Date Published: May 1, 2019
Publisher: Public Library of Science
Author(s): Loren K. Liebrecht, Jason Newton, Erika J. Martin, Niluka Wickramaratne, Sudha Jayaraman, Jinfeng Han, Michel Aboutanos, Donald F. Brophy, Martin J. Mangino, Esmaiel Jabbari.
Novel crystalloid solutions containing polyethylene glycol polymers (PEG-20k) produce dramatic resuscitation effects but dose-dependently produce a hypocoagulative state. The objective of this study was to examine possible mechanisms of this effect. Based on previous thromboelastography data, we hypothesize the effect is largely due to platelet interactions with the polymers.
Whole citrated blood from healthy volunteers was diluted ex-vivo 10% with crystalloids and tested for coagulation and platelet function. The specific tests included prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and von Willebrand factor (vWf) activity, thrombin generation, thromboelastography with and without platelet mapping, platelet flow cytometry, and erythrocyte sedimentation rate.
Fibrinogen and vWF activities, PT, and aPTT were not affected by PEG-20k dilutions. Thrombin activity was mildly suppressed with PEG-20k (TTP- 20%). Platelet mapping demonstrated significantly greater % inhibition of both ADP and arachidonic acid-induced platelet aggregation with PEG-20k, but direct ADP-activated gpIIa/IIIb (PAC1) and P-selectin (CD62P) binding site expression was not altered. Mild dose-dependent suppression of TEG-MA was seen with PEG-20k using platelet poor plasma. Erythrocyte Sedimentation Rates (ESR) were dramatically accelerated after dilution with 10% PEG-20k, which was competitively blocked by smaller PEG polymers, suggesting nonspecific PEG-20k cell binding effects.
PEG-20k creates a mild hypocoagulative state in whole blood at concentrations ≥10%, which may be due to platelet-PEG interactions at the IIb/IIIa interface with lesser effects on fibrin polymerization. This interaction may cause a functional thrombasthenia induced by nonspecific platelet surface passivation by the PEG polymer.
Trauma is the number one cause of death for people under 44 years of age in the US and the third leading cause of death overall for all age groups. Trauma accounts for about 30% of all life-years lost in the US, compared to cancer (16%), heart disease (12%), and HIV (2%) . For all traumatic injuries, hemorrhagic shock is responsible for over 35% of pre-hospital deaths and over 40% of all deaths within the first 24 hours. This is second only to deaths induced by severe CNS injury . Hemorrhagic hypotension exposes the patient to immediate complications of life-threatening infections, coagulopathies, and multiple organ failure [3, 4].
The plasma concentrations of fibrinogen and von Willebrand factor (vWF) activity obtained from healthy volunteers that had been diluted 10% with either PEG-20k (10% w:v) or a saline dilution control are shown Fig 1. There was no difference in fibrinogen concentrations due to dilution with PEG-20k (Panel A). However, there was a small but statistically significant decrease in vWF activity observed for the PEG-20k (Panel B) samples but the levels in this group were still within the normal range.
PEG-20k, a new LVR crystalloid solution has recently been developed that induces profound tolerance to the low volume state when compared to other commonly used solutions. In preliminary testing using thromboelastography  it was determined that these solutions, which contain 10% PEG-20k, produced a dose-dependent hypocoagulative state, namely a significant decrease in MA and decreases in α-angle and k. Since MA represents clot firmness associated with platelets (80–90%) and fibrinogen (10–20%) , it was posited that PEG-20k effects on coagulation may interfere with platelet function and/or fibrin polymerization. Deficiencies in fibrin polymerization or fibrin cross-linking were suspected, given the decreases in the fibrinogen dependent TEG factors such as α-angle and k and changes in clot strength. These changes are affected by low fibrinogen activity, fibrinogen deficiency, Factor XIII defects, or thrombocytopenia/thrombocytopathy. Therefore, to dissect out effects of PEG on coagulation factors or platelet function, we conducted more specific testing on diluted volunteer whole blood.