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

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

Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways

NIH/NHLBI; German Research Foundation

The effect of sulforaphane on leukocyte-endothelial interactions and platelet activation during inflammation and thrombosis

Inflammation is thought to play a driving role in an expanding number of vascular and cerebral pathologies. Sulforaphane (SFN) is a naturally occurring isothiocyanate which has previously been shown to harbour anti-inflammatory properties in several immune cell types. In this work, intra vital microscopy was used to visualise the cellular interactions within the cerebral microvasculature stimulated downstream of an inflammatory challenge, namely intraperitoneal injection of LPS (0.1-4mg/kg). This resulted in a time, not dose, dependent stimulation of leukocyte-endothelial interactions; the number of rolling cells significantly increased, cells exhibited a slow rolling velocity and the number of adherent cells significantly increased versus sham or vehicle treated animals. SFN pre-treatment at 50mg/kg 24hr prior to LPS challenge (0.5mg/kg), increased the number of cells rolling through the cerebral microvasculature, significantly increased the speed at which they were rolling versus LPS treated animals and decreased the number of cells that were adherent to the pial vessel walls. These alterations were not associated with alterations in systemic cytokine levels (IL12p70, IL-6, TNFα, IL-10, IFNγ, MCP-1) or nuclear Nrf2 expression within the cerebral cortex. LPS (1µg/ml) increased IL-1β release from isolated human neutrophils which also showed no alteration following SFN incubation (0.1-25µM). Investigation into the effects of SFN revealed that SFN significantly altered the ability of platelets to aggregation in response to several agonists (thrombin, collagen and ADP), and that this response was not associated with the intracellular Ca2+ movement or induction of LDH release. This work highlights the ability of SFN to alter inflammatory cell interactions within the cerebral microvasculature in vivo, and also indicates the inhibitory effect of SFN on isolated platelet function ex vivo.Open Acces

Data from: Sexual selection is influenced by both developmental and adult environments

Sexual selection is often assumed to be strong and consistent, yet increasing research shows it can fluctuate over space and time. Few experimental studies have examined changes in sexual selection in response to natural environmental variation. Here, we use a difference in resource quality to test for the influence of past environmental conditions and current environmental conditions on male and female mate choice and resulting selection gradients for leaf-footed cactus bugs, Narnia femorata. We raised juveniles on natural high and low quality diets, cactus pads with and without ripe cactus fruits. New adults were again assigned a cactus pad with or without fruit, paired with a potential mate, and observed for mating behaviors. We found developmental and adult encounter environments affected mating decisions and the resulting patterns of sexual selection for both males and females. Males were not choosy in the low quality encounter environment, cactus without fruit, but they avoided mating with small females in the high quality encounter environment. Females were choosy in both encounter environments, avoiding mating with small males. However, they were the choosiest when they were in the low quality encounter environment. Female mate choice was also context-dependent by male developmental environment. Females were more likely to mate with males that had developed on cactus with fruit when they were currently in the cactus with fruit environment. This pattern disappeared when females were in the cactus without fruit environment. Altogether, these results experimentally demonstrate context-dependent mate choice by both males and females. Furthermore, we demonstrate that simple, seasonal changes in resources can lead to fluctuations in sexual selection

Sexual selection is influenced by both developmental and adult environments - data

Data used in generalized linear models and selection analyse

Early Abortion in Family Medicine: Clinical Outcomes

PURPOSE Clinical innovations have made it more feasible to incorporate early abortion into family medicine, yet the outcomes of early abortion procedures in this setting have not been well studied. We wished to assess the outcomes of first-trimester medication and aspiration abortion procedures by family physicians

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

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

The S100A10 Pathway Mediates an Occult Hyperfibrinolytic Subtype in Trauma Patients

OBJECTIVE: To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. BACKGROUND: Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. METHODS: A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. RESULTS: Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be <5%. Heterogeneity existed among patients with low ML, with survivors sharing similar clinical and injury characteristics to patients with normal ML values (5-15%). Those who died were critically injured with a preponderance of traumatic brain injury and had a 7-fold higher DD level (died vs. survived: 103,170 vs. 13,672 ng/mL, P < 0.001). Patients with low ML and high DD demonstrated a hyperfibrinolytic biomarker profile, low tissue plasminogen activator levels but high plasma levels of S100A10. S100A10 was negatively correlated with %ML (r = -0.26, P < 0.001) and caused a significant reduction in %ML when added to whole blood ex-vivo. CONCLUSIONS: Patients presenting with low ML and low DD levels have low injury severity and normal outcomes. Conversely, patients with low ML but high DD levels are severely injured, functionally coagulopathic and have poor clinical outcomes. These patients have low tissue plasminogen activator levels and are not detectable by ROTEM. S100A10 is a cell surface plasminogen receptor which may drive the hyperfibrinolysis in these patients and which when shed artificially lowers %ML ex-vivo