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Acetaminophen (Ace) and meloxicam (Mel) are the two types of analgesic and antipyretic medications. This study investigated the dose responses of acetaminophen and meloxicam on platelet aggregation and coagulation function in human blood samples. Blood samples were collected from six healthy humans and processed to make platelet-adjusted (100T103 cells/ml) blood samples. Acetaminophen (Tylenol, Q-PAP, 100 mg/ml) was added at the doses of 0mg/ml (control), 214mg/ml (the standard dose, 1T), 4T, 8T, 10T, 12T, 16T, and 20T. Similarly, meloxicam (Metacam, 5 mg/ml) was added at doses of 0mg/ml (control), 2.85mg/ml (the standard dose, 1T), 4T, 8T, 10T, 12T, 16T, and 20T. Fifteen minutes after the addition of acetaminophen and/or meloxicam, platelet aggregation was stimulated with collagen (2mg/ml) or arachidonic acid (0.5 mmol/l) and assessed using a Chrono-Log 700 aggregometer. Coagulation function was assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), and using Rotem thrombelastogram. A robust inhibition by acetaminophen and/or meloxicam was observed in arachidonic acid-stimulated platelet aggregation starting at 1T dose. Collagen-stimulated platelet aggregation was inhibited by ACE starting at 1T (78W10% of control), and by meloxicam starting at 4T (72W5% of control, both P0.05). The inhibitions by acetaminophen and meloxicam combined were similar to those by acetaminophen or meloxicam. aPTT was prolonged by meloxicam starting at 4T. No changes were observed in PT or any of Rotem measurements by acetaminophen and/or meloxicam. Acetaminophen and meloxicam compromised platelet aggregation and aPTT. Further effort is warranted to characterize the effects of acetaminophen and meloxicam on bleeding in vivo., Published in Blood Coagulation and Fibrinolysis, v25 n8 p831-837, 2014. Prepared in collaboration with Rice University, Houston, TX.

Background: Ongoing improvements in trauma care now recommend earlier use of blood products as part of damage control resuscitation, but generally these products are not available at far forward battlefield locations. For the military, questions continue to arise regarding efficacy of normal saline (NS) vs. lactated Ringer s (LR). Thus, this study compared the effects of LR and NS after severe hemorrhage in pigs. Methods: 20 anesthetized pigs were randomized into control (n = 6), LR (n = 7), and NS (n = 7) groups. Hemorrhage of 60% estimated total blood volume was induced in LR and NS groups by removing blood from the left femoral artery using a computer-controlled pump. Afterwards, the pigs were resuscitated with either LR at 3 times the bled volume or the volume of NS to reach the same mean arterial pressure (MAP) as in LR group. Hemodynamics were measured hourly and blood samples were taken at baseline (BL), 15 min, 3 h and 6 h after resuscitation to measure changes in coagulation using thrombelastograph . Results: MAP was decreased by hemorrhage but returned to BL within 1 h after resuscitation with LR (119 7 ml/kg) or NS (183 9 ml/kg, p 0.05). Base excess (BE) was decreased by hemorrhage; resuscitation with LR recovered BE but not with NS. Total peripheral resistance was decreased with NS and LR, with a larger drop shown in NS. Serum potassium was increased with NS, but not affected with LR. Coagulation changes were similar between LR and NS. Conclusions: NS may be inferior to LR in resuscitation due to its vasodilator effects and the risks of metabolic acidosis and hyperkalemia., Published in the Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, v21 n86, 11 Dec 2013.

We sincerely appreciate the interest in and comment from Drs. Vico, Dubost, and Merat regarding our article of Comparisons of lactated Ringer s and Hextend resuscitation on hemodynamics and coagulation following femur injury and severe hemorrhage in pigs published in the Journal of Trauma and Acute Care Surgery. In our article, we reported that Hextend was effective in restoring hemodynamics and acid-base status with one-third volume of lactated Ringer s solution. However, this advantage was associated with undesired effects on coagulation possibly owing to greater and sustained hemodilution from Hextend resuscitation. Vico et al. reported that the French army uses HyperHES (a colloid and 7.5% saline) and suggested that HyperHES has the potential to be more effective in treating hypovolemic shock. We agree with their comments, since the effects on volume expansion have been reported in a large body of literature with 7.5% hypertonic saline as well as hypertonic saline with colloids such as dextran and hydroxyethyl starch.1Y4 However, we are unaware of studies evaluating the effects of HyperHES on coagulation after hemorrhagic shock. With well-documented effects of large molecular weight hydroxyethyl starch on coagulation and the findings of prolonged compromise in coagulation function from Hextend resuscitation in our study and by others in our group,5,6 additional research effort is warranted to determine the effects of HyperHES on hemostasis under trauma and hemorrhagic shock. Perhaps, the lower molecular weight starch of HyperHES may have less effect on coagulation, but this will require confirmation. In addition, only 3% and 5% hypertonic saline solutions are approved by the US Food and Drug Administration, and HyperHES is not an approved product available in United States., Published in the Journal of Trauma and Acute Care Surgery, v75 n2 p349, 2013.

BACKGROUND: This study compared coagulation function after resuscitation with Hextend and lactated Ringer s (LR) solution in pigs with tissue injury and hemorrhagic shock. METHODS: Pigs were randomized into control (n = 7 each), LR, and Hextend groups. Femur fracture was induced using the captive bolt stunner at midshaft of the pigs left legs, followed by hemorrhage of 60% total blood volume and resuscitation with either Hextend (equal to bled volume) or LR to reach the same mean arterial pressure. Pigs in the control group were not bled or resuscitated. Hemodynamics was monitored hourly for 6 hours. Blood samples were taken at baseline (BL), after hemorrhage, 15 minutes, 3 hours, and 6 hours after resuscitation for blood and coagulation measurements. RESULTS: Mean arterial pressure decreased to 50% of BL by the 60% hemorrhage but returned to near BL within 1 hour after LR or Hextend resuscitation. Heart rate was increased (from 91 +/- 4 beats per minute to 214 +/- 20 beats per minute) by hemorrhage and decreased after resuscitation but remained elevated above BL in both groups. Resuscitation with Hextend (42 mL/kg) or LR (118 +/- 3 mL/kg) reduced hematocrit, total protein, fibrinogen, and platelet counts, with greater decreases shown in the Hextend group. Clot strength was lower but returned to BL by 3 hours in the LR group, whereas it remained reduced for the 6-hour period after Hextend. The overall clotting capacity after LR was decreased after hemorrhage and resuscitation but returned to BL by 3 hours, whereas it remained low after Hextend for the 6-hour experiment period. CONCLUSION: After traumatic hemorrhage, coagulation function was restored within 6 hours with LR resuscitation but not with Hextend., Published in the Journal of Trauma and Acute Care Surgery, v74 n3 p732-740, 2013.

BACKGROUND: Hemorrhagic shock contributes to coagulopathy after trauma. We investigated daily changes of coagulation components and coagulation function for 5 days in hemorrhaged and resuscitated pigs. METHODS: Fourteen pigs were randomized into the sham control (C) and the hemorrhage and lactated Ringer s resuscitation (H-LR) groups. On day 1, hemorrhage was induced in the H-LR group by bleeding 35% of the total blood volume, followed by LR resuscitation at three times the bled volume. Pigs in the C group were not hemorrhaged or resuscitated. Hemodynamics and coagulation were measured daily after H-LR on day 1 to day 5. RESULTS: No changes in hemodynamics and coagulation function occurred in C. Hemorrhage decreased mean arterial pressure and increased heart rate. LR resuscitation corrected these changes within 2 hours. Compared with the baseline values (BL) on day 1, fibrinogen levels were decreased to 76% T 6% by H-LR on day 1, increased to 217% T 16% on day 2, and remained increased thereafter; platelet counts were decreased to 63% T 5% by H-LR on day 1 and remained lower on days 2 and 3 but returned to BL by days 4 and 5 (all p G 0.05). Thrombin generation was decreased by H-LR on days 1 and 2 but then increased to above BL on days 4 and 5. Coagulation factor levels were decreased by H-LR on day 1 but returned to BL on day 3 except for factor XIII. Clot strength was decreased by H-LR on day 1 and returned to BL by day 2. Clot rapidity did not change on day 1 but was decreased on days 2 and 3 and returned to BL on days 4 and 5. CONCLUSION: Hemorrhage and resuscitation reduced coagulation components and compromised coagulation function, which showed different recovery profiles over the 5-day study period., Published in the Journal of Trauma and Acute Care Surgery, v73 n3 p640-647, 6 Jun 2012.

This study's objective was to investigate the daily dynamics of fibrinogen metabolism and coagulation function for 5 days after hemorrhagic shock in pigs. Sixteen pigs were randomized into the control (C) and the hemorrhage (H) groups. On day 1, hemorrhage was induced in H by bleeding 35% of the estimated total blood volume, followed by resuscitation with lactated Ringer's solution at three times the bled volume. Then, a primed constant infusion of stable isotopes was performed in both groups daily for 5 days to measure changes in fibrinogen metabolism, together with changes in hemodynamics and coagulation function. Hemorrhage caused a decrease in mean arterial pressure and an increase in heart rate. Fluid resuscitation corrected these changes. Compared with baseline day 1, fibrinogen levels in H were decreased to 76% +/- 6% by hemorrhage and resuscitation on day 1, increased to 217% +/- 16% on day 2, and remained elevated afterward; clot strength in H was decreased by hemorrhage on day 1 and returned to baseline values on day 2 and afterward. Compared with day 1 control value (1.3 +/- 0.1 mg/kg per hour), fibrinogen synthesis in H was increased to 3.6 +/- 0.1, 5.1 +/- 0.5, 2.6 +/- 0.4, 2.7 +/- 0.5, and 2.3 +/- 0.3 mg/kg per hour on days 1 through 5 (all P 0.05); fibrinogen breakdown in H was elevated on days 1 and 2 but returned to control values afterward. Hemorrhage caused acute decreases in fibrinogen concentration and clot strength, followed by an increase in fibrinogen concentration and recovery of clot strength. The increase in fibrinogen appeared primarily due to a sustained increase in fibrinogen synthesis., Published in Shock, v37 n6 p605-610, 2012.

Background: Hemorrhagic shock and trauma are associated with acidosis and altered coagulation. A fall in pH has been reported to attenuate the activity of recombinant activated Factor VII (rFVIIa) in vitro. However, it is not known if acidosis induced by hemorrhagic shock or infusion of HCl attenuates FVIIa activity in vivo. The purpose of this study was to determine if acidosis, induced by two methods, affects recombinant FVIIa (rFVIIa) activity in swine, and if correction of the pH restores rFVIIa activity to normal. Methods: Acidosis was induce in anesthetized swine in two separate models: 1) HCl infusion (n=10) and 2) hemorrhage/hypoventilation (n=8). Three groups per model were used: Control (pH7.4), Acidosis (arterial pH7.1) and Acidosis-Corrected (bicarbonate infusion to return pH from 7.1 to 7.4). Pigs were then injected with rFVIIa (micro g/kg) or vehicle (saline) at target pH and arterial blood samples were taken for measurement of coagulation function, including Thromboelastography -TEG, Thrombin Generation Activated Clotting Time, Prothrombin Time, activated Partial Thromboplastin Time, Fibrinogen Concentration and Platelet count before and 5min after injection of rFVIIa. Results: Acidosis led to a hypocoagulation as measured by almost all coagulation parameters in both models. Furthermore, the change in coagulation function produced after infusion of rFVIIa was not different between control, acidosis and acidosis-corrected groups for all coagulation parameters measured. Conclusion: Acidosis associated with hemorrhagic shock or HCl infusion led to a hypocoagulation that was not corrected with bicarbonate infusion. Furthermore, acidosis did not affect rFVIIa function and correction of the acidosis with bicarbonate had no effect on rFVIIa function in these models. This suggests that in vivo acidosis did not diminish rFVIIa function., Published in the International Journal of Burn Trauma, v2 n3 p145-157, 15 Dec 2012.

Hemorrhagic coagulopathy (without neurological injuries) constitutes 40% of injury-related death in civilian hospitals and on the battlefield, and the underlying contributing mechanisms remain unclear. The purpose of this study is to investigate the effects of fibrinogen availability on coagulation function after hemorrhage in pigs. Sixteen crossbred commercial Yorkshire swine were randomized into the control group (group C) (n = 8) and hemorrhage group (group H) (n = 8). Hemorrhage was induced in group H by bleeding 35% of the estimated total blood volume, followed by resuscitation with lactated Ringer solution at three times the bled volume. Pigs in group C were not hemorrhaged or resuscitated. Blood samples were withdrawn at baseline, 15 min, 3 h, 6 h, and 24 h after hemorrhage and lactated Ringer (LR) resuscitation (H LR). Coagulation was assessed by using thrombelastography. All baseline measurements were similar between groups C and H. Hemorrhage caused a decrease in mean arterial pressure and an increase in heart rate in group H, but LR resuscitation corrected these changes within 1 h. Compared to baseline values, fibrinogen concentrations in group H decreased at 15 min, 3 h and 6 h after H LR, but increased to double that of the baseline value at 24 h; platelet counts decreased throughout the study; clot strength was decreased at 15 min, 3 h and 6 h, but returned to baseline value at 24 h after H LR. Hemorrhage caused decreases in fibrinogen and platelets, and compromised clot strength. The rebound of fibrinogen at 24 h restored clot strength despite platelet deficit. These data suggest the potential compensatory role of fibrinogen in restoring coagulation function in vivo after hemorrhagic shock., Published in Molecular Medicine, v17 n7-8 p757-761, Jul-Aug 2011.

Background: To treat the coagulopathy of trauma, some have suggested early and aggressive use of cryoprecipitate as a source of fibrinogen. Our objective was to determine whether increased ratios of fibrinogen to red blood cells (RBCs) decreased mortality in combat casualties requiring massive transfusion. Methods: We performed a retrospective chart review of 252 patients at a U.S. Army combat support hospital who received a massive transfusion (>10 units of RBCs in 24 hours). The typical amount of fibrinogen within each blood product was used to calculate the fibrinogen-to-RBC (F:R) ratio transfused for each patient. Two groups of patients who received either a low (<0.2 g fibrinogen/RBC Unit) or high (>0.2 g fibrinogen/RBC Unit) F:R ratio were identified. Mortality rates and the cause of death were compared between these groups, and logistic regression was used to determine if the F:R ratio was independently associated with survival. Conclusions: In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. Prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion., Pub. in The Journal of Trauma: Injury, Infection, and Critical Care, v64 n2 pS79-S85, Feb Supplement 2008.