Supplementation with antithrombin III ex vivo optimizes enoxaparin responses in critically injured patients

Cardenas, Jessica C.; Wang, Yaowei; Karri, Jay; Vincent, Seenya; Andrew, P.; Cotton, Bryan A.; Wade, Charles E.

doi:10.1016/j.thromres.2020.01.014

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…Normal thrombin generation in healthy donors is highly variable, and reported values depend on the presence of platelets and concentration of TF used to initiation the reaction. Based on our past findings, most individuals falling within the broad range of 150 to 250 peak nM (8,30). Our past characterization of thrombin generation phenotypes in highest-level activation trauma patients shows that the overwhelming majority of patients present in a hypercoagulable state, with an overall median peak thrombin of 316.2 nM (270.2, 355.5) (8).…”

Section: Patterns Of Thrombin Generation Following Severe Traumamentioning

confidence: 87%

Thrombin Generation Following Severe Trauma: Mechanisms, Modulators, and Implications for Hemostasis and Thrombosis

Cardenas

2021

Shock

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Thrombin is the central coagulation enzyme that catalyzes the conversion of fibrinogen to form insoluble fibrin blood clots. In vivo, thrombin production results from the concerted effort of plasma enzymatic reactions with essential contributions from circulating and vessel wall cells. The relative amount of thrombin produced directly dictates the structure and stability of fibrin clots; therefore, sufficient thrombin generation is essential for normal hemostasis to occur. Examination of thrombin generation phenotypes among severely injury trauma patients reveals important relationships between the potential for generating thrombin and risks of bleeding and thrombotic complications. Thus, understanding determinants of thrombin generation following traumatic injury is of high clinical importance. This review will focus on patterns and mechanisms of thrombin generation in severely injured patients, the role of fluid resuscitation in modulating thrombin generation and implications for outcomes.

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Section: Patterns Of Thrombin Generation Following Severe Traumamentioning

confidence: 87%

Thrombin Generation Following Severe Trauma: Mechanisms, Modulators, and Implications for Hemostasis and Thrombosis

Cardenas

2021

Shock

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“…The detection kits of factor I and D-dimer were purchased from Abcam (Abcam, Cambridge, MA), and the ELISA kit for protein C was purchased from Helena Laboratories (Beaumont, TX, US), respectively. Thrombin generation of the endogenous thrombin potential (ETP) and the highest amount of thrombin generated (peak) was measured using a calibrated automated thrombogram (Thermo Fisher Scientific, Waltham, MA) as previously described ( 44 ). The fibrinolysis parameters of k -time, alpha (α)-angle, and percentage of clot lysis at 30 minutes after maximal clot strength (LY30) were tested in the hospital lab by Thrombelastograph 5000 (Haemoscope Corporation, Niles, IL).…”

Section: Methodsmentioning

confidence: 99%

Traumatized triad of complementopathy, endotheliopathy, and coagulopathy ˗ Impact on clinical outcomes in severe polytrauma patients

Yang

Simovic

et al. 2022

Front. Immunol.

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Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.

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“…Through animal models of trauma and HS, which recapitulate this hypercoagulable phenotype, we have learned that resuscitation with plasma normalizes this aberrant activation of the coagulation system by reducing thrombin generation in an AT‐dependent manner. In vitro models in human trauma patient plasma reiterate these findings 78, 79 and have further shown that in patients with profound hypercoagulability, plasma treatment reduces thrombin generation, whereas in hypocoagulable patients, plasma enhances thrombin generation 78 . Taken together, these findings demonstrate that plasma is neither specifically pro‐ nor anti‐coagulant.…”

Section: Addressing Concerns Of Treating Hypercoagulable Covid‐19 Patients With Plasmamentioning

confidence: 87%

Treating the endotheliopathy of SARS‐CoV‐2 infection with plasma: Lessons learned from optimized trauma resuscitation with blood products

et al. 2021

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Supplementation with antithrombin III ex vivo optimizes enoxaparin responses in critically injured patients

Cited by 13 publications

References 28 publications

Thrombin Generation Following Severe Trauma: Mechanisms, Modulators, and Implications for Hemostasis and Thrombosis

Thrombin Generation Following Severe Trauma: Mechanisms, Modulators, and Implications for Hemostasis and Thrombosis

Traumatized triad of complementopathy, endotheliopathy, and coagulopathy ˗ Impact on clinical outcomes in severe polytrauma patients

Treating the endotheliopathy of SARS‐CoV‐2 infection with plasma: Lessons learned from optimized trauma resuscitation with blood products

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