Accepted Manuscript Fibrinogen and Prothrombin Complex Concentrate in Trauma Coagulopathy Matthew Hannon, MD, Jacob Quail, MD, Matthew Johnson, DVM, Cara Pugliese, DVM, Kejian Chen, MD, PhD, Heidi Shorter, Robert Riffenburgh, PhD, Ronald Jackson, PhD PII:

S0022-4804(15)00281-4

DOI:

10.1016/j.jss.2015.03.013

Reference:

YJSRE 13192

To appear in:

Journal of Surgical Research

Received Date: 3 October 2014 Revised Date:

16 January 2015

Accepted Date: 10 March 2015

Please cite this article as: Hannon M, Quail J, Johnson M, Pugliese C, Chen K, Shorter H, Riffenburgh R, Jackson R, Fibrinogen and Prothrombin Complex Concentrate in Trauma Coagulopathy, Journal of Surgical Research (2015), doi: 10.1016/j.jss.2015.03.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Fibrinogen and Prothrombin Complex Concentrate in Trauma Coagulopathy

Matthew Hannona, MD (Corresponding author. E-mail: [email protected], [email protected]) Jacob Quaila, MD

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Matthew Johnsonb, DVM

Kejian Chenb, MD, PhD Heidi Shorterb Robert Riffenburghb, PhD Ronald Jacksonb, PhD

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a. Department of General Surgery Naval Medical Center San Diego 34730 Bob Wilson Drive Building 3, 4th floor San Diego, CA 92134

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Cara Puglieseb, DVM

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b. Clinical Investigation Department Naval Medical Center 34730 Bob Wilson Drive Building 1, ground floor San Diego, CA 92134

Author contribution: M.H., C.P., K.J. and R.J. conceived and designed the study. M.H. and R.J. obtained funding. K.J. and H.S. collected data. M.H., J.Q., M.J., R.R. and R.J. analyzed and interpreted the data. M.H. and J.Q. wrote the article. M.H., J.Q. and M.J. critically reviewed the article. The views expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the U.S. Government.

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ABSTRACT Background: Coagulopathy after injury contributes to hemorrhage and death. Treatment with specific coagulation factors could decrease hemorrhage and mortality. Our aim was to compare fibrinogen and

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prothrombin complex concentrate (PCC) in a rabbit model of hemorrhagic shock.

Materials and Methods: New Zealand White rabbits were anesthetized. Blood was withdrawn to a mean arterial pressure (MAP) of 30 to 40 mmHg for 30 minutes. Animals were resuscitated with Lactated

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Ringers (LR) to a MAP of 50 to 60 mmHg and randomized to receive fibrinogen 100 mg/kg, PCC 25 IU/kg or LR. A liver injury was created. A MAP of 50 to 60 mmHg was maintained for 60 minutes. Primary

measured by plasma based tests.

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outcome was blood loss and secondary outcomes were fluid administered and coagulopathy as

Results: There are eight animals in each group. Median blood loss was significantly higher in the fibrinogen group, at 122 ml (95% CI 75-194), when compared to the control group, 35 ml (95% CI 23-46)

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(p-value=0.001), and the PCC group, 26 ml (95% CI 4-54) (p-value=0.002. Resuscitation fluid requirement was highest in the fibrinogen group, at 374 ml (95% CI 274-519) and lowest in the PCC group, at 238 ml

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(95% CI 212-309) (p=0.01). Plasma based coagulation tests were not different between groups. Conclusion: In a rabbit model, PCC did not have a significant effect on blood loss. Fibrinogen increased

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blood loss and fluid requirements.

Keywords: prothrombin complex concentrate; fibrinogen; trauma coagulopathy; hemorrhagic shock; animal model.

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1. Introduction Hemorrhage is a leading cause of death in civilian trauma.1 In military trauma, hemorrhage has also been shown to be the most common cause of death in potentially survivable injuries.2 Coagulopathy

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after traumatic injury is a significant factor in blood loss. Coagulopathy is present early after injury and is associated with increased mortality.3, 4 The etiology of trauma associated coagulopathy is complex and multifactorial. Consumption of coagulation factors, dilution from administration of fluids, hypothermia,

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shock and acidosis all play a role.5 It has also been postulated that hypoperfusion leads to increased activation of the anticoagulant protein C through the thrombin-thrombomodulin pathway.6

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Hypoperfusion also results in a decrease in plasminogen activator inhibitor-1, increasing tissue plasminogen activator and resulting in hyperfibrinolysis. These findings and other efforts to elucidate the specific coagulation defects causing acute traumatic coagulopathy, would allow resuscitation to focus on correcting these defects.

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Fibrinogen has been shown to be one of the first coagulation factors to fall below critical levels with major blood loss.7 Fries et al8 showed in a porcine model of hemodilution and liver injury, that treatment with fibrinogen resulted in normalization of clot formation and decreased blood loss compared to

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controls. In trauma patients with evidence of hypoperfusion, there is also a significant decrease in activity level in factors II, VII, IX, X and XI early after admission.9 Prothrombin complex concentrate

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(PCC), containing factors II, VII, IX and X, should correct this deficiency. This has been shown to be the case in a porcine model, where administration of PCC resulted in normalization of the prothrombin time and decreased blood loss.10 We speculated that administration of fibrinogen would be as effective as PCC in controlling bleeding and correcting coagulopathy in a rabbit model of hemorrhagic shock and liver injury. 2. Materials and Methods

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This study was reviewed and approved by the Institutional Animal Care and Use Committee of Naval Medical Center San Diego. New Zealand White female rabbits in this study were purchased specific pathogen free (Pasteurella multocida) from a United States Department of Agriculture licensed vendor.

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They were housed and studied in an Association for Assessment and Accreditation of Laboratory Animal Care International accredited facility maintained on a 12:12-hour light:dark cycle. All animals were housed in stainless steel, solid floor rabbit caging and maintained on standard laboratory diet (Harlan,

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Sacramento, CA) and reverse osmosis purified drinking water. After an overnight fast, rabbits 2.9 to 4.0 kg in weight were anesthetized with an intramuscular injection of ketamine 39-46 mg/kg. A size 1.5

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pediatric laryngeal mask airway was placed and general anesthesia was maintained with isoflurane. A 4 cm scalpel incision was performed in the right jugular furrow with subsequent blunt dissection to the depth of the carotid sheath. The carotid artery was exposed and a 20 gauge catheter was placed in the carotid artery for blood pressure monitoring and blood withdrawal. Two 2-0 silk sutures were placed

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around the artery to secure the catheter. A second incision was performed on the opposite side in a similar fashion and a 20 gauge venous catheter was inserted and secured in the internal jugular vein for infusion of fluids and medication. Mean arterial blood pressure, oxygen saturation, and heart rate were

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monitored and recorded every five minutes. After stabilization, blood was withdrawn until a mean arterial pressure (MAP) of 30 to 40 mm Hg was achieved. After a 30 minute hypotensive period, animals

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were resuscitated with Lactated Ringers (LR) solution to a MAP of 50 to 60 mmHg. Animals were prerandomized to the control group or one of two treatment groups. Treatment groups received fibrinogen (RiaSTAP ®, CSL Behring GmBH, Marburg, Germany) at a dose of 100 mg/kg or PCC (Profilnine® SD, Grifols Biologicals Inc, Los Angeles, CA) at 25 IU/kg. The control group received only LR. Animals in the fibrinogen and PCC groups received the drug in 20 ml of LR as part of the resuscitation phase. This was also included in the total volume of resuscitation fluid for these animals. A laparotomy was performed with scalpel incision and a standardized 15 mm left medial lobe hepatectomy injury was created. The

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abdomen was closed with surgical staples. Animals were maintained with a MAP of 50 to 60 mmHg for an additional 60 minutes. Animals surviving to 60 minutes post drug infusion were humanely euthanized with a lethal injection of sodium pentobarbital (0.28-0.30 ml/kg). The abdomen was then re-opened and

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all blood and blood clot was removed with pre-weighed gauze pads. The amount of blood loss was then determined by the weight of blood and clot evacuated from the abdomen. Four milliliters of blood was withdrawn for analysis at five time points throughout the experiment: (1) at the beginning of the

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experiment after induction of anesthesia and stabilization, (2) after the 30 minute hypotensive period, (3) after resuscitation and (4) 30 and (5) 60 minutes after drug infusion. The total blood loss does not

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include the amount withdrawn for laboratory studies. Prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR) and fibrinogen tests were performed on a Stago Evolution® (Diagnostica Stago, Inc, U.S.). Complete blood counts were performed using a Sysmex XE5000™ (Sysmex Corporation, Japan). Blood tests for pH, PCO2, HCO3, PO2 and base excess were

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performed on an i-STAT® machine (Abbott Laboratories, Abbott Park, IL). Our primary outcome was blood loss and secondary outcomes were fluid administered and coagulopathy as measured by plasma based laboratory values.

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2.1 Statistical Analysis

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Based on data from previously published studies in porcine models, we estimated that blood loss would be 20 to 40 mls per animal. Using an alpha = 0.05 and power = 0.80 we calculated a requirement for 11 rabbits per group to detect a 10% difference in blood loss among groups. The rank-sum test with Bonferroni adjustment was used to compare blood loss and fluid given among the three groups. Thus a p-value of < 0.017 was required for significance. A two way repeated measures analysis of variance was used to compare hemoglobin, hematocrit and platelets among groups over time. A Wilcoxon signed rank test was used to compare PT, PTT and INR over time.

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3. Results There are eight animals in each group that survived the entire 60 minute experiment. One animal in the

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fibrinogen group expired 42 minutes into the experiment and was not included in the analysis. At baseline, the median MAP did not differ between groups. In the control group MAP was 60.0 mmHg (95% CI 47.8-66.7), in the fibrinogen group MAP was 57.5 mmHg (95% CI 40.1-70.5) and in the PCC group MAP was 60.5 mmHg (95% CI 53.0-66.6) (p-value=0.7). Median animal weights at baseline were

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not different between groups. The median weight in the control group was 3.65 kg (95% CI 3.07-3.95), the fibrinogen group was 3.56 kg (95% CI 3.10-3.70) and in the PCC group 3.57 kg (95% CI 3.09-3.86) (p-

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value=0.7). Table 1 shows median resuscitation fluid requirements and blood loss both as the total volume per animal as well as the volume per kilogram of body weight. As seen in table 1, median blood loss was highest in the fibrinogen group, at 122 ml (95% CI 75-194), intermediate in the control group, at 35 ml (95% CI 23-46) and lowest in the PCC group at 26 ml (95% CI 4-54) . Pair wise comparison of blood

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loss between the three groups showed that there was a significant difference in blood loss between the fibrinogen group and the control group (p-value=0.001) and the fibrinogen and PCC groups (pvalue=0.002), however there was not a significant difference in blood loss between the control and PCC

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groups (p-value=0.67). Pair wise comparison of blood loss per kilogram of body weight showed that the fibrinogen group still had significantly more blood loss than the control (p-value=0.002) and PCC groups

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(p-value=0.002). However, resuscitation fluid requirement per kilogram of body weight was not significantly different among the three groups. Hemoglobin, hematocrit and platelet values decreased in all groups, as seen in table 2. The fibrinogen level was highest in the group receiving fibrinogen as would be expected. Interestingly, fibrinogen levels were maintained in most of the animals. At the end of the hypotensive and resuscitation phases, only one animal in the control group had a fibrinogen level below 100 mg/dl. With regards to plasma based

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coagulation tests, PTT and PT at baseline were compared to values at subsequent time points and did not change over time. Table 3 shows a comparison of PTT and PT at baseline, at the end of the

therefore, not all animals have a calculated INR reported. 4. Discussion

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resuscitation phase and at the end of the experiment. The measured PT was frequently normal or low

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We found fibrinogen is not an effective hemostatic agent and actually increased blood loss and fluid requirements in a rabbit model of shock and uncontrolled liver hemorrhage. PCC decreased blood loss

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and fluid requirements in our model, but not significantly so. The fact that fibrinogen did not decrease blood loss was surprising to us. There are conflicting reports about fibrinogen levels soon after trauma and hemorrhage; therefore the contribution of fibrinogen to acute coagulopathy is debatable. Some investigators have reported normal fibrinogen levels early after trauma6, while others have shown a decrease early after major hemorrhage or trauma.7, 11 Nonetheless, treatment with fibrinogen in porcine

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models of dilutional coagulopathy has been shown to correct coagulopathy and decrease blood loss.8, 12 Guidelines have variably recommended that fibrinogen be replaced in trauma patients when plasma levels are below 80 to 100 mg/dl 13 or 150 to 200 mg/dl.14 Fibrinogen levels in the animals in our

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experiment decreased, but in most animals they were still above 100 mg/dl, so perhaps fibrinogen

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deficiency was not the most critical coagulation defect. One possible explanation for our results is that fibrinogen may have had an anticoagulant effect. It is known that fibrinogen can increase plasmin generation.15 It is possible that in coagulopathic animals receiving only fibrinogen, fibrinolysis was stimulated, thus increasing blood loss. Fibrinogen is also known to stimulate the production of inflammatory cytokines. Both fibrin and fibrinogen have been shown to increase production of IL-6, TNF-α 16 and IL-1 β 17 from human mononuclear cells. The inflammatory cytokines IL-6 and TNF have been shown to activate coagulation and fibrinolysis in

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human18 and animal19 models of endotoxemia. Conceivably, after trauma, fibrinogen stimulated increases in levels of inflammatory cytokines could cause a consumptive coagulopathy and fibrinolysis,

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therefore exacerbating acute trauma coagulopathy. Prothrombin complex concentrate was not as effective at decreasing blood loss in our model as has been previously reported. Use of PCC in a porcine model of dilutional coagulopathy has been shown to reduce time to hemostasis and blood loss.10,20 In this porcine model, coagulopathy was induced by

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dilution with synthetic colloids, whereas in our model we relied on hypoperfusion and dilution with resuscitation fluid. Our model likely did not induce as severe a coagulopathy and therefore replacement

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of clotting factors with PCC did not have as great an effect on hemostasis and blood loss. In our experiments, plasma based tests of coagulopathy such as PT and PTT, did not show a significant change over time. It has been shown that 24.4% of trauma patients will have a coagulopathy on presentation as measured by PT, PTT or thrombin time.4 However, in a rabbit model of coagulopathy

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and uncontrolled bleeding from a splenic injury, bleeding time and thromboelastography (TEG) predicted lethal hemorrhage better than PT.21 Similarly, in a swine model of hypothermia and hemorrhage induced coagulopathy, activated clotting time and TEG were better at detecting

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coagulation abnormalities than PT and PTT.22 In our study, 30 minutes of hypotension followed by fluid

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resuscitation would result in some degree of coagulopathy, unfortunately we were not able to measure this with plasma based coagulation tests. This study is one of the first to test the hypothesis that fibrinogen alone could correct the coagulopathy of trauma, in direct comparison to PCC in a clinically relevant model of hemorrhagic shock. This study may have been more informative if we had been able to evaluate more elements contributing to coagulopathy, such as measuring coagulation factor levels. In the future we would also like to use

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viscoelastic measures of coagulation, such as TEG, to measure the effectiveness of hemostatic treatments.

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Given that fibrinogen was not effective in this model it raises the question of when fibrinogen would be effective. Using fibrinogen in models inducing less severe or more severe levels of shock and injury may elucidate the proper indication for fibrinogen. Another factor to consider is that we induced

hypotensive shock and then gave fibrinogen before administering a significant amount of intravenous

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fluids. Therefore, animals in this study did not have a significant dilutional coagulopathy until late in the experiment. Also, potential exists that a different animal model could provide better representation of

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the clotting cascade interactions and proportions of factors present in a human and account for differences from previous studies.23, 24 Utilizing other animal models in future studies to account for interspecies differences and their relation to human physiology may elucidate a role for fibrinogen.

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5. Conclusion

Prothrombin complex concentrate did not limit blood loss to a significant degree in a rabbit model of hemorrhagic shock and liver injury. Fibrinogen may increase blood loss and should be used cautiously

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and only to correct known deficits after hemorrhage. Additional clotting factor deficits should also be studied to better determine the role fibrinogen treatment will have in promoting or preventing clotting

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and potentially contributing to coagulopathy. More studies are warranted to fully elucidate the effect of fibrinogen and its interactions in coagulation and fibrinolysis during a massive hemorrhage event in the rabbit model.

Acknowledgements:

Financial support: This work was supported by a grant from the Navy Bureau of Medicine and Surgery Clinical Investigation Program.

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Financial disclosures: The authors have no conflicts to disclose.

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Table 1: Resuscitation Fluid Requirement and Blood Loss

Control Fibrinogen PCC

Number 8 8 8

Total Resuscitation Fluid (ml) median (95% CI) 304 (234-387) 374 (274-519) 238 (212-309)

Resuscitation Fluid (ml/kg) median (95% CI) 82 (62-129) 103 (75-161) 68 ( 56-95)

Blood Loss (ml) median (95% CI) 35 (23-46) 122 (75-194) 26 (4-54)

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PCC-prothrombin complex concentrate, CI-confidence interval .

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Blood Loss (ml/kg) median (95% CI) 9 (6-15) 38 (21-56) 8 (1-6)

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Group

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Table 2: Blood Counts at Baseline and After Liver Injury and Drug Infusion

Hematocrit (%) Platelets 3

(10 / mcl)

Fibrinogen (mg/dl)

Post-injury

median (95% CI)

median (95% CI)

Control

11.5(2.3)

8.2(0.7)

Fibrinogen

12.5(0.5)

4.8(1.4)

PCC

12.1(0.8)

7.8(0.9)

Control

35.0(6.9)

25.6(2.5)

Fibrinogen

37.2(1.7)

15.0(4.2)

PCC

36.6(2.6)

24.2(2.4)

Control

177(22)

Fibrinogen

174(30)

PCC

185(30)

Control Fibrinogen PCC

0.002

0.003

0.8

107(26)

133(34)

117(24)

222(66)

273(64)

183(43)

144(34)

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119(33)

179(51)

PCC-prothrombin complex concentrate, CI-confidence interval.

p-value

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(gm/dl)

Baseline

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Hemoglobin

Group

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Variable

0.0002

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Table 3: Coagulation Values Over Time

PTT (sec)

PT (sec)

Group Control Fibrinogen PCC Control Fibrinogen PCC

Baseline median(95% CI) 67(25-118) 86(51-106) 70(10-82) 10(10-10) 10(10-10) 10(10-11)

Post-resuscitation median(95% CI) 30(23-87) 67(20-107) 58(20-88) 10(10-10) 10(10-11) 10(10-12)

PTT-Partial thromboplastin time; PT-Prothrombin time; sec-seconds

0.05 0.14 0.11 0.09 0.16 0.88

Post-injury median(95% CI) 52(20-120) 98(53-105) 75(20-125) 10(10-32) 10(10-14) 10(10-11)

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PCC- prothrombin complex concentrate; CI-confidence interval

p-value

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Variable

p-value 0.35 0.47 1 0.32 0.1 0.88