scholarly journals Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy

2017 ◽  
Vol 126 (1) ◽  
pp. 115-127 ◽  
Author(s):  
Ross A. Davenport ◽  
Maria Guerreiro ◽  
Daniel Frith ◽  
Claire Rourke ◽  
Sean Platton ◽  
...  
Keyword(s):  
Murine Model ◽  
Protein C ◽  
Major Trauma ◽  
Activated Protein C ◽  
Genetic Mutation ◽  
Trauma Patients ◽  
Acute Traumatic Coagulopathy ◽  
Rotational Thromboelastometry ◽  
Level 1 Trauma Center ◽  
Traumatic Coagulopathy

Abstract Background Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors’ objective was to determine the predominant pathophysiology of acute traumatic coagulopathy. Methods First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed. Results In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C–mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation. Conclusions Activated protein C–associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.

scholarly journals INCREASE IN ACTIVATED PROTEIN C MEDIATES ACUTE TRAUMATIC COAGULOPATHY IN MICE

Shock ◽  
2009 ◽  
Vol 32 (6) ◽  
pp. 659-665 ◽  
Author(s):  
Brian B. Chesebro ◽  
Pamela Rahn ◽  
Michel Carles ◽  
Charles T. Esmon ◽  
Jun Xu ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Acute Traumatic Coagulopathy ◽  
Traumatic Coagulopathy

scholarly journals O1: DISCOVERING NOVEL THERAPEUTICS TO TREAT ACUTE TRAUMATIC COAGULOPATHY (ATC)

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
A Thaventhiran ◽  
C Thiemermann ◽  
K Brohi ◽  
JL Tremoleda ◽  
RA Davenport
Keyword(s):  
Activated Protein C ◽  
Blood Component ◽  
Trauma Patients ◽  
Factor V ◽  
The Novel ◽  
Acute Traumatic Coagulopathy ◽  
Antifibrinolytic Drugs ◽  
The Uk ◽  
Novel Therapeutic ◽  
Traumatic Coagulopathy

Abstract Introduction In the UK, 17,000 people die from injury each year, with uncontrolled bleeding the most significant cause of preventable mortality. Acute Traumatic Coagulopathy (ATC) exacerbates bleeding through the failure of blood-clotting with accelerated clot breakdown that mechanistically is driven by activated Protein C (aPC). No targeted therapy to treat the underlying cause of ATC exists with treatment limited to blood component resuscitation and antifibrinolytic drugs to prevent premature clot breakdown. Method Two hundred fifty-four bleeding trauma patients had Factor V and aPC measured on arrival and during resuscitation. A preclinical ATC model was used to test the novel therapeutic recombinant Factor V (rFV), which is resistant to aPC mediated cleavage. Mice underwent combined injury and pressure controlled-blood loss with intervention at 30-minutes to represent a clinically relevant model. Coagulopathy was measured by ROTEM and biomarkers of coagulation/fibrinolysis. Result Admission levels of FV were 38% lower (83 vs 134u/dL, p<0.0001), deteriorated during resuscitation to 65% of normal after transfusion of eight RBC units and were inversely related to aPC levels. Compared to vehicle, animals treated with rFV had reduced coagulopathy (Clot Strength at 5 minutes: 31 vs 24mm, p<0.01) and significantly improved survival (80% vs 44%, p≤ 0.001). Conclusion FV falls significantly during bleeding in trauma patients and in the murine model, rFV improved coagulation suggesting it may represent a potential therapeutic target for ATC. Take-home message Directly targeting the cause of ATC represents a novel therapeutic strategy in trauma and may improve survival after major haemorrhage by directly improving clot function.

scholarly journals Inducing Acute Traumatic Coagulopathy In Vitro: The Effects of Activated Protein C on Healthy Human Whole Blood

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0150930 ◽  
Author(s):  
Benjamin M. Howard ◽  
Lucy Z. Kornblith ◽  
Christopher K. Cheung ◽  
Matthew E. Kutcher ◽  
Byron Y. Miyazawa ◽  
...  
Keyword(s):  
Whole Blood ◽  
Protein C ◽  
Activated Protein C ◽  
Acute Traumatic Coagulopathy ◽  
Healthy Human ◽  
Human Whole Blood ◽  
Traumatic Coagulopathy

scholarly journals Trauma and Hemorrhage: Functional Characterization of Acute Traumatic Coagulopathy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1516-1516
Author(s):  
Mitchell Jay Cohen ◽  
Thomas Orfeo ◽  
Benjamin Howard ◽  
Lucy Korrnblith ◽  
Amanda Conroy ◽  
...  
Keyword(s):  
Functional Activity ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Shock Group ◽  
Plasma Composition ◽  
Normal Range ◽  
Acute Traumatic Coagulopathy ◽  
Group 4 ◽  
Traumatic Coagulopathy

Abstract BACKGROUND: Trauma is the leading cause of death in individuals under the age of 44. Acute traumatic coagulopathy (ATC) occurs when severe injury is combined with shock and results in a hypocoagulable state resulting in increased bleeding, increased resuscitation requirements and worsened outcomes including a 4-fold increase in mortality. Our group has implicated protein C activation as a likely mechanism for ATC. We have evaluated whether activated protein C (APC) induces coagulopathy through cleavage of factor (f)V/Va by systematically evaluating 4 groups of increasing level of traumatic coagulopathy. METHODS: From a large cohort of plasma samples collected from trauma patients at time of admission to a major level 1 trauma sample, 80 plasma samples distributed equally between the following trauma severity groupings were selected: Group 1: ISS ≤ 15 and BD > -6 (less injured, no shock); Group 2: ISS ≤ 15 and BD ≤ -6 (less injured, with shock); Group 3:ISS > 15 and BD > -6 (more injured, no shock); Group 4:ISS > 15 and BD ≤ -6 (more injured, with shock). Each plasma sample was evaluated for plasma composition (functional activity of fII, fV, fVII, fVIII, fIX, fX, antithrombin, tissue factor pathway inhibitor, protein C), plasmin-antiplasmin complex (PAP), α-thrombin-antithrombin complex (TAT), and mathematically modeled thrombin generation. Quantitative Western blot analyses were performed using an anti-fV antibody directed at the fV heavy chain (residues 307-506). Intact fV levels were quantified via densitometry to determine whether levels were the within range characterizing healthy individuals and the presence of APC derived and other degradation products assessed via mobility comparison to purified standards. Demographic, resuscitation, and outcomes data were collected in parallel. RESULTS: All data were quantitated and evaluated for having concentrations above and/or below the normal range for each analyte. For PAP, Groups 3 (18/20) and 4 (17/20) had a greater percentage of individuals over Groups 1 (5/20) and 2 (6/20) that were above the normal range. Groups 3 (12/20) and 4 (12/20) also had a higher percentage of detectable α-TAT over Groups 1 (5/20) and 2 (2/20). For fV antigen, Group 4 had 16/20 individuals that were below the lower limit of normal. Groups 1, 2 and 3 were all similar with 5/20 below the limit of normal but had 3-5/20 above the upper limit of normal. Products associated with activated protein C were found (fV 30kD fragment) but also other cleavage products not associated with APC were observed. There was more fV fragmentation in Group 4, with the 30kD fragment being detected in 10 individuals. No detectable fV 30kD fragments were detected in either Groups 1 or 2. In terms of the overall plasma composition there is a large variation in functional activity, especially fVIII. Group 4 showed a pattern of all factors reduced except for TFPI versus Groups 1,2, 3. These pro and anticoagulant differences between individuals results in heterogenous modeled thrombin generation profiles with the majority all being procoagulant versus a normal control. Group 4 had a higher percentage of individuals that had a prolonged clot time and a pattern towards diminished thrombin generation. CONCLUSIONS: These data suggest that the combination of injury and shock were associated with altered PAP, TAT and functional activity changes of the plasma composition resulting in hemorrhagic thrombin generation profiles. In addition the most severely injured and shocked patients had less fVa activity, less intact fV and increased degradation of fV/fVa suggesting the presence of increased APC activity in mediating ATC. Disclosures No relevant conflicts of interest to declare.

scholarly journals A prospective study to assess serum level of soluble thrombomodulin as early marker of acute traumatic coagulopathy in polytrauma patients

2021 ◽  
Vol 8 (11) ◽  
pp. 3381
Author(s):  
Ruby Kataria ◽  
M. Quamar Azam ◽  
Geeta Negi ◽  
Ajay Kumar ◽  
Bhaskar Sarkar ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Major Trauma ◽  
International Normalized Ratio ◽  
Trauma Patients ◽  
Acute Traumatic Coagulopathy ◽  
Soluble Thrombomodulin ◽  
Early Marker ◽  
Tissue Hypoperfusion ◽  
Transfusion Requirements ◽  
Traumatic Coagulopathy

Background: Coagulopathy following major trauma is conventionally attributed to activation of coagulation factors. We hypothesized that early coagulopathy is due to tissue hypoperfusion and investigated thrombomodulin (TM) as early marker of endothelial injury in poly trauma patient.Methods: This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of TM. We assess its association with blood transfusion, length of hospital stays and mortality.Results: A total of 90 patients were enrolled. An increasing lactate was associated with high soluble TM. High TM was significantly associated with increased mortality, blood transfusion requirements, hospital stay.Conclusions: Acute traumatic coagulopathy (ATC) occurs only in the presence of tissue hypoperfusion which we have measured in form of lactate and coagulopathy measured using international normalized ratio (INR) as standard. Admission serum TM can be predictive of clinical outcomes following major trauma.

Synergistic Anticoagulant Effect of Activated Protein C and Tissue Factor Pathway Inhibitor As a Mechanism for Acute Traumatic Coagulopathy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1487-1487
Author(s):  
Michael A Meledeo ◽  
Melanie V Valenciana ◽  
Armando C Rodriguez ◽  
Andrew P Cap
Keyword(s):  
Synergistic Effect ◽  
Tissue Factor ◽  
Protein C ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Activated Protein C ◽  
Lag Time ◽  
Acute Traumatic Coagulopathy ◽  
Tissue Factor Pathway ◽  
Traumatic Coagulopathy

Abstract Introduction Severe trauma with tissue damage and shock can rapidly (<30 min) result in abnormal coagulation function which is independent of consumption or dilution effects; this acute traumatic coagulopathy (ATC) has been linked to increased transfusion requirements, morbidity and mortality. It has been suggested that ATC is caused by an increase in activated protein C (aPC; from 40 pM in normal to 175 pM) which has been identified in trauma patients [Cohen MJ, Ann Surg 255:379 (2012)]. aPC inactivates factor Va (FVa) as part of normal hemostasis, but our previous results indicate that aPC at trauma levels is not sufficient to prevent coagulation, particularly when platelets are present, as platelet fVa is resistant to aPC [Campbell JE, PLoS ONE 9:e99181 (2014); Camire RM, Blood 91:2818 (1998)]. Tissue Factor Pathway Inhibitor (TFPI) is an endothelial-bound protein which inhibits coagulation through effects on factor Xa and the factor VIIa-tissue factor complex. It is released in the plasma (normal level 2.5nM, pathophysiologic states including trauma up to 10nM) and is typically cleared by the liver or kidneys. TFPIα accounts for 20% of circulating TFPI and binds FV and FVa [Ndonwi M, J Thromb Haemost 10:1944 (2012)]. Recently, a truncated FV (termed FV-short) produced by an autosomal dominant mutation was found to form complexes with TFPIα, resulting in retention of TFPIα in a 10-fold increase over normal levels in affected individuals [Vincent LM, J Clin Invest 123:3777 (2013)]. FV-short has significantly reduced thrombogenic potential and, by concomitantly raising TFPIα, causes a bleeding disorder. We hypothesize that the activation of PC in acute trauma may result in the production of FV-degradation products which could stabilize TFPIα similarly to the effect of FV-short. The combination of reduced FVa and increased TFPIα may contribute to ATC. Methods Whole blood from healthy volunteers was drawn by phlebotomy into ACD-containing tubes. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were collected by centrifugation (200g for 10 min and 1000g for 15 min, respectively). Calibrated automated thrombogram (CAT) assays and thromboelastography (TEG) were conducted using PRP and PPP with exogenously delivered aPC (0, 100pM, or 1nM) and TFPI (0, 2.5nM, or 10nM). An immunodepleted FV-deficient (<1% normal) plasma (FVdp) was used as a reference. Results CAT assays verified that aPC and TFPI each delay and suppress thrombin generation in PPP in a dose-dependent manner, but the combination of aPC and TFPI had a synergistic effect at the highest doses tested. The endogenous thrombin potential (ETP) was eliminated in PPP (control: 1663 nM-min; 1nM aPC + 10nM TFPI: 0 nM-min; P<0.001); lag time was similarly affected (control: 2.5 min; 1nM aPC + 10nM TFPI: >60 min; P<0.001). FVdp also featured a delayed lag time (11.17 min, P<0.001 versus control), but the delay induced by the addition of 10nM TFPI was not nearly as severe in FVdp (19.67 min) as in the PPP + 10nM aPC sample (>60 min, P<0.001). For PRP, there was no statistical difference between control and the highest doses of aPC and TFPI in ETP (1636 nM-min versus 1388 nM-min) or lag time (8.72 min versus 9.13 min). Conclusions In vitro studies suggest that PC activation is not the sole cause of ATC; the concentrations of aPC measured in trauma patient blood have little effect on the coagulation potential of plasma with or without platelets when aPC is delivered exogenously. The results here demonstrate that there is a synergistic effect between aPC and TFPI. When TFPI is added to FV deficient plasma, the thrombin generation is delayed and suppressed; however, in normal plasma digested with aPC (containing fragmented FVa), the addition of TFPI is sufficient to suppress the generation of thrombin beyond the window of measurement (>60 min). The addition of platelets to the milieu eliminated the effects of aPC, TFPI, and the combination on thrombin generation, highlighting the central role of platelets in maintaining hemostatic function. Disclosures No relevant conflicts of interest to declare.

scholarly journals New considerations on pathways involved in acute traumatic coagulopathy: the thrombin generation paradox

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Cedric Gangloff ◽  
Fanny Mingant ◽  
Michael Theron ◽  
Hubert Galinat ◽  
Ollivier Grimault ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Coagulation Factor ◽  
Protective Mechanism ◽  
Fibrinogen Concentration ◽  
Acute Traumatic Coagulopathy ◽  
Platelet Aggregometry ◽  
Traumatic Coagulopathy

Abstract Background An acute traumatic coagulopathy (ATC) is observed in about one third of severely traumatized patients. This early, specific, and endogenous disorder is triggered by the association of trauma and hemorrhage. The early phase of this condition is characterized by the expression of a bleeding phenotype leading to hemorrhagic shock and the late phase by a prothrombotic profile leading to multiple organ failure. The physiopathology of this phenomenon is still poorly understood. Hypotheses of disseminated intravascular coagulation, activated protein C-mediated fibrinolysis, fibrinogen consumption, and platelet functional impairment were developed by previous authors and continue to be debated. The objective of this study was to observe general hemostasis disorders in case of ATC to confront these hypotheses. Method Four groups of 15 rats were compared: C, control; T, trauma; H, hemorrhage; and TH, trauma and hemorrhage. Blood samples were drawn at baseline and 90 min. Thrombin generation tests, platelet aggregometry, and standard hemostasis tests were performed. Results Significant differences were observed between the baseline and TH groups for aPTT (17.9 ± 0.8 s vs 24.3 ± 1.4 s, p < 0.001, mean ± SEM), MAP (79.7 ± 1.3 mmHg vs 43.8 ± 1.3 mmHg, p < 0.001, mean ± SEM), and hemoglobin (16.5 ± 0.1 g/dL vs 14.1 ± 0.3 g/dL, p < 0.001, mean ± SEM), indicating the presence of an hemorrhagic shock due to ATC. Compared to all other groups, coagulation factor activities were decreased in the TH group, but endogenous thrombin potential was (paradoxically) higher than in group C (312 ± 17 nM/min vs. 228 ± 23 nM/min; p = 0.016; mean ± SEM). We also observed a subtle decrease in platelet count and function in case of ATC and retrieved an inversed linear relationship between fibrinogen concentration and aPTT (intercept, 26.53 ± 3.16; coefficient, − 3.40 ± 1.26; adjusted R2: 0.1878; p = 0.0123). Conclusions The clinical-biological profile that we observed, combining normal thrombin generation, fibrinogen depletion, and a hemorrhagic phenotype, reinforced the hypothesis of activated protein C mediated-fibrinolysis. The key role of fibrinogen, but not of the platelets, was confirmed in this study. The paradoxical preservation of thrombin generation suggests a protective mechanism mediated by rhabdomyolysis in case of major trauma. Based on these results, we propose a new conception concerning the pathophysiology of ATC.

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