Abstract
BackgroundAggressive fluid management and other external factors may lead to hypothermia, acidosis and hemodilution (defined as Lethal Triad, LT) contributing to a trauma-induced coagulopathy (TIC) that worsens patients’ outcomes. Procoagulant microparticles (MP) are crucial players at the interface of cellular and plasmatic coagulation. However, their functions remain largely unexplored. This study aimed to characterize effects of MP subtypes and concentrations on functional coagulation under in vitro simulated conditions.MethodsBlood from eleven volunteers were collected to simulate in vitro conditions of hemodilution (HD) and LT, respectively. HD was induced by replacing a blood volume of 33% by crystalloids and for LT, samples were further processed by reducing the temperature to 32 °C and lowering the pH to 6.8. MP were obtained either from platelet concentrates (platelet-derived MP, PDMP) or from cell culture (ECV304 cells for endothelial-derived MP, EDMP) by targeted stimulation. After introducing MP to in vitro conditions, we measured their concentration-dependent effects (1.000, 10.000 and 15.000 MP/μl blood) on coagulation compared to whole blood (WB). For each condition, coagulation was characterized by flow cytometric platelet activation and by quantification of fibrin clot propagation using Thrombodynamics® technology.ResultsMP originated from platelets and endothelial cells affected blood coagulation in a concentration-dependent manner. Particularly, high PDMP quantities (10.000 and 15.000 PDMP/μl blood) significantly induced platelet activation and fibrin clot growth and size in HD conditions. In LT conditions as well, only high PDMP concentration induced platelet activation, clot growth and size. In contrast, EDMP did not induce platelet activation, but resulted in enhanced formation of spontaneous clots, irrespective of simulated condition. With increasing EDMP concentration, the time until the onset of spontaneous clotting decreased in both HD and LT conditions.DiscussionThe study demonstrates an essential role of MP within the coagulation process under simulated coagulopathic conditions. PDMP affected platelets promoting clot formation likely by providing a surface enlargement. EDMP presumably affected clotting factors of the plasmatic coagulation resulting in an increased formation of spontaneous clots.ConclusionUnder simulated conditions of a dilutional coagulopathy, MP from different cellular origin indicate a divergent but both procoagulant mechanism within the coagulation process.
Highlights
Despite continuous improvements in trauma management, traumatic injuries are still the leading cause of death and disability in adults under 40 years [1,2,3]
Under HD conditions, high Platelet-derived microparticles (PDMP) quantities (10 k and 15 k MP/μl blood) induced an activation of platelets, which was demonstrated by a significant increase of the cell surface marker CD42b+/CD62p+ expression compared to Kinetics of fibrin clot formation and density after PDMP application The kinetics of clot formation measured by Tlag, clot growth (V) and the initial rate of clot growth (Vi) remained unaffected in the experimental controls of whole blood (WB), HD and lethal triad” (LT)
After introduction of low concentrated PDMP (1 k PDMP/μl blood) to the whole blood condition a significant change of all clot formation parameters could be observed but remained unaffected under simulated conditions of HD and LT (Table 1)
Summary
Despite continuous improvements in trauma management, traumatic injuries are still the leading cause of death and disability in adults under 40 years [1,2,3]. This study aimed to characterize effects of MP subtypes and concentrations on functional coagulation under in vitro simulated coagulopathic conditions. In relation to their potential to facilitate coagulation complexes and initiate the coagulation process via TF−/FVII-dependent and independent pathways, our goal was to understand and to differentiate the role of platelet- and endothelial-derived MP (PDMP, EDMP) on functional coagulation [26, 27]. Aggressive fluid management and other external factors may lead to hypothermia, acidosis and hemodilution (defined as Lethal Triad, LT) contributing to a trauma-induced coagulopathy (TIC) that worsens patients’ outcomes. This study aimed to characterize effects of MP subtypes and concentrations on functional coagulation under in vitro simulated conditions
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