Thromboelastometry fails to detect autoheparinization after major trauma and hemorrhagic shock.

BACKGROUND: Heparan sulfate is an integral component of the glycocalyx that provides an anticoagulant layer close to the endothelium. Hypoperfusion, inflammation, and sympathoadrenal activation following major trauma result in glycocalyx shedding and subsequent release of heparan sulfate into the bloodstream. The possible anticoagulant effect of this "autoheparinization" has been suggested as a potential driver of trauma-induced coagulopathy. We investigated whether thromboelastometry can be used to detect trauma-induced autoheparinization. METHODS: This study comprised three parts. First, in a retrospective clinical study of 264 major trauma patients, the clotting time (CT) in the intrinsic activation (INTEM) and intrinsic activation plus heparinase (HEPTEM) assays were evaluated upon emergency room admission. Second, in an in vivo experimental rat model of hemorrhagic-traumatic shock, the release of heparan sulfate was investigated with INTEM and HEPTEM analyses of whole blood. Third, in vitro spiking of whole blood from healthy volunteers was undertaken to assess the effects of clinically relevant quantities of heparan sulfate and heparin on CT in the INTEM and HEPTEM assays. RESULTS: In the first part, severe injury and hemorrhagic shock was not associated with any increases in INTEM CT versus HEPTEM CT. Part 2 showed that an approximate threefold increase in heparan sulfate resulting from hemorrhagic traumatic shock in rats did not prolong INTEM CT, and no significant differences between INTEM CT and HEPTEM CT were observed. Third, spiking of whole blood with heparan sulfate had no impact on INTEM CT, whereas heparin elicited significant prolongation of INTEM CT. CONCLUSION: Despite structural similarity between heparan sulfate and heparin, the amounts of heparan sulfate shed in response to trauma did not exert an anticoagulant effect that was measurable by the intrinsically activated CT in thromboelastometry. The extent to which heparan sulfate contributes to trauma-induced coagulopathy has yet to be elucidated. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock.

BACKGROUND: Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. METHODS: Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). RESULTS: Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). CONCLUSION: The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. LEVEL OF EVIDENCE: VExperimental in vivo study.

Experimental Models of Endotheliopathy: Impact of Shock Severity.

BACKGROUND: Hemorrhagic shock (HS) followed by resuscitation is often associated with sympathoadrenal activation (SAA) and endothelial damage (ED). OBJECTIVE: We aimed to evaluate the impact of HS alone on the magnitude of SAA and consecutive ED, and to characterize potential targets for a standardized and reproducible model of HS-induced endotheliopathy in rats. METHODS: Rats were subjected either to a volume-controlled HS (40% of total blood volume: v-HS group) or to a laboratory-guided HS (l-HS) targeting base deficit (BD) more than 5.5 mmol/L and/or lactate more than 2.2 mmol/L using a pressure-controlled volume loss. RESULTS: At the end of shock, mean arterial pressure was significantly higher in the v-HS than the l-HS group (36 ±â€Š5.6 vs. 30 ±â€Š3.0 mmHg; P < 0.01). Base deficit and lactate were higher in l-HS than the v-HS group (BD: 9.5 ±â€Š2.5 vs. 3.0 ±â€Š1.0 mmol/L; P < 0.001; lactate: 4.1 ±â€Š1.3 vs. 1.6 ±â€Š0.6 mmol/L; P < 0.001). sVEGFR-1 and syndecan-1 were approximately 50% higher in the l-HS than the v-HS group (% changes vs. baseline: 160 ±â€Š10 vs. 116 ±â€Š36; P < 0.01; 170 ±â€Š37 vs. 113 ±â€Š27; P < 0.001). Adrenaline was 2-fold higher in l-HS than the v-HS group (1964 ±â€Š961% vs. 855 ±â€Š451%; P < 0.02, respectively). Moreover, linear regression analysis revealed an independent association of shock severity BD with syndecan-1 (rho = 0.55, P = 0.0005), sVEGFR1 (rho = 0.25, P < 0.05), and adrenaline (rho = 0.31, P = 0.021). CONCLUSIONS: Our findings indicate that ED has already occurred during HS without reperfusion; intensity is strongly related to the severity of HS and consecutive SAA; and severity may appropriately be targeted and standardized in a HS model controlled by biological endpoints such as BD and/or lactate.

[Coagulation management in trauma-related massive bleeding. - Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI)]. / Gerinnungsmanagement bei traumatisch bedingter Massivblutung - Empfehlungen der Arbeitsgruppe für perioperative Gerinnung der OGARI.

Even nowadays and at specialized centers, one of the leading causes of death is exsanguination. Trauma-induced coagulopathy (TIC) occuring with massive blood loss primarily results from loss of coagualtion factors and platelets and is aggravated by hemodilution. In addition, hyperfibrinolysis, hypothermia, acidosis and hypocalcaemia also contribute to the development of severe haemostatic derangement. During the past few years new insights into the pathophysiology of TIC and the widespread use of viscoelastic coagulation monitoring provoked the development of alternative treatment concepts. As for the previously recommended standard therapy using fresh frozen plasma and platelet concentrates also for alternative strategies no data from large prospective randomized studies are available until now, however, the evidence is growing favoring the use of coagulation factor concentrates guided by viscoelastic measurements.