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Loss of GPVI and GPIb? contributes to trauma-induced platelet dysfunction in severely 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 GPIb? 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 GPIb? 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.

SUBMITTER: Vulliamy P

PROVIDER: S-EPMC7322946 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Vulliamy Paul P Montague Samantha J SJ Gillespie Scarlett S Chan Melissa V MV Coupland Lucy A LA Andrews Robert K RK Warner Timothy D TD Gardiner Elizabeth E EE Brohi Karim K Armstrong Paul C PC

Blood advances 20200601 12

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 ...[more]

PMID: 32556282

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Project description:BackgroundBone marrow (BM) dysfunction is common in severely injured trauma patients, resulting from elevated catecholamines and plasma granulocyte colony-stimulating factor (G-CSF) as well as prolonged mobilization of hematopoietic progenitor cells (HPCs). We have previously shown that propranolol (β-blocker [BB]) reduces HPC mobilization in a rodent model of injury and hemorrhagic shock. We hypothesize that BB would prevent BM dysfunction in humans following severe injury.MethodsForty-five severely injured trauma patients were studied in a prospective, randomized pilot trial. Twenty-five patients received BB, and 20 served as untreated controls. The dose of propranolol was adjusted to decrease the heart rate by 10% to 20% from baseline. Blood was analyzed for the presence of HPC (blast-forming unit erythroid cells [BFU-E] and colony-forming unit erythroid cells) and G-CSF. Demographic data, Injury Severity Score (ISS), hemoglobin, reticulocyte number, and outcome data were obtained.ResultsThe mean age of the study population was 33 years; 87% were male, with a mean ISS of 29. There is a significant increase in BFU-E in peripheral blood immediately following traumatic injury, and this mobilization persists for 30 days. The use of BB significantly decreases BFU-E and colony-forming unit erythroid cells at all time points. G-CSF is significantly elevated in both groups on admission; the use of BB decreases G-CSF levels by 51% as compared with 37% for controls. The average hemoglobin is nearly 1 g higher on the day of discharge with propranolol treatment (BB, 9.9 ± 0.4 g/dL vs. no BB, 9.1 ± 0.6 g/dL).ConclusionFollowing severe trauma, early treatment with propranolol following resuscitation is safe. The use of propranolol blunts early tachycardia, reduces HPC mobilization, and results in a faster return to baseline of the G-CSF peak seen after injury. There is also a trend toward faster recovery and resolution of anemia. Propranolol may be the first therapeutic agent to show improved BM function after severe injury.Level of evidenceTherapeutic study, level III.

Project description:PurposeWhile survival rates after a trauma are increasing a considerable part of the trauma population are still at risk for both short and long term disabilities. Little is known about prognostic factors over time after a severe trauma. The aim of the present prospective cohort study was to examine trauma and patient related prognostic factors for a lower health status over time after a severe trauma.MethodsA multicentre prospective observational cohort study was conducted. Adult trauma patients with severe injuries (ISS???16) were included from August 2015 until November 2016 if admitted to one of the hospitals in Noord-Brabant (the Netherlands). Outcome measure was health status, measured by the EuroQol-5D (EQ-5D utility and EQ-Visual analogue scale) and the Health Utilities Index (HUI2 and HUI3) one week and one, three, six, and twelve months after injury. Patient and trauma characteristics were analysed as prognostic factors with linear mixed models. The effect of each prognostic factor over time was analysed by adding the interaction term between the prognostic factor and time point in a multivariable linear mixed model, adjusted for confounders. Additionally, the risk factors for problems in the EQ-5 dimensions of HS and cognition were analysed.ResultsIn total 239 severely injured patients participated. Pre-injury health status, hospital length of stay, ISS and comorbidities were significant prognostic factors for a lower health status. A younger age and extremity injury were prognostic factors for a lower health status until one month after trauma and unemployment before trauma and comorbidities six until twelve months after trauma. In the EQ-5 dimensions 44.1% remained problems in mobility, 15.3% in self-care, 46.4% in activity, 53.3% in pain, 32.5% in anxiety and 35.7% in cognition.ConclusionsLower pre-injury health status, longer hospital length of stay, higher ISS, and comorbidities were significant prognostic factors for a lower health status during one year after a severe injury. A younger age and an extremity injury were short-term prognostic factors and unemployment before trauma and comorbidities were long-term prognostic factors. Even after twelve months patients in our population reported more problems in all EQ-5D dimensions when compared to the Dutch reference population.

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Loss of GPVI and GPIb? contributes to trauma-induced platelet dysfunction in severely injured patients.

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

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