bims-heshmo 2021-06-13 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–06–13
eight papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Extracellular Vesicles Derived from Cardiosphere-Derived Cells (CDC-EVs) as a Potential Anti-Shock Therapeutic.
Fibrinogen in traumatic haemorrhage.
Kidney Injury in a Hemodilution Model of Hemorrhagic Shock and Fluid Resuscitation.
Patterns and Effects of Admission Hyperglycemia and Inflammatory Response in Trauma Patients: A Prospective Clinical Study.
Acquired antithrombin deficiency is a risk factor for venous thromboembolism after major trauma.
Synthetic platelet microgels containing fibrin knob B mimetic motifs enhance clotting responses.
Performance of a Novel Temporary Arterial Shunt in a Military-Relevant Controlled Hemorrhage Swine Model.
Application of Thromboelastographic Markers to Predict the Survival in Acute Trauma Patients.

J Trauma Acute Care Surg. 2021 Apr 08.

Extracellular Vesicles Derived from Cardiosphere-Derived Cells (CDC-EVs) as a Potential Anti-Shock Therapeutic.

Tiffani C Chance, Xiaowu Wu, Jeffrey D Keesee, Josue Garcia-Marcano, Christi L Salgado, Bin Liu, Jennifer J Moseley, Kiel A Peck, Luis R -Borlado, Nadia A Atai, Stephen J Gould, Linda S Marban, Andrew P Cap, Christopher R Rathbone, James A Bynum.

BACKGROUND: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique, cell free therapeutic. Due to 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 polytrauma and hemorrhagic shock is outlined.
METHODS AND MATERIALS: EV surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. EV 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 polytrauma and hemorrhagic shock.
RESULTS: CDC-EVs are not functionally procoagulant and do not interfere with platelet function. In a rat model of polytrauma 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 anti-shock therapeutic if administered early. These results demonstrate that research utilizing CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardio-protective benefits.
LEVEL OF EVIDENCE: Basic or Foundational Research; Original Article.

DOI: https://doi.org/10.1097/TA.0000000000003218
Curr Opin Anaesthesiol. 2021 Jun 04.

Fibrinogen in traumatic haemorrhage.

James Winearls, Michael Reade, Zoe McQuilten, Nicola Curry.

PURPOSE OF REVIEW: Recent advances in the understanding of the pathophysiological processes associated with traumatic haemorrhage and trauma-induced coagulopathy (TIC) have resulted in improved outcomes for seriously injured trauma patients. However, a significant number of trauma patients still die from haemorrhage. This article reviews the role of fibrinogen in normal haemostasis, the effect of trauma and TIC on fibrinogen levels and current evidence for fibrinogen replacement in the management of traumatic haemorrhage.
RECENT FINDINGS: Fibrinogen is usually the first factor to reach critically low levels in traumatic haemorrhage and hypofibrinogenaemia after severe trauma is associated with increased risk of massive transfusion and death. It is postulated that the early replacement of fibrinogen in severely injured trauma patients can improve outcomes. There is, however, a paucity of evidence to support this, and in addition, there is little evidence to support or refute the effects of cryoprecipitate or fibrinogen concentrate for fibrinogen replacement.
SUMMARY: The important role fibrinogen plays in haemostasis and effective clot formation is clear. A number of pilot trials have investigated different strategies for fibrinogen replacement in severe trauma. These trials have formed the basis of several large-scale phase III trials, which, cumulatively will provide a firm evidence base to harmonise worldwide clinical management of severely injured trauma patients with major haemorrhage.

DOI: https://doi.org/10.1097/ACO.0000000000001027
Am J Med Sci. 2021 Jun 08. pii: S0002-9629(21)00215-9. [Epub ahead of print]

Kidney Injury in a Hemodilution Model of Hemorrhagic Shock and Fluid Resuscitation.

Luhao Wang, Fei Pei, Jianfeng Wu, Bin Ouyang, Xiangdong Guan.

   BACKGROUND: Fluid therapy is indispensable in treating patients with hemorrhagic shock. However, fluid overload correlates with kidney injury in patients with hemorrhagic shock. We hypothesized that hemodilution after fluid treatment contributes to the kidney injury.
METHODS: An animal model was established to mimic different severity of hemodilution, through resuscitating hemorrhagic shock with mixture of blood and lactated Ringer's solution (LR) in different ratios. A total of 20 rats were divided into the following four groups, the Sham group, Mild group, Moderate group, and Severe group. In the Sham group, rats were anesthetized and catheterized only. In the other three groups, shock was induced by extracting 40% of the estimated circulating blood. One hour later, rats were resuscitated with a mixture of blood and LR with ratio 1:0 in the Mild group, 0.5:0.5 in the Moderate group, and 0:1 in the Severe group. The histology of the kidneys was observed with hematoxylin and eosin (HE) staining. The mitochondria membrane potential ψ and adenosine triphosphate (ATP) production of the kidneys were measured. The serum creatinine (SCr) and blood urine nitrogen (BUN) were measured.
RESULTS: Renal tubular lumina dilation and mild interstitial edema occurred in the Mild group with HE staining. Proximal convoluted tubule damage, including tubular casts, narrow renal tubular lumina, and interstitial edema occurred in the Moderate group and Severe group. Mitochondrial JC-1 and ATP production decreased as hemodilution progressed. SCr and BUN increased in the Moderate group and Severe group.
CONCLUSIONS: The hemodilution post hemorrhagic shock and fluid resuscitation led to kidney injury.

Keywords:  Fluid resuscitation; Hemodilution; Kidney injury; Mitochondria damage

DOI:  https://doi.org/10.1016/j.amjms.2021.06.002
World J Surg. 2021 Jun 11.

Patterns and Effects of Admission Hyperglycemia and Inflammatory Response in Trauma Patients: A Prospective Clinical Study.

Ayman El-Menyar, Mohammad Asim, Fayaz Mir, Suhail Hakim, Ahad Kanbar, Tariq Siddiqui, Basil Younis, Khalid Ahmed, Ismail Mahmood, Sajid Atique, Hisham Al Jogol, Ibrahim Taha, Fuad Mustafa, Mohammad Alabdallat, Husham Abdelrahman, Ruben Peralta, Hassan Al-Thani.

BACKGROUND: The constellation of the initial hyperglycemia, proinflammatory cytokines and severity of injury among trauma patients is understudied. We aimed to evaluate the patterns and effects of on-admission hyperglycemia and inflammatory response in a level 1 trauma center. We hypothesized that higher initial readings of blood glucose and cytokines are associated with severe injuries and worse in-hospital outcomes in trauma patients.
METHODS: A prospective, observational study was conducted for adult trauma patients who were admitted and tested for on-admission blood glucose, hemoglobin A1c, interleukin (IL)-6, IL-18 and hs-CRP. Patients were categorized into four groups [non-diabetic normoglycemic, diabetic normoglycemic, diabetic hyperglycemic (DH) and stress-induced hyperglycemic (SIH)]. The inflammatory markers were measured on three time points (admission, 24 h and 48 h). Generalized estimating equations (GEE) were used to account for the correlation for the inflammatory markers. Pearson's correlation test and logistic regression analysis were also performed.
RESULTS: During the study period, 250 adult trauma patients were enrolled. Almost 13% of patients presented with hyperglycemia (50% had SIH and 50% had DH). Patients with SIH were younger, had significantly higher Injury Severity Score (ISS), higher IL-6 readings, prolonged hospital length of stay and higher mortality. The SIH group had lower Revised Trauma Score (p = 0.005), lower Trauma Injury Severity Score (p = 0.01) and lower GCS (p = 0.001). Patients with hyperglycemia had higher in-hospital mortality than the normoglycemia group (12.5% vs 3.7%; p = 0.02). A significant correlation was identified between the initial blood glucose level and serum lactate, IL-6, ISS and hospital length of stay. Overall rate of change in slope 88.54 (95% CI:-143.39-33.68) points was found more in hyperglycemia than normoglycemia group (p = 0.002) for IL-6 values, whereas there was no statistical significant change in slopes of age, gender and their interaction. The initial IL-6 levels correlated with ISS (r = 0.40, p = 0.001). On-admission hyperglycemia had an adjusted odds ratio 2.42 (95% CI: 1.076-5.447, p = 0.03) for severe injury (ISS > 12) after adjusting for age, shock index and blood transfusion.
CONCLUSIONS: In trauma patients, on-admission hyperglycemia correlates well with the initial serum IL-6 level and is associated with more severe injuries. Therefore, it could be a simple marker of injury severity and useful tool for patient triage and risk assessment.
TRIAL REGISTRATION: This study was registered at the ClinicalTrials.gov (Identifier: NCT02999386), retrospectively Registered on December 21, 2016. https://clinicaltrials.gov/ct2/show/NCT02999386 .

DOI: https://doi.org/10.1007/s00268-021-06190-5
Thromb Res. 2021 May 28. pii: S0049-3848(21)00346-7. [Epub ahead of print]204 9-12

Acquired antithrombin deficiency is a risk factor for venous thromboembolism after major trauma.

Elaheh Rahbar, Bryan A Cotton, Charles E Wade, Jessica C Cardenas.

   BACKGROUND: Up to 30% of severely injured patients on prophylactic anticoagulation experience venous thromboembolism (VTE). Our previous work shows that acquired antithrombin (AT) deficiency [AT<80%] occurs in approximately 20% of trauma patients upon admission and drives poor responsiveness to enoxaparin. However, changes in AT over time and its association with VTE remain unknown. The aim of this study was to determine the relationship between acquired AT deficiency and VTE in severely injured patients.
METHODS: A secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) clinical trial was performed. Patients who died within 24 h of hemorrhage were excluded from analysis. Demographics, mechanism and severity of injury, transfusions volumes, and outcomes were compared between patients who did and did not develop VTE. Non-parametric statistical tests were used to compare patients with and without VTE. Logistic regression analyses were performed to identify predictors of VTE risk, controlling for AT deficiency (over first 72 h), age, gender, race, body mass index, study site, randomization group and injury severity. A Cox proportional hazards model was used to assess the contribution of AT deficiency to the risk of VTE, while censoring for early deaths.
RESULTS: Of the 680 patients enrolled in PROPPR, 101 died of hemorrhage. Of the remaining 579 patients, 86 (14.9%) developed VTE. The median time to VTE was 6 days (IQR 3, 13). No differences in demographics, injuries, or transfusion volumes were identified between VTE cases and controls. AT deficiency at 72 h post-admission was independently associated with VTE. Patients who experienced AT deficiency at 72 h had a 3.3 fold increased risk of VTE [p < 0.01; 95% CI 1.56, 6.98]. Lastly, patients who developed VTE had worse outcomes as displayed by significantly fewer hospital-free days compared to non-VTE patients [0 (0, 8) vs. 4 (0, 18), p < 0.01, respectively].
CONCLUSIONS: Acquired AT deficiency (AT<80%) is an important risk factor for VTE in severely injured patients. These data indicate that intervening, perhaps through AT supplementation, in the first three days after injury could mitigate the risk of VTE and improve patient outcomes.

Keywords:  Anticoagulation; Antithrombin; Injury; Thrombosis; Trauma; Venous thromboembolism

DOI:  https://doi.org/10.1016/j.thromres.2021.05.015
Adv Ther (Weinh). 2021 May 10. pii: 2100010. [Epub ahead of print]4(5):

Synthetic platelet microgels containing fibrin knob B mimetic motifs enhance clotting responses.

Seema Nandi, Emily Mihalko, Kimberly Nellenbach, Mario Castaneda, John Schneible, Mary Harp, Halston Deal, Michael Daniele, Stefano Menegatti, Thomas H Barker, Ashley C Brown.

  Native platelets are crucial players in wound healing. Key to their role is the ability of their surface receptor GPIIb/IIIa to bind fibrin at injury sites, thereby promoting clotting. When platelet activity is impaired as a result of traumatic injury or certain diseases, uncontrolled bleeding can result. To aid clotting and tissue repair in cases of poor platelet activity, our lab has previously developed synthetic platelet-like particles capable of promoting clotting and improving wound healing responses. These are constructed by functionalizing highly deformable hydrogel microparticles (microgels) with fibrin-binding ligands including a fibrin-specific whole antibody or a single-domain variable fragment. To improve the translational potential of these clotting materials, we explored the use of fibrin-binding peptides as cost-effective, robust, high-specificity alternatives to antibodies. Herein, we present the development and characterization of soft microgels decorated with the peptide AHRPYAAK that mimics fibrin knob 'B' and targets fibrin hole 'b'. These "Fibrin-Affine Microgels with Clotting Yield" (FAMCY) were found to significantly increase clot density in vitro and decrease bleeding in a rodent trauma model in vivo. These results indicate that FAMCYs are capable of recapitulating the platelet-mimetic properties of previous designs while utilizing a less costly, more translational design.

Keywords:  biomimetic; clotting; fibrin; hemorrhage; knob B; synthetic platelets; trauma; wound healing

DOI:  https://doi.org/10.1002/adtp.202100010
J Trauma Acute Care Surg. 2021 May 18.

Performance of a Novel Temporary Arterial Shunt in a Military-Relevant Controlled Hemorrhage Swine Model.

Kyle S Stigall, Justin J Sleeter, Sarah B Thomas, David W Schechtman, Perry E Blough, Jason M Rall, David S Kauvar.

BACKGROUND: In military trauma, temporary vascular shunts (TVSs) restore arterial continuity until delayed vascular reconstruction, often for a period of hours. A novel US Air Force-developed trauma specific vascular injury shunt (TS-VIS) incorporates an accessible sideport for intervention or monitoring which may improve patency under adverse hemodynamic conditions. Our objective was to evaluate TS-VIS patency in the setting of volume-limited resuscitation from hemorrhagic shock.
METHODS: Female swine (70-90kg) underwent 30% hemorrhage and occlusion of the left external iliac artery (LEIA) for 30min. Animals were allocated to one of three groups (n=5/group) by LEIA treatment: Sundt shunt (SUNDT), TS-VIS with arterial pressure monitoring (TS-VIS), or TS-VIS with heparin infusion (10u/kg/h, TS-VISHep). Animals were resuscitated with up to 3 units whole blood to maintain a MAP >60mmHg and were monitored for 6 hours. Bilateral femoral arterial flow was continuously monitored with transonic flow probes, and shunt thrombosis was defined as the absence of flow for greater than 5 minutes.
RESULTS: No intergroup differences in MAP or flow were observed at baseline or following hemorrhage. Animals were hypotensive at shunt placement (MAP 35.5±7.3 mmHg); resuscitation raised MAP to >60 mmHg by 26.5±15.5 min. Shunt placement required 4.5 ± 1.8 minutes with no difference between groups. Four SUNDT thrombosed (3 before 60 min). One SUNDT thrombosed at 240min, two TS-VIS and one TS-VISHep thrombosed between 230 and 282 min. Median patency was 21 min for SUNDT and 360 min for both TS-VIS groups (P=0.04). While patent, all shunts maintained flow between 60 and 90% of contralateral.
CONCLUSIONS: The TS-VIS demonstrated sustained patency superior to the Sundt under adverse hemodynamic conditions. No benefit was observed by the addition of localized heparin therapy over arterial pressure monitoring by the TS-VIS sideport.
LEVEL OF EVIDENCE: Level II, preclinical (translational) randomized trial.

DOI: https://doi.org/10.1097/TA.0000000000003282
Clin Lab. 2021 Jun 01. 67(6):

Application of Thromboelastographic Markers to Predict the Survival in Acute Trauma Patients.

Hyunjung Kim, Maru Kim, Hae Kyung Lee, Dae Sang Lee, Dae Hyun Cho, Hangjoo Cho.

BACKGROUND: The aim of the study is to investigate the coagulation status in trauma patients using thromboelastography and their association with survival and blood transfusion.
METHODS: We included 452 trauma patients who visited the trauma center of Uijeongbu St. Mary's Hospital. The thromboelastography (TEG) clotting variables and routine coagulation tests were evaluated. Also, we investigated the transfusion requirement and mortality during hospitalization period.
RESULTS: The mean age was 52.3 years and the mortality rate was 39/452 (8.6%). Lower GCS, longer TEG K-time, and lower TEG MA were independent factors associated with mortality. The lower MA group demonstrated the highest probability of survival (odds ratio 0.207), followed by prolonged R-time (odds ratio 0.220). The patient numbers in fibrinolysis shutdown (SD), physiologic fibrinolysis, and hyperfibrinolysis groups were 219 (52.3%), 131 (31.4%), and 68 (16.3%), respectively. The mortality rates of fibrinolysis SD group (11.9%) and hyperfibrinolysis (8.8%) were higher than the physiologic fibrinolysis groups (3.8%). The cutoff obtained from ROC analysis was found to be suitable for predicting survival. The transfusion requirements were significantly higher in the fibrinolysis SD group than in the other two groups.
CONCLUSIONS: TEG based markers were shown to be more useful to make a diagnosis of coagulopathies including dysfibrinolysis and predict the survival than routine coagulation tests. Dysfunctional fibrinolysis showed higher mortality than physiologic group. If multiple integrations of each TEG markers are used, it would be helpful for prompt diagnosis and management of coagulopathies and to decrease preventable deaths in trauma.

DOI: https://doi.org/10.7754/Clin.Lab.2020.200834