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Valproic acid attenuates platelet dysfunction, endothelial glycocalyx shedding and protein C activation in a porcine model of traumatic brain injury and shock
Vol. 217, No. 3S, September 2013
Surgical Forum Abstracts
S51
endthelial
by thrombelastography (TEG) and platelet function was assessed using platelet aggregometry.
METHODS: Multisystem trauma (traumatic brain injury, grade IV liver injury, rib fracture and soft tissue injury) with concurrent hemorrhagic shock (40% of blood volume) was produced in 12 swine. Animals were left in shock (mean arterial pressure of 35mmHg) for 2 hrs followed by resuscitation with either 0.9% normal saline (NS, n¼6; volume¼3x shed blood) or FFP (n¼6; volume¼1x shed blood), and monitored for 6 hours. Adenosine diphosphate (ADP) induced platelet aggregation was measured at baseline, after shock, immediately postresuscitation and 6 hours later. Souble markers of in-vivo platelet activation (TGF-B and sP-Selectin) as well endothelial injury (sICAM-1, sVCAM-1) were measured by ELISA. Thromboelastography (TEG) was used to measure clotting.
RESULTS: After shock, VPA treated animals had significantly higher adenosine-diphosphate induced platelet aggregation (71.43U vs 62.70U, p¼0.04). This was associated with a reduction in platelet activation markers TGF-B (1536pg/ml vs 1921pg/ml, p¼0.01) and soluble P-Selectin (7.97ng/ml vs 9.40ng/ml, p¼0.01), as well as increased TEG-measured clot strength. Shedding of the endothelial glycocalyx as measured by Syndecan-1 was also significantly attenuated. In-vivo thrombin generation as measured by prothrombin fragment 1+2 was lower in the TBI/shock+VPA group (148ng/ml vs 289ng/ml, p<0.01) as was activation of the protein C system. No difference in markers of complement and sympatho-adrenal activation was observed.
attenuate platelet activation.
dysfunction
through
reduced
RESULTS: ADP-induced platelet aggregation was significantly higher in the FFP group following resuscitation (54.20U vs 46.05U, p¼0.04), which was sustained over the observation period. This was associated with an attenuation of endothelial activation with an early drop in VCAM-1 (1.25ng/ml vs 3.87ng/ml, p¼0.05), and late decrease in ICAM-1 (21.0ng/ml vs 24.4ng/ml, p¼0.05). In-vivo platelet activation as measured by TGF-B was higher in the FFP group (2138pg/ml vs 1801pg/ml, p¼0.03). TEG confirmed increased clot strength in the FFP group at both of the postresuscitation time points. CONCLUSIONS: In this model, resuscitation with FFP resulted in an immediate and sustained improvement in platelet function and clot strength, with an associated decrease in endothelial activation. Valproic acid attenuates platelet dysfunction, endothelial glycocalyx shedding and protein C activation in a porcine model of traumatic brain injury and shock Martin Sillesen, MD, Per I Johansson, MD, Lars S Rasmussen, MD, PhD, Guang Jin, MD, PhD, Cecilie H Jepsen, MD, Ayesha Imam, MD, John O Hwabejire, MD, MPH, George Velmahos, MD, PhD, FACS, Marc A deMoya, MD, FACS, Hasan B Alam, MD, FACS Massachusetts General Hospital, Boston, MA INTRODUCTION: Treatment with valproic acid (VPA) has been shown to improve outcomes after traumatic brain injury (TBI) and shock, but its effect on trauma-induced coagulopathy remain unknown. We hypothesize that VPA attenuates coagulation and endothelial dysfunction following TBI and shock. METHODS: 36 swine were allocated to either TBI and shock (n¼27, TBI and volume-controlled 40% hemorrhage) or TBI/ Shock+VPA (n¼9). Animals were left hypotensive (mean arterial pressure of 35mmHg) for 2 hours. In the TBI/shock+VPA group, a VPA infusion of 100mg/kg/hour was started 1 hour into shock. Following shock, blood samples were analyzed for markers of coagulation and platelet activation, natural anticoagulation, endothelial activation/glycocalyx shedding, complement/ sympatho-adrenal activation. Coagulation function was measured
CONCLUSIONS: Treatment with VPA attenuated platelet dysfunction and improved clot strength. This was associated with a reduction in platelet activation, thrombin generation and protein C system activation. Furthermore, shedding of the endothelial glycocalyx was attenuated. Obese patients are at increased risk for venous thromboembolism in trauma David A Hampton, MD, Belinda H McCully, PhD, Tim H Lee, MD, Matthew Kutcher, MD, Britt J Redick, BA, Jeanette Podbielski, BS, Timothy Welch, Mitchell J Cohen, MD, FACS, Bryan A Cotton, MD, FACS, Martin A Schreiber, MD, FACS Oregon Health & Science University, Portland, OR INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of late mortality in trauma patients. Elevated BMI is associated with a hypercoagulable state. We hypothesized that obese trauma patients would be hypercoagulable at admission as measured by rapid thrombelastography (r-TEG) and have a higher incidence of VTE compared to lean patients. METHODS: Prospective observational data from three Level-I trauma centers were collected. Patient demographics, admission vital signs, and VTE data were recorded. rTEG data were obtained during the first five days of admission. Data were matched by BMI (lean:25 kg/m2 and obese:>30 kg/m2). Mann-Whitney U and chi-square tests were utilized to assess significance. RESULTS: The study population consisted of 479 trauma patients: lean (n¼281) and obese (n¼198). Obese patients demonstrated a higher TEG-alpha (74o IQR [77,69] versus 73o IQR [76,68], p<0.03) and larger TEG-MA (64mm IQR [68,61] versus 62mm IQR (66,58), p<0.01) than the lean group. Obese patients were more likely to develop DVT (9% versus 3%, p<0.01). There were no differences in PE (4% versus 1%, p¼NS). CONCLUSIONS: Obese patients are more likely to be hypercoagulable after trauma and they have a higher incidence of DVTs. Compared to lean trauma patients, increased attention to prophylaxis and monitoring TEG parameters should be considered.
Surgical Forum Abstracts
S51
endthelial
by thrombelastography (TEG) and platelet function was assessed using platelet aggregometry.
METHODS: Multisystem trauma (traumatic brain injury, grade IV liver injury, rib fracture and soft tissue injury) with concurrent hemorrhagic shock (40% of blood volume) was produced in 12 swine. Animals were left in shock (mean arterial pressure of 35mmHg) for 2 hrs followed by resuscitation with either 0.9% normal saline (NS, n¼6; volume¼3x shed blood) or FFP (n¼6; volume¼1x shed blood), and monitored for 6 hours. Adenosine diphosphate (ADP) induced platelet aggregation was measured at baseline, after shock, immediately postresuscitation and 6 hours later. Souble markers of in-vivo platelet activation (TGF-B and sP-Selectin) as well endothelial injury (sICAM-1, sVCAM-1) were measured by ELISA. Thromboelastography (TEG) was used to measure clotting.
RESULTS: After shock, VPA treated animals had significantly higher adenosine-diphosphate induced platelet aggregation (71.43U vs 62.70U, p¼0.04). This was associated with a reduction in platelet activation markers TGF-B (1536pg/ml vs 1921pg/ml, p¼0.01) and soluble P-Selectin (7.97ng/ml vs 9.40ng/ml, p¼0.01), as well as increased TEG-measured clot strength. Shedding of the endothelial glycocalyx as measured by Syndecan-1 was also significantly attenuated. In-vivo thrombin generation as measured by prothrombin fragment 1+2 was lower in the TBI/shock+VPA group (148ng/ml vs 289ng/ml, p<0.01) as was activation of the protein C system. No difference in markers of complement and sympatho-adrenal activation was observed.
attenuate platelet activation.
dysfunction
through
reduced
RESULTS: ADP-induced platelet aggregation was significantly higher in the FFP group following resuscitation (54.20U vs 46.05U, p¼0.04), which was sustained over the observation period. This was associated with an attenuation of endothelial activation with an early drop in VCAM-1 (1.25ng/ml vs 3.87ng/ml, p¼0.05), and late decrease in ICAM-1 (21.0ng/ml vs 24.4ng/ml, p¼0.05). In-vivo platelet activation as measured by TGF-B was higher in the FFP group (2138pg/ml vs 1801pg/ml, p¼0.03). TEG confirmed increased clot strength in the FFP group at both of the postresuscitation time points. CONCLUSIONS: In this model, resuscitation with FFP resulted in an immediate and sustained improvement in platelet function and clot strength, with an associated decrease in endothelial activation. Valproic acid attenuates platelet dysfunction, endothelial glycocalyx shedding and protein C activation in a porcine model of traumatic brain injury and shock Martin Sillesen, MD, Per I Johansson, MD, Lars S Rasmussen, MD, PhD, Guang Jin, MD, PhD, Cecilie H Jepsen, MD, Ayesha Imam, MD, John O Hwabejire, MD, MPH, George Velmahos, MD, PhD, FACS, Marc A deMoya, MD, FACS, Hasan B Alam, MD, FACS Massachusetts General Hospital, Boston, MA INTRODUCTION: Treatment with valproic acid (VPA) has been shown to improve outcomes after traumatic brain injury (TBI) and shock, but its effect on trauma-induced coagulopathy remain unknown. We hypothesize that VPA attenuates coagulation and endothelial dysfunction following TBI and shock. METHODS: 36 swine were allocated to either TBI and shock (n¼27, TBI and volume-controlled 40% hemorrhage) or TBI/ Shock+VPA (n¼9). Animals were left hypotensive (mean arterial pressure of 35mmHg) for 2 hours. In the TBI/shock+VPA group, a VPA infusion of 100mg/kg/hour was started 1 hour into shock. Following shock, blood samples were analyzed for markers of coagulation and platelet activation, natural anticoagulation, endothelial activation/glycocalyx shedding, complement/ sympatho-adrenal activation. Coagulation function was measured
CONCLUSIONS: Treatment with VPA attenuated platelet dysfunction and improved clot strength. This was associated with a reduction in platelet activation, thrombin generation and protein C system activation. Furthermore, shedding of the endothelial glycocalyx was attenuated. Obese patients are at increased risk for venous thromboembolism in trauma David A Hampton, MD, Belinda H McCully, PhD, Tim H Lee, MD, Matthew Kutcher, MD, Britt J Redick, BA, Jeanette Podbielski, BS, Timothy Welch, Mitchell J Cohen, MD, FACS, Bryan A Cotton, MD, FACS, Martin A Schreiber, MD, FACS Oregon Health & Science University, Portland, OR INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of late mortality in trauma patients. Elevated BMI is associated with a hypercoagulable state. We hypothesized that obese trauma patients would be hypercoagulable at admission as measured by rapid thrombelastography (r-TEG) and have a higher incidence of VTE compared to lean patients. METHODS: Prospective observational data from three Level-I trauma centers were collected. Patient demographics, admission vital signs, and VTE data were recorded. rTEG data were obtained during the first five days of admission. Data were matched by BMI (lean:25 kg/m2 and obese:>30 kg/m2). Mann-Whitney U and chi-square tests were utilized to assess significance. RESULTS: The study population consisted of 479 trauma patients: lean (n¼281) and obese (n¼198). Obese patients demonstrated a higher TEG-alpha (74o IQR [77,69] versus 73o IQR [76,68], p<0.03) and larger TEG-MA (64mm IQR [68,61] versus 62mm IQR (66,58), p<0.01) than the lean group. Obese patients were more likely to develop DVT (9% versus 3%, p<0.01). There were no differences in PE (4% versus 1%, p¼NS). CONCLUSIONS: Obese patients are more likely to be hypercoagulable after trauma and they have a higher incidence of DVTs. Compared to lean trauma patients, increased attention to prophylaxis and monitoring TEG parameters should be considered.