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The TEG 6s (Haemonetics) point-of-care viscoelastic analyzer is portable, compact, simple to use, and has the potential for rapid viscoelastic analysis that can guide the treatment of veterinary patients at the site of care. Although approved for use in people, the TEG 6s has yet to be evaluated for hemostatic analysis in veterinary medicine. Citrated whole blood (CWB) was collected from 27 healthy dogs. An aliquot of CWB from each dog was diluted by 33% with an isotonic crystalloid, representing an in vitro model of hemodilution. Unaltered and diluted CWB samples were analyzed using 2 TEG 6s and 6 TEG 5000 (Haemonetics) analyzers. The 6 TEG 5000 analyzers ran duplicate analyses of either unaltered or diluted samples using 1 of 3 reagents (Haemonetics): Kaolin TEG, RapidTEG, or TEG Functional Fibrinogen. Duplicate TEG 5000 analyses were averaged and compared with a single TEG 6s analysis. Lin concordance correlation coefficient and Bland-Altman plots were used to evaluate agreement of reaction time, kinetic time, alpha angle, maximum amplitude (MA), and G value (G) for samples activated with Kaolin TEG, and agreement of MA for samples activated with RapidTEG between the 2 machines. Overall, agreement between the TEG 6s and TEG 5000 analyzers was poor. Viscoelastic measurements by the TEG 6s and TEG 5000 in healthy dogs were not all interchangeable. Agreement was satisfactory only for MA and G measurements of diluted blood samples activated with Kaolin TEG, and MA measurements for both unaltered and diluted blood samples activated with RapidTEG.

Background: Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats., Methods: Tissue factor expression of rat bone marrow-derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma., Results: Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow-derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe., Conclusion: Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined., Methods: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock., Results: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy., Conclusion: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the hemostatic potential of canine chilled whole blood maintained at clinically relevant storage conditions., Design: In vitro experimental study., Setting: Government blood and coagulation research laboratory and government referral veterinary hospital., Animals: Ten healthy Department of Defense military working dogs., Interventions: One unit of fresh whole blood was collected from each of 10 military working dogs using aseptic technique. Blood was maintained in a medical-grade refrigerator for 28 days at 4°C (39°F) and analyzed before refrigeration (day 0) and after (days 2, 4, 7, 9, 11, 14, 21, and 28)., Measurements and Main Results: Ten units of canine blood were analyzed with whole blood platelet aggregation, thromboelastography, CBC, biochemical analysis, blood gas, and prothrombin/activated partial thromboplastin/fibrinogen assay. Clotting strength of chilled blood was maintained up to 21 days despite significant decreases in platelet aggregation to ADP, collagen, or γ-thrombin, significant prolongation of prothrombin and activated partial thromboplastin times, and reduced speed of clot formation (K time, alpha angle). Fibrinogen concentration, WBC, RBC, and platelet counts did not change over time., Conclusions: Chilled canine whole blood loses a small percentage of clot strength through 21 days of refrigerated storage. Further research is needed to determine if this hemostatic potential is clinically relevant in hemorrhaging dogs who require surgical intervention or are exposed to traumatic events., (© Veterinary Emergency and Critical Care Society 2021.)

Introduction: Rats subjected to polytrauma and hemorrhage develop a coagulopathy that is similar to acute coagulopathy of trauma in humans, and is associated with a rise in prothrombin time and a fall in clot strength. Because platelet aggregation accounts for a major proportion of clot strength, we set out to characterize the effects of polytrauma on platelet function., Methods: Sprague-Dawley rats were anesthetized with isoflurane. Polytrauma included laparotomy and damage to 10 cm of the small intestines, right and medial liver lobes, right leg skeletal muscle, femur fracture, and hemorrhage (40% of blood volume). No resuscitation was given. Blood samples were taken before and after trauma for the measurement of impedance electrode aggregometry, and intracellular levels of cyclic adenosine and guanosine monophosphate (cAMP, cGMP), inositol trisphosphate (IP3), and adenosine and guanosine triphosphates (ATP, GTP)., Results: Polytrauma significantly increased the response of collagen (24%) and thrombin (12%) to stimulate platelet aggregation. However, aggregation to adenosine diphosphate (ADP) or arachidonic acid (AA) was significantly decreased at 2 (52% and 46%, respectively) and 4 h (45% and 39%). Polytrauma and hemorrhage also led to a significant early rise in cAMP (101 ± 11 to 202 ± 29 pg/mL per 1,000 platelets), mirrored by a decrease in cGMP (7.8 ± 0.9 to 0.6 ± 0.5). In addition, there was a late fall in ATP (8.1 ± 0.7 to 2.2 ± 0.6 ng/mL per 1,000 platelets) and GTP (1.5 ± 0.2 to 0.3 ± 0.1). IP3 rose initially, and then fell back to baseline., Conclusions: Polytrauma and hemorrhage led to a deficit in the platelet aggregation response to ADP and AA after trauma, likely due to the early rise in cAMP, and a later fall in energy substrates, and may explain the decrease in clot strength and impaired hemostasis observed after severe trauma.

Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA's various sites and modes of action may further improve patient outcomes., Competing Interests: The authors have declared that no competing interests exist.

The in vitro haemostatic functions of fresh whole blood (FWB) are well preserved after cold storage. This study aimed to determine whether platelets derived from FWB and stored whole blood (SWB) contribute to clot formation in tissue injury after transfusion into coagulopathic rats with polytrauma/haemorrhage (T/H). The rats were resuscitated 1 h after trauma with FWB or SWB collected from green fluorescence protein (GFP) transgenic rats. After transfusion, a liver incision was made and the tissue was collected 10 min after injury to identify GFP + platelets by immunohistochemistry. In comparison to FWB, platelet aggregation to adenosine diphosphate and protease-activated receptor-4 was reduced by 35% and 20%, and clotting time was shortened by 25% in SWB. After transfusion, SWB led to a significant increase in platelet activation as measured by an elevation of CD62P and phosphatidylserine expression. The platelets from SWB were in a higher activation state, and showed higher clearance rate and formation of platelet-leucocyte aggregates than those from FWB after transfusion. Platelets from both FWB and SWB were equivalently incorporated into the clot at the incisional site, as determined by co-localization of CD61 and GFP. This study suggests that SWB contributes to haemostatic function and is an effective alternative resource to treat trauma patients., (© 2017 John Wiley & Sons Ltd.)

Background: The use of prehospital tranexamic acid (TXA) in patients with trauma has attracted considerable attention. This systematic review and meta-analysis aimed to provide the best evidence for clinicians. Methods: All related literature in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (Central) databases were searched systematically from their establishment to July 1, 2023. The outcome measures included 24-hour and 28–30-day mortality and adverse events (multiple organ dysfunction syndrome, acute respiratory distress syndrome, thrombotic events, and infection events). The Revised Cochrane Risk of Bias Tool for Randomized Trials was used to evaluate the quality of the randomized controlled trials (RCTs). The Methodological Index for Nonrandomized Studies (MINORS) was used to evaluate the risk of bias in non-RCTs. The required information size was estimated using trial sequential analysis. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to evaluate the evidence quality. Results: Eleven studies (comprising 11,259 patients) were included; two of these were RCTs. The overall risks of bias were low in the RCTs. ROBINS-I risk of bias was Moderate in 3 studies, serious in 5 studies, and critical in 1 study. A significant reduction in 24-hour mortality was observed (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.71–0.94). A subgroup analysis that included only RCTs revealed that prehospital TXA was associated with reduced 28–30-day mortality (OR, 0.80; 95% CI, 0.66–0.97) and increased risks of thromboembolism (OR, 1.22; 95% CI, 1.03–1.44) and infection (OR, 1.13; 95% CI, 1.00–1.28) events. The blood products for transfusion decreased by 2.3 units on average (weighted mean difference [WMD], − 2.30; 95%CI, − 3.59 to − 1.01). Conclusions: This updated systematic review showed that prehospital TXA reduced the 24-hour and 28–38-day mortality and blood transfusion but increased the risks of infection and thromboembolism in patients with trauma. Future RCTs with larger and more homogeneous samples will help verify our results. [ABSTRACT FROM AUTHOR]

Introduction: In veterinary medicine there are few readily available products for platelet transfusion to patients with thrombocytopenia. Commercial tabletop platelet concentrating systems have recently become available to veterinarians, primarily directed towards uses associated with regenerative medicine. These systems could potentially be used to produce fresh concentrated platelets for use in transfusion medicine. This study evaluated the concentration, activation, and sterility of a double centrifugation platelet concentrate (PC) produced by a commercial benchtop system. Methods: Ten healthy dogs were studied. Whole blood was collected and mixed with ACD-A in a 1:7.6 ratio of ACD-A to whole blood. 12 mL of this mixture was processed into PC via single centrifugation, while 60 mL of the anticoagulated whole blood was processed via a commercial double centrifugation system. Both types of PC were evaluated for platelet concentration, CD62P expression with and without thrombin stimulation, and for sterility. Results: Mean platelet count in the double centrifuged PC was 863 ± 352 × 10³/µL, with very low white blood cell contamination (median of 0.47 × 10³ leukocyte/µL (range 0.15-2.18 × 10³/µL)). The double-centrifuged PC had similar baseline activation characteristics (as determined by P-selectin expression) as the single centrifuge PC (0.76% vs. 0.72% unstimulated, 30.5% vs. 34.9% stimulated, p = 0.432). Discussion: The benchtop PC system studied here did not cause activation of platelets during production and produced a sterile product that can be further investigated as a source of fresh platelet concentrates for transfusion purposes. [ABSTRACT FROM AUTHOR]

Background: Hyperactive coagulation might cause dangerous complications such as portal vein thrombosis and pulmonary embolism after mesenchymal stem/stromal cell (MSC) therapy. Tissue factor (TF), an initiator of the extrinsic coagulation pathway, has been suggested as a predictor of this process. Methods: The expression of TF and other pro- and anticoagulant genes was analyzed in xeno- and serum-free manufactured MSCs. Furthermore, culture factors affecting its expression in MSCs were investigated. Finally, coagulation tests of fibrinogen, D-dimer, aPPTs, PTs, and TTs were measured in patient serum after umbilical cord (UC)-MSC infusions to challenge a potential connection between TF expression and MSC-induced coagulant activity. Results: Xeno- and serum-free cultured adipose tissue and UC-derived MSCs expressed the highest level of TF, followed by those from dental pulp, and the lowest expression was observed in MSCs of bone marrow origin. Environmental factors such as cell density, hypoxia, and inflammation impact TF expression, so in vitro analysis might fail to reflect their in vivo behaviors. MSCs also expressed heterogeneous levels of the coagulant factor COL1A1 and surface phosphatidylserine and anticoagulant factors TFPI and PTGIR. MSCs of diverse origins induced fibrin clots in healthy plasma that were partially suppressed by an anti-TF inhibitory monoclonal antibody. Furthermore, human umbilical vein endothelial cells exhibited coagulant activity in vitro despite their negative expression of TF and COL1A1. Patients receiving intravenous UC-MSC infusion exhibited a transient increase in D-dimer serum concentration, while this remained stable in the group with intrathecal infusion. There was no correlation between TF expression and D-dimer or other coagulation indicators. Conclusions: The study suggests that TF cannot be used as a solid biomarker to predict MSC-induced hypercoagulation. Local administration, prophylactic intervention with anticoagulation drugs, and monitoring of coagulation indicators are useful to prevent thrombogenic events in patients receiving MSCs. Trial registration NCT05292625. Registered March 23, 2022, retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT05292625?term=NCT05292625&draw=2&rank=1. NCT04919135. Registered June 9, 2021, https://www.clinicaltrials.gov/ct2/show/NCT04919135?term=NCT04919135&draw=2&rank=1. [ABSTRACT FROM AUTHOR]

Thromboelastography (TEG) is a hemostatic assay evaluating clot initiation time, kinetics, strength, and extent of fibrinolysis. Hemostatic assays in nonmammalian species have been less extensively studied because of lack of taxon-specific reagents and unique physiology. Hemostatic or hemorrhagic disease has been described postmortem in elasmobranchs, but antemortem detection of coagulopathies is limited in this taxon. The study aimed to establish an elasmobranch TEG protocol to improve hemostatic evaluation and facilitate advanced treatment options for animals under human care. Multiple clotting initiators were assessed for efficacy with frozen-thawed citrated plasma, fresh citrated plasma, and fresh whole citrated blood: RapidTEG TM , citrated kaolin, Reptilase ® , and species brain-derived thromboplastin prepared by two different methods. Initial evaluation found plasma samples clot inconsistently, but TEG analyses using fresh whole blood consistently led to measurable TEG reactions using multiple clotting initiators. The most reliable elasmobranch TEG results were observed using citrated fresh whole blood and the RapidTEG clot initiation reagent.

Background: The risk of military and civilian radiation exposure is increasing, and determining the effects of exposure is a high priority. Irradiation of the nearby blood supply after a nuclear event may impede mobilization of blood products for resuscitation at a time of great need. RBCs are administered to patients with trauma and hemorrhage to transport and deliver oxygen and avoid tissue hypoxia. Here we determine the effects of ionizing radiation on the energy metabolome of RBCs isolated from cold stored whole blood to determine if their stability is compromised by radiation exposure. Study Design and Methods: Whole blood from healthy volunteers was subjected to 0, 25, or 75 Gy of X‐irradiation, and stored at 4°C. RBCs were isolated from stored WB at 0, 1, 7, 14, and 21 days of storage. The levels of extracted Krebs cycle intermediates, nicotinamide adenine dinucleotides, and phosphorylated derivatives of adenosine and guanosine were determined by tandem mass spectroscopy. Results: Irradiation at either 25Gy or 75Gy had no significant effect on any parameter measured compared to control (0Gy). However, there was a significant change over time in storage for ATP, GDP, and guanosine. Discussion: Irradiation at doses up to 75Gy had no effect on the energy metabolome of RBCs prepared from blood stored at 4°C for up to 21 days, suggesting that the RBC energy metabolome is not affected by radiation exposure and the blood can still be used for resuscitation in trauma patients. [ABSTRACT FROM AUTHOR]

Background: Exposure to radiation through battlefield use of nuclear weapons, terrorist attacks or accidents at nuclear power plants is a current concern for the military. Beyond the risk of exposure to personnel is the intentional or accidental irradiation of our blood banking supply system. It is unknown how large doses of ionizing radiation affect storage of blood and blood products, including platelets. The major function of platelets is clot formation which includes aggregation, shape change, vesicle release, and fibrinogen attachment; these tasks require a significant amount of energy. Here, we determine whether the ionizing radiation effects the energy metabolome of platelets in storage. Study Design and Methods: Fresh whole blood from healthy volunteers was subjected to 0, 25, or 75Gy of X‐irradiation, and stored at 4°C. Platelets were isolated from stored WB at 0, 1, 7, 14, and 21 days of storage. Krebs cycle intermediates, nicotinamide adenine dinucleotides, and the tri‐, di, and mono‐ phosphorylated versions of adenosine and guanosine were extracted and measured by tandem mass spectroscopy. Results: Irradiation at either 25Gy or 75Gy had no significant effect on the amount of any metabolite measured compared to control (0Gy). However, there was a significant fall over time in storage for most of the metabolites measured. Discussion: These data show that irradiation at high doses has no effect on the concentration of the energy metabolome of platelets derived from whole blood stored in 4°C for up to 21 days and suggests that platelets can maintain their metabolome even after radiation exposure. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been studied for their potential benefits in treating acute respiratory distress syndrome (ARDS) and have reported mild effects when trialed within human clinical trials. MSCs have been investigated in preclinical models with efficacy when administered at the time of lung injury. Human integrin α10β1-selected adipose tissue-derived MSCs (integrin α10β1-MSCs) have shown immunomodulatory and regenerative effects in various disease models. We hypothesized that integrin α10β1 selected-MSCs can be used to treat a sepsis-induced ARDS in a porcine model when administering cells after established injury rather than simultaneously. This was hypothesized to reflect a clinical picture of treatment with MSCs in human ARDS. 12 pigs were randomized to the treated or placebo-controlled group prior to the induction of mild to moderate ARDS via lipopolysaccharide administration. The treated group received 5 × 106 cells/kg integrin α10β1-selected MSCs and both groups were followed for 12 h. ARDS was confirmed with blood gases and retrospectively with histological changes. After intervention, the treated group showed decreased need for inotropic support, fewer signs of histopathological lung injury including less alveolar wall thickening and reduction of the hypercoagulative disease state. The MSC treatment was not associated with adverse events over the monitoring period. This provides new opportunities to investigate integrin α10β1-selected MSCs as a treatment for a disease which does not yet have any definitive therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) affects civilian and military populations with high morbidity and mortality rates and devastating sequelae. As the US military shifts its operational paradigm to prepare for future large-scale combat operations, the need for prolonged casualty care is expected to intensify. Identifying efficacious prehospital TBI management strategies is therefore vital. Numerous pharmacotherapies are beneficial in the inpatient management of TBI, including beta blockers, calcium channel blockers, statins, and other agents. However, their utility in prehospital management of moderate or severe TBI is not well understood. We performed a systematic review to elucidate agents of potential prehospital benefit in moderate and severe TBI. Methods: We searched 6 databases from January 2000 through December 2021 without limitations in outcome metrics using a variety of search terms designed to encapsulate all studies pertaining to prehospital TBI management. We identified 2,142 unique articles, which netted 114 studies for full review. Seven studies met stringent inclusion criteria for our aims. Results: Studies meeting inclusion criteria assessed tranexamic acid (TXA) (n=6) and ethanol (n=1). Of the TXA studies, 3 were randomized controlled trials, 2 were retrospective cohort studies, 1 was a prospective cohort study, and 1 was a meta-analysis. Notably absent were papers investigating therapeutics shown to be beneficial in inpatient hospital treatment of TBI. Overall, data suggest TXA administration is potentially beneficial in moderate or severe TBI with or without intracranial hemorrhage. Severe TBI with or without penetrating trauma was associated with worse overall outcomes, regardless of TXA use. Conclusion: Effective interventions for treating moderate or severe TBI are lacking. TXA is the most widely studied pharmacologic intervention and appears to offer some benefit without adverse effects in moderate TBI (with or without intracranial hemorrhage) in the pre-hospital setting despite heterogeneous results. Limitations of these studies include heterogeneity in outcome metrics, patient populations, and circumstances of TXA use. We identified a gap in the literature in translating agents with demonstrated inpatient benefit to the prehospital setting. Further investigation into these and other novel therapeutic options in the prehospital arena is crucial to improving clinical outcomes in TBI. [ABSTRACT FROM AUTHOR]

Transfused platelets may adapt the same dysfunction as their endogenous counterparts and do not appear to improve platelet aggregation during active bleeding.125,126 Interestingly, circulating PAI-1 concentration increases after platelet transfusion in trauma patients.125 The clinical benefits of platelet transfusion could therefore be partly due to a reduction in hyperfibrinolysis rather than an improvement in platelet function. Platelets further stimulate neutrophil extracellular trap (NET) formation, which is composed of DNA, histones and high-mobility group box 1 (HMGB1).49,50 NETs further promote platelet PolyP release, amplifying fibrin formation.51 In all, platelets exert numerous functions following local tissue injury orchestrating hemostasis and the initial immune response. In vitro, sCD39 inhibited platelet aggregation27 and adenosine restored ADP induced platelet aggregation.186 Lastly, NO inhalation during ventilation may reduce platelet activation and aggregation.187-189 Together, targeting the endothelium may reduce organ dysfunction by improving late trauma-induced platelet dysfunction. In this narrative review the aims are to: (1) describe "normal" platelet function following local tissue injury, (2) describe the characteristics of platelet dysfunction after trauma, (3) outline potential mechanisms, and (4) summarize current and novel treatment strategies for early and late trauma-induced platelet dysfunction. [Extracted from the article]

Background and Objectives: Cold‐stored platelets are currently under clinical evaluation and have been approved for limited clinical use in the United States. Most studies have focused on the haemostatic functionality of cold‐stored platelets; however, limited information is available examining changes to their immune function. Materials and Methods: Two buffy‐coat‐derived platelet components were combined and split into two treatment arms: room temperature (RT)‐stored (20–24°C) or refrigerated (cold‐stored, 2–6°C). The concentration of select soluble factors was measured in the supernatant using commercial ELISA kits. The abundance of surface receptors associated with immunological function was assessed by flow cytometry. Platelet aggregation was assessed in response to Escherichia coli and Staphylococcus aureus, in the presence and absence of RGDS (blocks active conformation of integrin α2β3). Results: Cold‐stored platelet components contained a lower supernatant concentration of C3a, RANTES and PF4. The abundance of surface‐bound P‐selectin and integrin α2β3 in the activated conformation increased during cold storage. In comparison, the abundance of CD86, CD44, ICAM‐2, CD40, TLR1, TLR2, TLR4, TLR3, TLR7 and TLR9 was lower on the surface membrane of cold‐stored platelets compared to RT‐stored components. Cold‐stored platelets exhibited an increased responsiveness to E. coli‐ and S. aureus‐induced aggregation compared to RT‐stored platelets. Inhibition of the active conformation of integrin α2β3 using RGDS reduced the potentiation of bacterial‐induced aggregation in cold‐stored platelets. Conclusion: Our data highlight that cold storage changes the in vitro immune characteristics of platelets, including their sensitivity to bacterial‐induced aggregation. Changes in these immune characteristics may have clinical implications post transfusion. [ABSTRACT FROM AUTHOR]

Background: Cryopreserved platelet products can be stored for years and are mainly used in military settings. Following thawing, cryopreserved platelets are activated, resulting in faster clot formation but reduced aggregation in vitro, rendering their efficacy in bleeding unknown. Also, concerns remain on the safety of these products. The aim was to investigate the efficacy and safety of cryopreserved platelets in a rat model of traumatic hemorrhage.Study Design and Methods: After 1 hour of shock, rats (n = 13/group) were randomized to receive a balanced transfusion pack (1:1:1 red blood cell:plasma:platelet) made from syngeneic rat blood, containing either liquid stored platelets or cryopreserved platelets. Primary outcome was the transfusion volume required to obtain a mean arterial pressure (MAP) of 60 mmHg. Secondary outcomes were coagulation as assessed by thromboelastometry (ROTEM®) and organ failure as assessed by biochemistry and histopathology.Results: The transfusion volume to obtain a MAP of 60 mmHg was lower in animals receiving cryopreserved platelets (5.4 [4.1-7.1] mL/kg) compared to those receiving liquid stored platelets (7.5 [6.4-8.5] mL/kg, p < 0.05). ROTEM® clotting times were shorter (45 [41-48] vs. 49 [45-53]sec, p < 0.05), while maximum clot firmness was slightly lower (68 [67-68] vs. 69 [69-71]mm, p < 0.01). Organ failure was similar in both groups.Conclusions: Use of cryopreserved platelets required less transfusion volume to reach a targeted MAP compared to liquid stored platelets, while organ injury was similar. These results provide a rationale for clinical trials with cryopreserved platelets in (traumatic) bleeding. [ABSTRACT FROM AUTHOR]