Post-Injury Platelet Biology: Mechanisms and Outcomes

Study Overview
=================
Brief Summary
-----------------
Trauma-induced coagulopathy is a central cause of preventable deaths from hemorrhage after injury. The contribution and impact of altered post injury platelet biology on trauma-induced coagulopathy is not well understood despite the pivotal contribution of platelets to normal coagulation and endothelial integrity. The central hypothesis for this study is that severe injury and shock drive altered platelet activation, platelet aggregation, and platelet-endothelial interactions that are associated with increased rates of transfusion, organ failure, and mortality. This study will investigate these causal pathways, mechanisms, and associated outcomes in a prospective observational trauma cohort through collection of biospecimens and detailed clinical data.

Detailed Description
-----------------
This is a prospective cohort study of trauma patients on admission to the emergency department and for the subsequent 28 days. All adult patients meeting criteria for full trauma team activation and admitted to Zuckerberg San Francisco General Hospital and Trauma center, a level-1 trauma center, are eligible for enrollment. A 20-ml sample of blood will be drawn within 10 minutes of arrival in the emergency department (ED), processed in the central laboratory, and plasma stored at -80°C. Blood samples will be collected immediately on presentation via initial placement of a 16-gauge or larger peripheral intravenous line. Plasma biomarkers of endothelial injury will be measured by enzyme-linked immunosorbent assays (von Willebrand factor, syndecan-1, and angiopoietin-2). Cellular biomarkers of platelet activation will be measured by flow cytometry (platelet-monocyte aggregates, integrin αIIbβ3, P-selectin, and platelet microparticles). Platelet aggregation will be measured by whole blood multiple electrode impedance aggregometry. The effect of post-injury platelets on endothelial integrity will be quantified by in vitro assays of platelet-induced endothelial permeability. Comprehensive demographic data and medical history will be collected from chart review, interviews of patients and family members. Detailed clinical and outcome data is collected including transfusion timing and doses, the incidence of organ failure (Denver Postinjury Multiple Organ Failure Score), acute respiratory distress syndrome (Berlin Definition), infection, symptomatic thromboembolic complications, ventilator-free days, length of intensive care unit (ICU) and hospital stay, and mortality (6 hours, 24 hours, 30 days). In hospital mortality after 30 days will be assessed for all patients. Standard coagulation measures (international normalized ratio, prothrombin time, platelet count) and other laboratory measures will be collected to account and control for other distinct but highly integrated pathways implicated in trauma-induced coagulopathy. The Trauma Registry, a large database managed under guidelines from the American Trauma society, uses chart review to retrospectively assign Injury Severity Scores (ISS) and Abbreviated Injury Scores (AIS).

Official Title
-----------------
Post-Injury Platelet Biology: Mechanisms and Outcomes

Conditions
-----------------
Blood Platelets, Wound and Injuries, Endothelium

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients meeting criteria for full trauma team activation and admitted to Zuckerberg San Francisco General Hospital. Exclusion Criteria: Patients <18 years old Patients transferred from other hospitals Patients who are pregnant Patients who are incarcerated Patients will be retrospectively excluded if they were taking anticoagulant or anti-platelet medications, have moderate or severe liver disease, or a known bleeding diathesis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe Injury/Shock<br>Severely injured trauma patients presenting with shock, as defined by an Injury Severity Score (ISS)>=25, and base deficit (BD)>=6. | |
| Without Severe Injury/Shock<br>Not severely injured trauma patients presenting without shock, as defined by an Injury Severity Score (ISS)<25, and base deficit (BD) <6. | |
| Healthy Controls<br>Uninjured healthy volunteers | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In Vitro Measurement of Endothelial Biomarkers | Plasma biomarkers of endothelial injury will be measured by enzyme-linked immunosorbent assays (von Willebrand factor, syndecan-1, and angiopoietin-2). | 0 hour (within 10 minutes of arrival to the Emergency Department) | 
| In Vitro Measurement Platelet Activation Biomarkers | Cellular biomarkers of platelet activation will be measured by flow cytometry (platelet-monocyte aggregates, integrin αIIbβ3, P-selectin, and platelet microparticles). | 0 hour (within 10 minutes of arrival to the Emergency Department) | 
| In Vitro Measurement of Platelet Aggregation | Platelet aggregation will be measured by whole blood multiple electrode impedance aggregometry. | 0 hour (within 10 minutes of arrival to the Emergency Department) | 
| In Vitro Assays of Platelet-Induced Endothelial Permeability | The effect of post-injury platelets on endothelial integrity will be quantified by in vitro assays of platelet-induced endothelial permeability using transendothelial permeability electrical resistance (TEER) assays. | 0 hour (within 10 minutes of arrival to the Emergency Department) | 
| Transfusion products received (red cell, plasma, platelet) | Continuous units of red cell, plasma, platelet; transfused in 24 hours (yes/no); massive transfusion (>10units red cell/24 hour, yes/no) | in first 24 hours after arrival to the emergency department | 
| Organ Failure | Rates of organ failure (yes/no) (Denver Postinjury Multiple Organ Failure Score) | Within 1 week of arrival to the emergency department | 
| 6-hour Mortality |  | 6 hours after arrival to the emergency department | 
| 24-hour Mortality |  | 24 hours after arrival to the emergency department | 
| 30-days Mortality |  | 30 days after arrival to the emergency department | 
| Hospital Discharge Mortality |  | Through hospital discharge (an average of 13 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Trauma, Platelets, Coagulopathy