Thrombin is the central coagulation enzyme that catalyzes the conversion of fibrinogen to form insoluble fibrin blood clots. In vivo, thrombin production results from the concerted effort of plasma ...enzymatic reactions with essential contributions from circulating and vessel wall cells. The relative amount of thrombin produced directly dictates the structure and stability of fibrin clots; therefore, sufficient thrombin generation is essential for normal hemostasis to occur. Examination of thrombin generation phenotypes among severely injury trauma patients reveals important relationships between the potential for generating thrombin and risks of bleeding and thrombotic complications. Thus, understanding determinants of thrombin generation following traumatic injury is of high clinical importance. This review will focus on patterns and mechanisms of thrombin generation in severely injured patients, the role of fluid resuscitation in modulating thrombin generation and implications for outcomes.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The endothelial glycocalyx layer (EGL) is a key regulator of vascular permeability, cell adhesion, and inflammation. The EGL is primarily composed of syndecan-1, hyaluronic acid (HA), heparan sulfate ...(HS) and chondroitin sulfate (CS). While many studies have observed increased shedding of syndecan-1 during hemorrhagic shock, little is known about the shedding of other EGL components, and their effects on altered permeability and coagulation. We characterized shedding of all four primary components of the EGL, as well as the plasma's effect on permeability and thrombin generation in a cohort of trauma patients.
Plasma samples were collected from 5 healthy consented volunteers and 22 severely injured trauma patients upon admission to the emergency department. ELISA assays were performed to quantify shed HA, HS, CS and syndecan-1 in plasma. A colloid osmometer and Electric Cell-substrate Impedance Sensing (ECIS) system were used to measure plasma colloid osmotic pressure (COP) and cell permeability, respectively. Thrombin generation was measured using a calibrated automated thrombogram (CAT). Initial vital signs, routine laboratory values, and injury severity scores (ISS) were recorded. Non-parametric statistical tests were used to compare differences between groups.
We observed increased shedding of all four proteins in trauma patient plasma compared to healthy controls: 31.7 vs. 21.2 U/L of CS, 175.8 vs. 121.9 ng/ml of HS, 946.7 vs. 618.6 ng/ml of HA and 245.8 vs. 31.6 ng/ml of syndecan-1 (all p<0.05). Patients with low plasma COP (≤16 mmHg) had significantly increased syndecan-1 and HA compared to those with normal COP, which corresponded to increased cell permeability via ECIS. CS and HS did not vary between COP groups. Lastly, patients with low COP displayed reduced peak thrombin generation of less than 250 nM on average (p<0.05).
Glycocalyx components were shed more in trauma patients compared to healthy controls in this cohort. However, only syndecan-1 and HA shedding were significantly higher in patients with reduced plasma COP. Thrombin generation was impaired in patients with low plasma COP. These data suggest that low plasma COP correlates well to glycocalyx degradation and thrombin loss following trauma, which consequently affect permeability and coagulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Endothelial glycocalyx breakdown elicits syndecan-1 shedding, and traumatic endotheliopathy (EoT). We hypothesized that a cutoff syndecan-1 level can identify patients with ...endothelial dysfunction who would have poorer outcomes. Study Design Prospective observational study; trauma patients with the highest level of activation admitted during July 2011-September 2013 were eligible. We recorded demographics, injury type/severity (ISS), physiology and outcome data, and quantified syndecan-1 and soluble thrombomodulin from plasma with ELISAs. With receiver operating characteristic curve (ROC) analysis, we defined EoT+ as the syndecan-1 cutoff level that maximized the sum of sensitivity and specificity (Youden index) in predicting 24-hour in-hospital mortality. We stratified by this cutoff, and compared both groups. Factors associated with 30-day in-hospital mortality were assessed with multivariable logistic regression (adjusted odds ratios (ORs) and 95% confidence intervals (CIs) reported). Results From ROC analysis (area under the curve=0.71, 95%CI 0.58-0.84), we defined EoT+ as syndecan-1 level ≥ 40 ng/ml (sensitivity= 0.62, specificity= 0.73). Of the 410 patients evaluated, 34% (n=138) were EoT+ patients, who presented with higher ISS ( p <0.001) and blunt trauma frequency ( p =0.016) than EoT- patients. While EoT+ patients had lower systolic blood pressure (median 119 vs. 128 mmHg; p <0.001), base excess and hemoglobin were similar between groups. The proportion of transfused (EoT+ 71.7% vs. EoT- 36.4%; p<0.001), and deceased EoT+ patients (EoT+ 24.6% vs. EoT- 12.1%; p <0.001) was higher. EoT+ was significantly associated with 30-day in-hospital mortality (adjusted OR 2.23, 95%CI 1.22-4.04). Conclusions A syndecan-1 level ≥40 ng/ml identified patients with significantly worse outcomes, despite similar admission physiology to those without the condition.
Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human ...pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti–human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Investigate and confirm the association between sympathoadrenal activation, endotheliopathy and poor outcome in trauma patients.
The association between sympathoadrenal activation, endotheliopathy, ...and poor outcome in trauma has only been demonstrated in smaller patient cohorts and animal models but needs confirmation in a large independent patient cohort.
Prospective observational study of 424 trauma patients admitted to a level 1 Trauma Center. Admission plasma levels of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial damage (syndecan-1, thrombomodulin, and sE-selectin) were measured and demography, injury type and severity, physiology, treatment, and mortality up till 28 days were recorded.
Patients had a median ISS of 17 with 72% suffering from blunt injury. Adrenaline and noradrenaline correlated with syndecan-1 (r = 0.38, P < 0.001 and r = 0.23, P < 0.001, respectively) but adrenaline was the only independent predictor of syndecan-1 by multiple linear regression adjusted for age, injury severity score, Glascow Coma Scale, systolic blood pressure, base excess, platelet count, hemoglobin, prehospital plasma, and prehospital fluids (100 pg/mL higher adrenaline predicted 2.75 ng/mL higher syndecan-1, P < 0.001). By Cox analyses adjusted for age, sex, injury severity score, Glascow Coma Scale, base excess, platelet count and hemoglobin, adrenaline, and syndecan-1 were the only independent predictors of both <24-hours, 7-day and 28-day mortality (all P < 0.05). Furthermore, noradrenaline was an independent predictor of <24-hours mortality and thrombomodulin was an independent predictor of 7-day and 28-day mortality (all P < 0.05).
We confirmed that sympathoadrenal activation was strongly and independently associated with endothelial glycocalyx and cell damage (ie, endotheliopathy) and furthermore that sympathoadrenal activation and endotheliopathy were independent predictors of mortality in trauma patients.
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