4-factor prothrombin complex concentrate is not inferior to andexanet alfa for the reversal or oral factor Xa inhibitors: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: Andexanet Alfa (AA) is the only FDA approved reversal agent for apixaban and rivaroxaban (DOAC). There are no studies comparing its efficacy with 4-Factor Prothrombin Complex Concentrate (PCC). This study aimed to compare PCC to AA for DOAC reversal, hypothesizing non-inferiority of PCC. METHODS: We performed a retrospective, non-inferiority multicenter study of adult patients admitted from July 1, 2018 to December 31, 2019 who had taken a DOAC within 12 hours of injury, were transfused red blood cells (RBCs) or had traumatic brain injury, and received AA or PCC. Primary outcome was PRBC unit transfusion. Secondary outcome with ICU length of stay. MICE imputation was used to account for missing data and zero-inflated poisson regression was used to account for an excess of zero units of RBC transfused. 2 Units difference in RBC transfusion was selected as non-inferior. RESULTS: Results: From 263 patients at 10 centers, 77 (29%) received PCC and 186 (71%) AA. Patients had similar transfusion rates across reversal treatment groups (23.7% AA vs 19.5% PCC) with median transfusion in both groups of 0 RBC. According to the Poisson component, PCC increases the amount of RBC transfusion by 1.02 times (95% CI: 0.79-1.33) compared to AA after adjusting for other covariates. The averaged amount of RBC transfusion (non-zero group) is 6.13. Multiplying this number by the estimated rate ratio, PCC is estimated to have an increase RBC transfusion by 0.123 (95% CI: 0.53-2.02) units compared to AA. CONCLUSION: PCC appears non-inferior to AA for reversal of DOACs for RBC transfusion in traumatically injured patients. Additional prospective, randomized trials are necessary to compare PCC and AA for the treatment of hemorrhage in injured patients on DOACs. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level III.

EFFECT OF IRRIGATION FLUID COMPOSITION ON HEMOSTASIS IN MOUSE BLEEDING MODELS.

ABSTRACT: Introduction: Intraoperative irrigation, usually with normal saline (NS), aids in bleeding identification and management. We investigated the effect of different irrigation fluids, with additives, on hemostasis using two bleeding models. Methods: C57BL/6 J mice were subjected to a tail bleed model or uncontrolled abdominal hemorrhage via liver laceration followed by abdominal cavity irrigation. We compared NS, lactated Ringer's (LR), and PlasmaLyte. We examined NS and LR at different temperatures. Normal saline or LR with calcium (Ca 2+ ) or tranexamic acid (TXA) was studied. Results: Compared with room temperature (RT), increasing the temperature of the irrigation fluid to 37°C and 42°C reduced tail vein bleeding times substantially in both NS and LR (all P < 0.001), with no significant differences between the two fluids. At RT, LR, but not PlasmaLyte, substantially reduced bleeding times in comparison to NS ( P < 0.0001). Liver injury blood loss was lower with LR ( P < 0.01). Normal saline supplemented with 2.7 mEq/L of Ca 2+ decreased bleeding time and blood loss volume ( P < 0.001 and P < 0.01, respectively) to similar levels as LR. Normal saline with 150 mg/mL of TXA markedly reduced bleeding time ( P < 0.0001), and NS with 62.5 mg/mL TXA decreased blood loss ( P < 0.01). Conclusion: Whereas Ca 2+ - and TXA-supplemented NS reduced bleeding, LR remained superior to all irrigation fluid compositions. As LR contains Ca 2+ , and Ca 2+ -supplemented NS mirrored LR in response, Ca 2+ presence in the irrigation fluid seems key to improving solution's hemostatic ability. Because warming the fluids normalized the choice of agents, the data also suggest that Ca 2+ -containing fluids such as LR may be more suitable for hemostasis when used at RT.

Platelet-mimicking procoagulant nanoparticles augment hemostasis in animal models of bleeding.

Treatment of bleeding disorders using transfusion of donor-derived platelets faces logistical challenges due to their limited availability, high risk of contamination, and short (5 to 7 days) shelf life. These challenges could be potentially addressed by designing platelet mimetics that emulate the adhesion, aggregation, and procoagulant functions of platelets. To this end, we created liposome-based platelet-mimicking procoagulant nanoparticles (PPNs) that can expose the phospholipid phosphatidylserine on their surface in response to plasmin. First, we tested PPNs in vitro using human plasma and demonstrated plasmin-triggered exposure of phosphatidylserine and the resultant assembly of coagulation factors on the PPN surface. We also showed that this phosphatidylserine exposed on the PPN surface could restore and enhance thrombin generation and fibrin formation in human plasma depleted of platelets. In human plasma and whole blood in vitro, PPNs improved fibrin stability and clot robustness in a fibrinolytic environment. We then tested PPNs in vivo in a mouse model of thrombocytopenia where treatment with PPNs reduced blood loss in a manner comparable to treatment with syngeneic platelets. Furthermore, in rat and mouse models of traumatic hemorrhage, treatment with PPNs substantially reduced bleeding and improved survival. No sign of systemic or off-target thrombotic risks was observed in the animal studies. These findings demonstrate the potential of PPNs as a platelet surrogate that should be further investigated for the management of bleeding.

Rapid detection of platelet inhibition and dysfunction in traumatic brain injury: A prospective observational study.

BACKGROUND: Rapid platelet function testing is frequently used to determine platelet function in patients with traumatic intracranial hemorrhage (tICH). Accuracy and clinical significance of decreased platelet response detected by these tests is not well understood. We sought to determine whether VerifyNow and whole blood aggregometry (WBA) can detect poor platelet response and to elucidate its clinical significance for tICH patients. METHODS: We prospectively enrolled patients with isolated tICH between 2018 and 2020. Demographics, medical history, injury characteristics, and patient outcomes were recorded. Platelet function was determined by VerifyNow and WBA testing at the time of arrival to the trauma bay and 6 hours later. RESULTS: A total of 221 patients were enrolled, including 111 patients on no antiplatelet medication, 78 on aspirin, 6 on clopidogrel, and 26 on aspirin and clopidogrel. In the trauma bay, 29.7% and 67.7% of patients on no antiplatelet medication had poor platelet response on VerifyNow and WBA, respectively. Among patients on aspirin, 72.2% and 82.2% had platelet dysfunction on VerifyNow and WBA. Among patients on clopidogrel, 67.9% and 88.9% had platelet dysfunction on VerifyNow and WBA. Patients with nonresponsive platelets had similar in-hospital mortality (3 [3.0%] vs. 6 [6.3%], p = 0.324), tICH progression (26 [27.1%] vs. 24 [26.1%], p = 0.877), intensive care unit admission rates (34 [34.3%] vs. 38 [40.0%), p = 0.415), and length of stay (3 [interquartile range, 2-8] vs. 3.2 [interquartile range, 2-7], p = 0.818) to those with responsive platelets. Platelet transfusion did not improve platelet response or patient outcomes. CONCLUSION: Rapid platelet function testing detects a highly prevalent poor platelet response among patients with tICH, irrespective of antiplatelet medication use. VerifyNow correlated fairly with whole blood aggregometry among patients with tICH and platelet responsiveness detectable by these tests did not correlate with clinical outcomes. In addition, our results suggest that platelet transfusion may not improve clinical outcomes in patients with tICH. LEVEL OF EVIDENCE: Diagnostic tests, level II.

Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253-349) vs. 100% (87-117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1-44.7) vs. 100.0% (83.1-121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4-35.3) vs. 27.8% (24.6-30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.

Correlation of Thromboelastography with Apparent Rivaroxaban Concentration: Has Point-of-Care Testing Improved?

BACKGROUND: Concern remains over reliable point-of-care testing to guide reversal of rivaroxaban, a commonly used factor Xa inhibitor, in high-acuity settings. Thromboelastography (TEG), a point-of-care viscoelastic assay, may have the ability to detect the anticoagulant effect of rivaroxaban. The authors ascertained the association of apparent rivaroxaban concentration with thromboelastography reaction time, i.e., time elapsed from blood sample placement in analyzer until beginning of clot formation, as measured using TEG and TEG6S instruments (Haemonetics Corporation, USA), hypothesizing that reaction time would correlate to degree of functional factor Xa impairment. METHODS: The authors prospectively performed a diagnostic accuracy study comparing coagulation assays to apparent (i.e., indirectly assessed) rivaroxaban concentration in trauma patients with and without preinjury rivaroxaban presenting to a single center between April 2016 and July 2018. Blood samples at admission and after reversal or 24 h postadmission underwent TEG, TEG6S, thrombin generation assay, anti-factor Xa chromogenic assay, prothrombin time (PT), and ecarin chromogenic assay testing. The authors determined correlation of kaolin TEG, TEG6S, and prothrombin time to apparent rivaroxaban concentration. Receiver operating characteristic curve compared capacity to distinguish therapeutic rivaroxaban concentration (i.e., greater than or equal to 50 ng/ml) from nontherapeutic concentrations. RESULTS: Eighty rivaroxaban patients were compared to 20 controls. Significant strong correlations existed between rivaroxaban concentration and TEG reaction time (ρ = 0.67; P < 0.001), TEG6S reaction time (ρ = 0.68; P < 0.001), and prothrombin time (ρ = 0.73; P < 0.001), however reaction time remained within the defined normal range for the assay. Rivaroxaban concentration demonstrated strong but not significant association with coagulation assays postreversal (n = 9; TEG reaction time ρ = 0.62; P = 0.101; TEG6S reaction time ρ = 0.57; P = 0.112) and small nonsignificant association for controls (TEG reaction time: ρ = -0.04; P = 0.845; TEG6S reaction time: ρ = -0.09; P = 0.667; PT-neoplastine: ρ = 0.19; P = 0.301). Rivaroxaban concentration (area under the curve, 0.91) and TEG6S reaction time (area under the curve, 0.84) best predicted therapeutic rivaroxaban concentration and exhibited similar receiver operating characteristic curves (P = 0.180). CONCLUSIONS: Although TEG6S demonstrates significant strong correlation with rivaroxaban concentration, values within normal range limit clinical utility rendering rivaroxaban concentration the gold standard in measuring anticoagulant effect.

Prehospital plasma in injured patients is associated with survival principally in blunt injury: Results from two randomized prehospital plasma trials.

INTRODUCTION: Recent evidence demonstrated that prehospital plasma in patients at risk of hemorrhagic shock was safe for ground transport and resulted in a 28-day survival benefit for air medical transport patients. Whether any beneficial effect of prehospital plasma varies across injury mechanism remains unknown. METHODS: We performed a secondary analysis using a harmonized data set derived from two recent prehospital plasma randomized trials. Identical inclusion/exclusion criteria and primary/secondary outcomes were used for the trials. Prehospital time, arrival shock parameters, and 24-hour transfusion requirements were compared across plasma and control groups stratified by mechanism of injury. Stratified survival analysis and Cox hazard regression were performed to determine the independent survival benefits of plasma across blunt and penetrating injury. RESULTS: Blunt patients had higher injury severity, were older, and had a lower Glasgow Coma Scale. Arrival indices of shock and coagulation parameters were similar across blunt and penetrating injury. The percentage of patients with a prehospital time less than 20 minutes was significantly higher for penetrating patients relative to blunt injured patients (28.0% vs. 11.6%, p < 0.01). Stratified Kaplan-Meier curves demonstrated a significant separation for blunt injured patients (n = 465, p = 0.01) with no separation demonstrated for penetrating injured patients (n = 161, p = 0.60) Stratified Cox hazard regression verified, after controlling for all important confounders, that prehospital plasma was associated with a 32% lower independent hazard for 28-day mortality in blunt injured patients (hazard ratio, 0.68; 95% confidence interval, 0.47-0.96; p = 0.03) with no independent survival benefit found in penetrating patients (hazard ratio, 1.16; 95% confidence interval, 0.4-3.1; p = 0.78). CONCLUSION: A survival benefit associated with prehospital plasma at 24 hours and 28 days exists primarily in blunt injured patients with no benefit shown in penetrating trauma patients. No detrimental effects attributable to plasma are demonstrated in penetrating injury. These results have important relevance to military and civilian trauma systems. LEVEL OF EVIDENCE: Therapeutic, I.

Platelet-derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice.

BACKGROUND: Traumatic injury can lead to dysregulation of the normal clotting system, resulting in hemorrhagic and thrombotic complications. Platelet activation is robust following traumatic injury and one process of platelet activation is to release of extracellular vesicles (PEV) that carry heterogenous cargo loads and surface ligands. OBJECTIVES: We sought to investigate and characterize the release and function of PEVs generated following traumatic injury. METHODS: PEV content and quantity in circulation following trauma in humans and mice was measured using flow cytometry, size exclusion chromatography, and nanoparticle tracking analysis. PEVs were isolated from circulation and the effects on thrombin generation, bleeding time, hemorrhage control, and thrombus formation were determined. Finally, the effect of hydroxychloroquine (HCQ) on PEV release and thrombosis were examined. RESULTS: Human and murine trauma results in a significant release of PEVs into circulation compared with healthy controls. These PEVs result in abundant thrombin generation, increased platelet aggregation, decreased bleeding times, and decreased hemorrhage in uncontrolled bleeding. Conversely, PEVs contributed to enhanced venous thrombus formation and were recruited to the developing thrombus site. Interestingly, HCQ treatment resulted in decreased platelet aggregation, decreased PEV release, and reduced deep vein thrombosis burden in mice. CONCLUSIONS: These data demonstrate that trauma results in significant release of PEVs which are both pro-hemostatic and pro-thrombotic. The effects of PEVs can be mitigated by treatment with HCQ, suggesting the potential use as a form of deep vein thrombosis prophylaxis.

Platelet Transfusion in Critical Care and Surgery: Evidence-Based Review of Contemporary Practice and Future Directions.

Thrombocytopenia is prevalent in critical care, surgical, and trauma settings. Despite the fact that a significant proportion of these patients receive platelet transfusion during their hospital course, much work remains to be done with regard to development of platelet transfusion guidelines. Given the wide variety of platelet transfusion practices and the frequency with which patients present with thrombocytopenia, it is paramount to understand standards of care and to identify deficiencies that may exist. This review explores evidence and recommendations for platelet transfusion thresholds and practices in a variety of critical care and surgical settings with specific focus on the role of platelet transfusion in trauma, management and reversal of anticoagulation, and point of care laboratory assays. To this end, a literature review was performed utilizing PubMed and Cochrane Central Register of Controlled Trials to select 153 manuscripts that evaluate the current data supporting platelet transfusions in surgical and critical care populations. Advances in transfusion medicine and synthetic platelet substitutes that can be engineered for potential future applications will also be discussed.