) contribute significantly to coagulation dysfunction after trauma and are sequelae of trauma-induced coagulopathy (TIC). CAY001 is a synthetic biomimetic of platelet-length polyP (polyP-SNP complex) under development as a pro-hemostatic therapeutic for serious or life-threatening bleeding. In this study, we assessed CAY001’s ability to restore hemostasis under conditions mimicking “the lethal triad” in human pooled normal plasma (hPNP).

Aims: To characterize the pro-hemostatic potential of CAY001 under TIC conditions by in vitro coagulation assays.

Methods: CAY001 and SNP were synthesized as ready-to-use research batches (Cayuga Biotech Inc.). TIC 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 (TGA) was performed in a 96-well fluorogenic assay format. The reaction was initiated by adding CaCl2/phospholipid to citrated hPNP with CAY001 or SNP (0, 0.25 mg/mL). Lipidated tissue factor (LTF, 0.5 ng/mL) was used as positive control. TGA-parameters were derived from relative fluorescence unit (RFU)-over-time profile and its first derivative (RFU/min). TEG was performed using TEG5000 analyzer (Haemonetics Corp). The reactions were initiated by adding CaCl2 to hPNP with CAY001 or SNP (0, 0.25 mg/mL).

Results: CAY001 improved thrombin generation at all diluted hPNP levels with Time-to-Peak ≤2-minutes at >33% hPNP. LTF-control failed to generate thrombin at ≤33% PNP. (Figure 1). CAY001 improved TGA Time-to-Peak by 10x under hypothermic conditions (32oC) and 50% under conditions of severe acidosis, respectively (Figure 2). Across all conditions, CAY001 also improved TEG-parameters.

Conclusion(s): The results demonstrate the potential of CAY001 as a pro-hemostatic therapeutic for serious, life-threatening bleeding, including TIC.