bims-heshmo 2021-10-10 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–10–10
seven papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Pathophysiology of Trauma-Induced Coagulopathy.
Increased Plasma Hyaluronan Levels are Associated with Acute Traumatic Coagulopathy.
Neutrophil kinetics and function after major trauma: A systematic review.
State-of-The-Art Review: Sex Hormone Therapy in Trauma-Hemorrhage.
Credibility Assessment of a Subject-Specific Mathematical Model of Blood Volume Kinetics for Prediction of Physiological Response to Hemorrhagic Shock and Fluid Resuscitation.
Tackling Ischemic Reperfusion Injury With the Aid of Stem Cells and Tissue Engineering.
Making sense of IL-6 signalling cues in pathophysiology.

Transfus Med Rev. 2021 Aug 29. pii: S0887-7963(21)00041-9. [Epub ahead of print]

Pathophysiology of Trauma-Induced Coagulopathy.

Patricia Duque, Alberto Calvo, Christopher Lockie, Herbert Schöchl.

  There is no standard definition for trauma-induced coagulopathy (TIC). However, it could be defined as an abnormal hemostatic response secondary to trauma. The terms "early TIC" and "late TIC" have been recently suggested. "Early TIC" would refer to the inability to achieve effective hemostasis exacerbating an uncontrolled bleeding in a shocked patient with ischemia-reperfusion damage (bleeding phenotype) and takes place usually early after injury, whereas "late TIC" would represent a hypercoagulable state after surviving a severe tissue injury, that would contribute to thromboembolic events and multiorgan failure (MOF), (thrombotic phenotype), occurring typically hours after the trauma insult though it could be delayed for days. In addition, severe tissue injury when there is no associated shock could be followed by an early hypercoagulable state, representing an evolutionary maladaptive response of a physiologic mechanism created to increase clot formation and prevent bleeding. Therefore, TIC is not a uniform phenotype, ranging from bleeding to pro-thrombotic profiles. This current concept of TIC is mainly based on the recognition of TIC as a unique clotting disorder following trauma in which alterations in the endothelial function, fibrinolysis regulation and platelet behavior after major trauma are the main cornerstones.

Keywords:  Hemorrhagic shock; Hemostasis; Multiple trauma; Thrombosis

DOI:  https://doi.org/10.1016/j.tmrv.2021.07.004
Shock. 2021 Oct 01.

Increased Plasma Hyaluronan Levels are Associated with Acute Traumatic Coagulopathy.

Shannon C Walker, Robert P Richter, Lei Zheng, Amit R Ashtekar, Jan O Jansen, Jeffrey D Kerby, Jillian R Richter.

INTRODUCTION: Acute traumatic coagulopathy (ATC) is an endogenous impairment in hemostasis that often contributes to early mortality after trauma. Endothelial glycocalyx damage is associated with trauma-induced coagulation abnormalities; however, the specific relationship between hyaluronan (HA), a key glycocalyx constituent, and ATC has not been evaluated.
METHODS: We performed a secondary analysis of prospectively collected data from a recent study in which trauma patients (>18 years) admitted to our Level I trauma center with an ABC Score≥2 were enrolled. Partial thromboplastin time (PTT), international normalized ratio (INR), and thromboelastography (TEG) parameters were recorded at arrival. Injury characteristics and clinical outcomes were obtained. Plasma HA levels were measured in healthy controls (HC) and in trauma subjects at arrival (t = 0 h) and 12, 24, and 48 h. ATC was defined as admission INR>1.2 or PTT≥36.5 s. Comparisons of HA levels were assessed, and Spearman's correlations were performed between 0 h and 24 h HA levels, coagulation measures and clinical outcomes. P values < 0.05 were considered significant.
RESULTS: Forty-eight trauma patients and 22 controls were enrolled for study. Sixteen trauma subjects were coagulopathic at admission. HA levels in subjects with ATC were higher than non-coagulopathic subjects at all time points and elevated above HC levels at 24 and 48 h. At arrival, HA levels correlated with TEG R-time, PTT, and INR. HA levels at 24 h correlated with increased transfusion requirements and intensive care unit and hospital lengths of stay.
CONCLUSION: Shed HA is associated with early coagulation abnormalities in trauma patients, which may contribute to worse outcomes. These findings highlight the need for additional studies to evaluate the mechanistic role of HA in ATC.

DOI: https://doi.org/10.1097/SHK.0000000000001867
World J Crit Care Med. 2021 Sep 09. 10(5): 260-277

Neutrophil kinetics and function after major trauma: A systematic review.

Liam Db Finlay, Andrew Conway Morris, Adam M Deane, Alexander Jt Wood.

   BACKGROUND: Immune dysfunction following major traumatic injury is complex and strongly associated with significant morbidity and mortality through the development of multiple organ dysfunction syndrome (MODS), persistent inflammation, immunosuppression, and catabolism syndrome and sepsis. Neutrophils are thought to be a pivotal mediator in the development of immune dysfunction.
AIM: To provide a review with a systematic approach of the recent literature describing neutrophil kinetics and functional changes after major trauma in humans and discuss hypotheses as to the mechanisms of the observed neutrophil dysfunction in this setting.
METHODS: Medline, Embase and PubMed were searched on January 15, 2021. Papers were screened by two reviewers and those included had their reference list hand searched for additional papers of interest. Inclusion criteria were adults > 18 years old, with an injury severity score > 12 requiring admission to an intensive care unit. Papers that analysed major trauma patients as a subgroup were included.
RESULTS: Of 107 papers screened, 48 were included in the review. Data were heterogeneous and most studies had a moderate to significant risk of bias owing to their observational nature and small sample sizes. Key findings included a persistently elevated neutrophil count, stereotyped alterations in cell-surface markers of activation, and the elaboration of heterogeneous and immunosuppressive populations of cells in the circulation. Some of these changes correlate with clinical outcomes such as MODS and secondary infection. Neutrophil phenotype remains a promising avenue for the development of predictive markers for immune dysfunction.
CONCLUSION: Understanding of neutrophil phenotypes after traumatic injury is expanding. A greater emphasis on incorporating functional and clinically significant markers, greater uniformity in study design and assessment of extravasated neutrophils may facilitate risk stratification in patients affected by major trauma.

Keywords:  Immunophenotypes; Inflammation; Intensive care units; Multiple trauma; Neutrophils; Systemic inflammatory response syndrome

DOI:  https://doi.org/10.5492/wjccm.v10.i5.260
Shock. 2021 Oct 01.

State-of-The-Art Review: Sex Hormone Therapy in Trauma-Hemorrhage.

Eric Lang, Hossam Abdou, Joseph Edwards, Neerav Patel, Jonathan J Morrison.

ABSTRACT: Trauma-hemorrhage is the leading cause of prehospital and early in-hospital deaths, while also significantly contributing to the later development of multisystem organ dysfunction/failure and sepsis. Common and advanced resuscitative methods would potentially demonstrate benefits in the prehospital setting; however, they face a variety of barriers to application and implementation. Thus, a dialogue around a novel adjunct has arisen, sex hormone therapy. Proposed candidates include estradiol and its derivatives, metoclopramide hydrochloride/prolactin, dehydroepiandrosterone, and flutamide; with each having demonstrated a range of salutary effects in several animal model studies. Several retrospective analyses have observed a gender-based dimorphism in mortality following trauma-hemorrhage, thus suggesting that estrogens contribute to this pattern. Trauma-hemorrhage animal models have shown estrogens offer protective effects to the cardiovascular, pulmonary, hepatic, gastrointestinal, and immune systems. Additionally, a series of survival studies utilizing 17α-ethinylestradiol-3-sulfate, a potent, water-soluble synthetic estrogen, have demonstrated a significant survival benefit and beneficial effects on cardiovascular function. This review presents the findings of retrospective clinical studies, preclinical animal studies, and discusses how and why 17α-ethinylestradiol-3-sulfate should be considered for investigation within a prospective clinical trial.

DOI: https://doi.org/10.1097/SHK.0000000000001871
Front Physiol. 2021 ;12 705222

Credibility Assessment of a Subject-Specific Mathematical Model of Blood Volume Kinetics for Prediction of Physiological Response to Hemorrhagic Shock and Fluid Resuscitation.

Bahram Parvinian, Ramin Bighamian, Christopher George Scully, Jin-Oh Hahn, Pras Pathmanathan.

  Subject-specific mathematical models for prediction of physiological parameters such as blood volume, cardiac output, and blood pressure in response to hemorrhage have been developed. In silico studies using these models may provide an effective tool to generate pre-clinical safety evidence for medical devices and help reduce the size and scope of animal studies that are performed prior to initiation of human trials. To achieve such a goal, the credibility of the mathematical model must be established for the purpose of pre-clinical in silico testing. In this work, the credibility of a subject-specific mathematical model of blood volume kinetics intended to predict blood volume response to hemorrhage and fluid resuscitation during fluid therapy was evaluated. A workflow was used in which: (i) the foundational properties of the mathematical model such as structural identifiability were evaluated; (ii) practical identifiability was evaluated both pre- and post-calibration, with the pre-calibration results used to determine an optimal splitting of experimental data into calibration and validation datasets; (iii) uncertainty in model parameters and the experimental uncertainty were quantified for each subject; and (iv) the uncertainty was propagated through the blood volume kinetics model and its predictive capability was evaluated via validation tests. The mathematical model was found to be structurally identifiable. Pre-calibration identifiability analysis led to splitting the 180 min of time series data per subject into 50 and 130 min calibration and validation windows, respectively. The average root mean squared error of the mathematical model was 12.6% using the calibration window of (0 min, 50 min). Practical identifiability was established post-calibration after fixing one of the parameters to a nominal value. In the validation tests, 82 and 75% of the subject-specific mathematical models were able to correctly predict blood volume response when predictive capability was evaluated at 180 min and at the time when amount of infused fluid equals fluid loss.

Keywords:  fluid resuscitation; mathematical model; model credibility assessment; model validation; subject-specific; workflow

DOI:  https://doi.org/10.3389/fphys.2021.705222
Front Physiol. 2021 ;12 705256

Tackling Ischemic Reperfusion Injury With the Aid of Stem Cells and Tissue Engineering.

Mauricio Zamorano, Rodrigo L Castillo, Jorge F Beltran, Lisandra Herrera, Joaquín A Farias, Christian Antileo, Cristobal Aguilar-Gallardo, Adalberto Pessoa, Yolanda Calle, Jorge G Farias.

  Ischemia is a severe condition in which blood supply, including oxygen (O), to organs and tissues is interrupted and reduced. This is usually due to a clog or blockage in the arteries that feed the affected organ. Reinstatement of blood flow is essential to salvage ischemic tissues, restoring O, and nutrient supply. However, reperfusion itself may lead to major adverse consequences. Ischemia-reperfusion injury is often prompted by the local and systemic inflammatory reaction, as well as oxidative stress, and contributes to organ and tissue damage. In addition, the duration and consecutive ischemia-reperfusion cycles are related to the severity of the damage and could lead to chronic wounds. Clinical pathophysiological conditions associated with reperfusion events, including stroke, myocardial infarction, wounds, lung, renal, liver, and intestinal damage or failure, are concomitant in due process with a disability, morbidity, and mortality. Consequently, preventive or palliative therapies for this injury are in demand. Tissue engineering offers a promising toolset to tackle ischemia-reperfusion injuries. It devises tissue-mimetics by using the following: (1) the unique therapeutic features of stem cells, i.e., self-renewal, differentiability, anti-inflammatory, and immunosuppressants effects; (2) growth factors to drive cell growth, and development; (3) functional biomaterials, to provide defined microarchitecture for cell-cell interactions; (4) bioprocess design tools to emulate the macroscopic environment that interacts with tissues. This strategy allows the production of cell therapeutics capable of addressing ischemia-reperfusion injury (IRI). In addition, it allows the development of physiological-tissue-mimetics to study this condition or to assess the effect of drugs. Thus, it provides a sound platform for a better understanding of the reperfusion condition. This review article presents a synopsis and discusses tissue engineering applications available to treat various types of ischemia-reperfusions, ultimately aiming to highlight possible therapies and to bring closer the gap between preclinical and clinical settings.

Keywords:  3D culture; IRI mechanism; ischemia reperfusion injury; stem cells; tissue engineering

DOI:  https://doi.org/10.3389/fphys.2021.705256
FEBS Lett. 2021 Oct 07.

Making sense of IL-6 signalling cues in pathophysiology.

David Millrine, Robert H Jenkins, Stuart To Hughes, Simon A Jones.

  Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine-receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomised by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal-dependent cytokine responses. Here, a regulatory interplay between STAT-transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.

Keywords:  Arthritis; Cytokine receptors; Cytokines; Epigenetics; Inflammation; Interleukin; Jak-STAT signalling; MicroRNA; Pathophysiology; STAT transcription factors

DOI:  https://doi.org/10.1002/1873-3468.14201