M. P. Chapman1,2, H. B. Moore1,2, E. Gonzalez1,2, A. P. Morton1,2, C. D. Fleming1,2, K. C. Hansen1, C. C. Silliman1,3,4, A. Sauaia1,2, A. Banerjee1, E. E. Moore1,2 1University Of Colorado Denver,Surgery,Aurora, CO, USA 2Denver Health Medical Center,Surgery,Aurora, CO, USA 3Children’s Hospital Colorado,Haematology,Aurora, CO, USA 4Bonfils Blood Center,Denver, CO, USA
Introduction: To answer the question of when to transfuse platelets to coagulopathic trauma patients with platelet dysfunction, it is ultimately necessary to answer the question of whether the observed platelet dysfunction is intrinsic to the platelets, or is extrinisic, i.e.: a function of a toxic circulatory milieu. We therefore endeavored to test a hypothesis analogous to the familiar Koch’s third postulate, wherein the causal agent of disease will transfer that disease state to a healthy organism. In our case, the causal agent in question was not infectious, but rather was plasma from coagulopathic trauma patients with platelet dysfunction. We hypothesized that plasma from coagulopathic trauma patients would cause inhibition of healthy donor platelets, and that this toxic effect would be associated with a shift in the plasma proteome.
Methods: We isolated platelet free plasma from 171 trauma activation patients, of which 8 were severely coagulopathic with severe platelet dysfunction. This plasma was mixed 1:1 with whole blood from healthy donors. Comparison was made to plasma from non-coagulopathic trauma patients and healthy donors (control). Platelet inhibition was measured using whole blood impedance aggregometry with TRAP and ADP agonists (ROTEM Platelet, Tem GmbH). Proteomic analysis of plasma samples was conducted using the QconCat platform (PolyQuant, GmbH).
Results: Plasma from severely coagulopathic trauma patients with platelet dysfunction, conveyed significant inhibition in platelet function to donor platelets (p=0.049); see figure. Plasma from non-coagulopathic trauma patients did not significantly decrease healthy donor platelet function, compared to exposure to self plasma. A subset of plasma samples, which inhibited healthy donor platelets ≥50% (p=0.0025), demonstrated significant proteomic shifts, including massive upregulation of alpha-enolase , GAPDH, fibronectin, von Willebrand factor, and alcohol dehydrogenase 1B, along with loss of coagulation factor V.
Conclusion: Plasma from coagulopathic trauma patients with platelet dysfunction is capable of conveying this dysfunction to healthy donor platelets. This pathogenic transfer is likely the result of a soluble toxic factor, as it is associated with an upregulatory proteomic shift, that is not buffered by healthy whole blood. These findings have two implications: (1) that it is critical to correct the platelet-inhibitory circulatory milieu of a coagulopathic trauma patient (e.g. with plasma resuscitation) before transfusing patients and (2) that the unidentified toxic soluble factor may represent a drug target for preserving platelet function in trauma patients.
