scholarly journals Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage

2019 ◽  
Vol 116 (35) ◽  
pp. 17444-17449 ◽  
Author(s):  
Paul Vulliamy ◽  
Scarlett Gillespie ◽  
Paul C. Armstrong ◽  
Harriet E. Allan ◽  
Timothy D. Warner ◽  
...  
Keyword(s):  
Trauma Patients ◽  
Histone H4 ◽  
Platelet Dysfunction ◽  
Innate Response ◽  
Primary Hemostasis ◽  
Molecular Pattern ◽  
Large Numbers ◽  
And Function ◽  
Injured Patients ◽  
Platelet Structure

Trauma hemorrhage is a leading cause of death and disability worldwide. Platelets are fundamental to primary hemostasis, but become profoundly dysfunctional in critically injured patients by an unknown mechanism, contributing to an acute coagulopathy which exacerbates bleeding and increases mortality. The objective of this study was to elucidate the mechanism of platelet dysfunction in critically injured patients. We found that circulating platelets are transformed into procoagulant balloons within minutes of injury, accompanied by the release of large numbers of activated microparticles which coat leukocytes. Ballooning platelets were decorated with histone H4, a damage-associated molecular pattern released in massive quantities after severe injury, and exposure of healthy platelets to histone H4 recapitulated the changes in platelet structure and function observed in trauma patients. This is a report of platelet ballooning in human disease and of a previously unrecognized mechanism by which platelets contribute to the innate response to tissue damage.

scholarly journals Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients

2020 ◽  
Vol 4 (12) ◽  
pp. 2623-2630 ◽  
Author(s):  
Paul Vulliamy ◽  
Samantha J. Montague ◽  
Scarlett Gillespie ◽  
Melissa V. Chan ◽  
Lucy A. Coupland ◽  
...  
Keyword(s):  
Patient Characteristics ◽  
Surface Expression ◽  
Trauma Patients ◽  
Severely Injured ◽  
Platelet Dysfunction ◽  
Severely Injured Patients ◽  
Severe Injuries ◽  
Glycoprotein Vi ◽  
Active Hemorrhage ◽  
Injured Patients

Abstract Trauma-induced coagulopathy (TIC) is a complex, multifactorial failure of hemostasis that occurs in 25% of severely injured patients and results in a fourfold higher mortality. However, the role of platelets in this state remains poorly understood. We set out to identify molecular changes that may underpin platelet dysfunction after major injury and to determine how they relate to coagulopathy and outcome. We performed a range of hemostatic and platelet-specific studies in blood samples obtained from critically injured patients within 2 hours of injury and collected prospective data on patient characteristics and clinical outcomes. We observed that, although platelet counts were preserved above critical levels, circulating platelets sampled from trauma patients exhibited a profoundly reduced response to both collagen and the selective glycoprotein VI (GPVI) agonist collagen-related peptide, compared with those from healthy volunteers. These responses correlated closely with overall clot strength and mortality. Surface expression of the collagen receptors GPIbα and GPVI was reduced on circulating platelets in trauma patients, with increased levels of the shed ectodomain fragment of GPVI detectable in plasma. Levels of shed GPVI were highest in patients with more severe injuries and TIC. Collectively, these observations demonstrate that platelets experience a loss of GPVI and GPIbα after severe injury and translate into a reduction in the responsiveness of platelets during active hemorrhage. In turn, they are associated with reduced hemostatic competence and increased mortality. Targeting proteolytic shedding of platelet receptors is a potential therapeutic strategy for maintaining hemostatic competence in bleeding and improving the efficacy of platelet transfusions.

scholarly journals Quantitation and Characterization of Cell-Free Mitochondrial DNA in Plasma by Deep Sequencing

2021 ◽  
Author(s):  
Grant T. Daly ◽  
Viktor M. Pastukh ◽  
Yong B. Tan ◽  
C. Michael Francis ◽  
C. Zack Aggen ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Deep Sequencing ◽  
Low Frequency ◽  
Trauma Patients ◽  
Molecular Pattern ◽  
Human Disorders ◽  
Total Dna ◽  
The Mean ◽  
Injured Patients

Abstract The presence in plasma of mitochondrial DNA (mtDNA) fragments, a proinflammatory damage-associated molecular pattern (DAMP), is positively associated with outcomes of multiple human disorders. Because mtDNA comprises only a small percentage of the total DNA in plasma, qPCR is typically employed as an analytic strategy. However, this method provides little insight into sequence origins or other characteristics of circulating mtDNA fragments. Here we found that target bait-capture applied to plasma mtDNA derived from severely injured patients enriched recovery by ≈ 1400-fold, thus affording depth sufficient for NextGen sequence analysis. Our method excluded nuclear mitochondrial insertions (NUMTs) using a stringent alignment and filtering strategy which calls and quantifies both NUMT in the reference genome and polymorphic NUMTs. After enrichment, we sequenced 2,000–60,000x mean coverage over the mtDNA genome. Normalization of mtDNA abundance to NUMT coverage reduced batch variability. Two massively-transfused trauma patients and two non-transfused patients displayed time-dependent increases in mtDNA DAMP coverage and decreases in the mean fragment length, which were more pronounced in massively transfused patients. Finally, our approach enabled detection of low-frequency heteroplasmic variants. Collectively, these findings suggest that our target bait-capture, deep sequencing and attendant analytic protocols could provide unprecedented characterization of cell-free plasma mtDNA and NUMTs.

The Influence of Ascorbic Acid on Platelet Structure and Function

1975 ◽  
Vol 34 (01) ◽  
pp. 050-062
Author(s):  
Dale H Cowan ◽  
Richard C Graham ◽  
Patricia Shook ◽  
Ronda Griffin
Keyword(s):  
Ascorbic Acid ◽  
Open Channel ◽  
Channel System ◽  
Short Intervals ◽  
Platelet Survival ◽  
Artifactual Changes ◽  
Survival Studies ◽  
And Function ◽  
Induced Aggregation ◽  
Platelet Structure

SummaryTo determine the effect on platelet behavior of transient exposure of platelets to ascorbic acid, studies of platelet function and ultrastructure were done before exposure to ascorbic acid at pH 6.5, during exposure to pH 6.5, and after restoration of pH to pre-acidifìcation levels. The effect of ascorbic acid (A. A.) was compared to that of HCl and citric acid (C. A.). ADP- and collagen-induced aggregation of normal platelets were significantly impaired by both A. A. and C. A. but were less affected by HCl. The release of 14C-serotonin was significantly reduced by each agent. The ultra-structure of normal platelets brought to pH 6.5 by A.A. was normal. After neutralization, there was marked dilatation of the open channel system and loss of the disc shape. When platelets were brought to pH 6.5 by A. A., then neutralized, the aggregates which formed after stimulation by ADP or collagen were smaller than normal, the platelets were less closely approximated, and degranulation was less complete. The data show that exposure of platelets to ascorbic acid for short intervals impairs their function when measured after restoration of pH to levels compatible with maximal responses. Platelet survival studies using autologous platelets labelled with 51Cr in the presence or absence of ascorbic acid showed that the recovery of normal platelets was unaffected by ascorbic acid, whereas recovery of platelets from patients with idiopathic thrombocytopenic purpura, idiopathic thrombocythemia, and alcohol-related thrombocytopenia was markedly reduced. The injury resulting from the use of ascorbic acid in preparing platelets for studies of platelet survival in patients with disorders affecting platelets may impair the recovery of the cells, resulting in artifactual changes in the survival studies.

Bleeding Time in Rats: A Comparison of Different Experimental Conditions

1982 ◽  
Vol 48 (01) ◽  
pp. 108-111 ◽  
Author(s):  
Elisabetta Dejana ◽  
Silvia Villa ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Function ◽  
Bleeding Time ◽  
Platelet Dysfunction ◽  
Experimental Conditions ◽  
Platelet Number ◽  
Coagulation Defects ◽  
Tail Tip ◽  
And Function ◽  
Storage Pool Disease ◽  
Type Of Anaesthesia

SummaryThe tail bleeding time (BT) in rats definitely varies according to the method applied. Of the various variables that may influence BT, we have evaluated the position (horizontal or vertical) of the tail, the environment (air or saline), the temperature (4°, 23° or 37° C) and the type of anaesthesia. Transection of the tail tip cannot be used to screen drugs active on platelet function since it is sensitive to coagulation defects. Template BT in contrast is not modified by heparin and is sensitive to defects of platelet number and function (“storage pool disease”, dipyridamole-like drugs, exogenous prostacyclin). In contrast the test fails to detect aspirin-induced platelet dysfunction. The evidence reported indicates that thromboxane A2-prostacyclin balance is not a factor regulating BT. Aspirin treatment however may be a precipitating factor when associated with other abnormalities of platelet function.Template BT is a valid screening test for platelet disorders and for antiplatelet drugs.

National temporal variation in major trauma in England, Wales and Northern Ireland

Trauma ◽  
2021 ◽  
pp. 146040862098226
Author(s):  
Will Kieffer ◽  
Daniel Michalik ◽  
Jason Bernard ◽  
Omar Bouamra ◽  
Benedict Rogers
Keyword(s):  
Northern Ireland ◽  
Temporal Variation ◽  
Major Trauma ◽  
Injury Severity ◽  
Research Network ◽  
Trauma Patients ◽  
Trauma Outcomes ◽  
Causes Of Mortality ◽  
Injured Patients ◽  
Time Of Admission

Introduction Trauma is one of the leading causes of mortality worldwide, but little is known of the temporal variation in major trauma across England, Wales and Northern Ireland. Proper workforce and infrastructure planning requires identification of the caseload burden and its temporal variation. Materials and Methods The Trauma Audit Research Network (TARN) database for admissions attending Major Trauma Centres (MTCs) between 1st April 2011 and 31st March 2018 was analysed. TARN records data on all trauma patients admitted to hospital who are alive at the time of admission to hospital. Major trauma was classified as an Injury Severity Score (ISS) >15. Results A total of 158,440 cases were analysed. Case ascertainment was over 95% for 2013 onwards. There was a statistically significant variation in caseload by year (p < 0.0001), times of admissions (p < 0.0001), caseload admitted during weekends vs weekdays, 53% vs 47% (p < 0.0001), caseload by season with most patients admitted during summer (p < 0.0001). The ISS varied by time of admission with most patients admitted between 1800 and 0559 (p < 0.0001), weekend vs weekday with more severely injured patients admitted during the weekend (p < 0.0001) and by season p < 0.0001). Discussion and Conclusion: There is a significant national temporal variation in major trauma workload. The reasons are complex and there are multiple theories and confounding factors to explain it. This is the largest dataset for hospitals submitting to TARN which can help guide workforce and resource allocation to further improve trauma outcomes.

scholarly journals Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Olav Sundnes ◽  
William Ottestad ◽  
Camilla Schjalm ◽  
Peter Lundbäck ◽  
Lars la Cour Poulsen ◽  
...  
Keyword(s):  
High Resolution ◽  
Prospective Observational Study ◽  
Tissue Injury ◽  
Trauma Patients ◽  
Decoy Receptor ◽  
Interleukin 33 ◽  
Injured Patients ◽  
First Time ◽  
Kinetics Of ◽  
Insight Into

Abstract Background Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma. Methods Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays. Results We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t1/2) was 1.4 h (95% CI 1.2–1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points. Conclusions We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.

scholarly journals Advances in the understanding of trauma-induced coagulopathy

Blood ◽  
2016 ◽  
Vol 128 (8) ◽  
pp. 1043-1049 ◽  
Author(s):  
Ronald Chang ◽  
Jessica C. Cardenas ◽  
Charles E. Wade ◽  
John B. Holcomb
Keyword(s):  
Animal Studies ◽  
Causes Of Death ◽  
Endothelial Activation ◽  
The United States ◽  
Trauma Patients ◽  
Platelet Dysfunction ◽  
Intracranial Injury ◽  
Trauma Induced Coagulopathy ◽  
Common Causes

Abstract Ten percent of deaths worldwide are due to trauma, and it is the third most common cause of death in the United States. Despite a profound upregulation in procoagulant mechanisms, one-quarter of trauma patients present with laboratory-based evidence of trauma-induced coagulopathy (TIC), which is associated with poorer outcomes including increased mortality. The most common causes of death after trauma are hemorrhage and traumatic brain injury (TBI). The management of TIC has significant implications in both because many hemorrhagic deaths could be preventable, and TIC is associated with progression of intracranial injury after TBI. This review covers the most recent evidence and advances in our understanding of TIC, including the role of platelet dysfunction, endothelial activation, and fibrinolysis. Trauma induces a plethora of biochemical and physiologic changes, and despite numerous studies reporting differences in coagulation parameters between trauma patients and uninjured controls, it is unclear whether some of these differences may be “normal” after trauma. Comparisons between trauma patients with differing outcomes and use of animal studies have shed some light on this issue, but much of the data continue to be correlative with causative links lacking. In particular, there are little data linking the laboratory-based abnormalities with true clinically evident coagulopathic bleeding. For these reasons, TIC continues to be a significant diagnostic and therapeutic challenge.

scholarly journals A retrospective cohort study of 27,049 polytraumatized patients age 60 and above: identifying changes over 16 years

2021 ◽  
Author(s):  
Y. Kalbas ◽  
M. Lempert ◽  
F. Ziegenhain ◽  
J. Scherer ◽  
V. Neuhaus ◽  
...  
Keyword(s):  
Length Of Stay ◽  
Injury Severity ◽  
Descriptive Analysis ◽  
Patient Characteristics ◽  
Severe Trauma ◽  
Diagnostic Tools ◽  
Trauma Patients ◽  
Treatment Algorithms ◽  
Injured Patients ◽  
Over Time

Abstract Purpose The number of severely injured patients exceeding the age of 60 has shown a steep increase within the last decades. These patients present with numerous co-morbidities, polypharmacy, and increased frailty requiring an adjusted treatment approach. In this study, we establish an overview of changes we observed in demographics of older severe trauma patients from 2002 to 2017. Methods A descriptive analysis of the data from the TraumaRegister DGU® (TR-DGU) was performed. Patients admitted to a level one trauma center in Germany, Austria and Switzerland between 2002 and 2017, aged 60 years or older and with an injury severity score (ISS) over 15 were included. Patients were stratified into subgroups based on the admission: 2002–2005 (1), 2006–2009 (2), 2010–2013 (3) and 2014–2017 (4). Trauma and patient characteristics, diagnostics, treatment and outcome were compared. Results In total 27,049 patients with an average age of 73.9 years met the inclusion criteria. The majority were males (64%), and the mean ISS was 27.4. The proportion of patients 60 years or older [(23% (1) to 40% (4)] rose considerably over time. Trauma mechanisms changed over time and more specifically low falls (< 3 m) rose from 17.6% (1) to 40.1% (4). Altered injury patterns were also identified. Length-of-stay decreased from 28.9 (1) to 19.5 days (4) and the length-of-stay on ICU decreased from 17.1 (1) to 12.7 days (4). Mortality decreased from 40.5% (1) to 31.8% (4). Conclusion Length of stay and mortality decreased despite an increase in patient age. We ascribe this observation mainly to increased use of diagnostic tools, improved treatment algorithms, and the implementation of specialized trauma centers for older patients allowing interdisciplinary care.

The origin of multiple mating types in mushrooms

1993 ◽  
Vol 104 (2) ◽  
pp. 227-230
Author(s):  
U. Kues ◽  
L.A. Casselton
Keyword(s):  
Mating Type ◽  
Multiple Mating ◽  
Mating Types ◽  
Mating Partner ◽  
Binucleate Cells ◽  
Large Numbers ◽  
Mating Type Genes ◽  
And Function ◽  
Developmental Switch ◽  
Sterile Mycelium

Having multiple mating types greatly improves the chances of meeting a compatible mating partner, particularly in an organism like the mushroom that has no sexual differentiation and no mechanism for signalling to a likely mate. Having several thousands of mating types, as some mushrooms do, is, however, remarkable - and even more remarkable is the fact that individuals only recognise that they have met a compatible mate after their cells have fused. How are such large numbers of mating types generated and what is the nature of the intracellular interaction that distinguishes self from non- self? Answers to these fascinating questions come from cloning some of the mating type genes of the ink cap mushroom Coprinus cinereus. A successful mating in Coprinus triggers a major switch in cell type, the conversion of a sterile mycelium with uninucleate cells (monokaryon) to a fertile mycelium with binucleate cells (dikaryon) which differentiates the characteristic fruit bodies. The mating type genes that regulate this developmental switch map to two multiallelic loci designated A and B and these must both carry different alleles for full mating compatibility. A and B independently regulate different steps in the developmental switch, making it possible to study just one component of the system and work in our laboratory has concentrated on understanding the structure and function of the A genes. It is estimated that some 160 different A mating types exist in nature, any two of which can together trigger the A-regulated part of sexual development. The first clue to how such large numbers are generated came from classical genetic analysis, which identified two functionally redundant A loci, (alpha) and beta. Functional redundancy is, indeed, the key to multiple A mating types and, as seen in Fig.1, molecular cloning has identified many more genes than was possible by recombination analysis.

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