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Anesth Analg 2008; 106:1070-1077
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318165dfbb
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CARDIOVASCULAR ANESTHESIOLOGY

Characterization of the Coagulation Deficit in Porcine Dilutional Coagulopathy and Substitution with a Prothrombin Complex Concentrate

Gerhard Dickneite, PhD, Baerbel Doerr, and Franz Kaspereit

From the Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany.

Address correspondence and reprint requests to Prof. Dr. Gerhard Dickneite, CSL Behring GmbH, Pharmacology/Toxicology, Emil von Behring-Straße 76, 35041 Marburg. Address e-mail to Gerhard.Dickneite{at}cslbehring.com.

Abstract

BACKGROUND: In this study, we used a porcine model to investigate whether impaired coagulation and severe arterial or venous bleeding could be normalized by substitution with a prothrombin complex concentrate (PCC), Beriplex P/N, containing coagulation factors II, VII, IX, and X.

METHODS: Dilutional coagulopathy was induced in anesthetized pigs by fractionated blood withdrawal (approximately 65% of total volume), followed by erythrocyte retransfusion and volume substitution with a total of 1000 mL of hydroxyethyl starch (Infukoll 6%). Animals were randomized to no treatment, treatment with placebo, or treatment with 35 U/kg PCC. Arterial (spleen incision) or venous (bone injury) bleeding was inflicted. Thromboelastometry, hematology, and coagulation tests were performed at baseline, after dilution, and after study treatments had been administered and injury inflicted. The primary end-point was postinjury time to hemostasis.

RESULTS: Hemodilution resulted in a decrease in coagulation factor concentrations to approximately 35% and prolonged prothrombin time. Platelet numbers decreased from approximately 400,000 to approximately 100,000/µL, and aggregation and adhesion were impaired. PCC effectively substituted the deficient prothrombin factors (II, VII, IX, and X) and normalized the prolonged prothrombin time. After spleen injury, PCC significantly reduced time to hemostasis versus dilutional control (median, 35 vs 82.5 min; P < 0.0001), and produced a nonsignificant trend towards reduction in blood loss (mean, 275 vs 589 mL). PCC also significantly reduced time to hemostasis (median, 27 vs 97 min; P < 0.0011) and blood loss (mean, 71 vs 589 mL; P < 0.0017) after bone injury.

CONCLUSIONS: Dilutional coagulopathy produced a generalized decrease in coagulation factors and impaired platelet function. Substitution with PCC effectively normalized coagulation and significantly improved hemostasis after venous and arterial bleeding.

Bleeding as a result of an acquired coagulopathy without an underlying genetic disorder can occur in a variety of clinical settings. For example, blood loss after civilian or military trauma, peri- or postoperative hemorrhage, or anticoagulant overdose can impair the coagulation system. In the case of trauma or major operations, the coagulation system becomes activated, whereas dilutional coagulopathy per se is not associated with activation of the coagulation system.

Bleeding can occur either from venous or arterial vessel damage. In severe cases, coagulopathy is associated with major blood loss which needs to be corrected by intravascular volume replacement and/or erythrocyte transfusion. Dilution or consumption of the functional elements of the coagulation system (dilutional coagulopathy) leads to an increased bleeding risk. Besides surgical wound closure, restitution of the patient's impaired hemostatic potential is essential.1

Dilutional coagulopathy affects the enzymes and coenzymes of the coagulation cascade, fibrinogen, and thrombocytes.2 Other factors known to impair coagulation and hemostasis include a decrease in hematocrit, the use of colloids, and hypothermia.3–5 Martini et al.6 demonstrated in a preclinical study that hypothermia caused a delay in thrombin generation. Acidosis, hypothermia, and coagulopathy form the "lethal triad" of trauma, and are predictive of life-threatening coagulopathy in affected patients.7 Activation of the fibrinolytic system may aggravate the situation by the consumption of fibrinogen and fibrin.8

Substitution with coagulation factors and cellular elements such as erythrocytes and platelets is essential to restore hemostatic balance.9 Fresh frozen plasma is widely used to correct coagulopathy, despite limited evidence of its effectiveness in the published literature.10 Based on the efficacy and safety concerns associated with current treatment strategies, the search for more effective options to treat dilutional coagulopathy remains an important clinical challenge. Treatment with a prothrombin complex concentrate (PCC) has demonstrated promising efficacy for anticoagulation reversal,11,12 and the British Committee for Standards in Hematology now recommends PCC as preferential to fresh frozen plasma for reversing anticoagulation in patients with major bleeding.13 Although anticoagulation reversal is a different indication from dilutional coagulopathy, the potential efficacy of PCC for treating dilutional coagulopathy warrants investigation.

Assessment of therapy for dilutional coagulopathy in a clinical setting is difficult; therefore, we used a porcine model to characterize the coagulation deficit and assess the utility of substitution therapy with a PCC (Beriplex P/N, CSL Behring, Marburg, Germany) for improving impaired coagulation and reducing arterial and venous hemorrhage. Beriplex P/N contains the vitamin K-dependent coagulation factors (II [200–480 IU], VII [100–250 IU], IX [200–310 IU] and X [220–600 IU]), as well as the coagulation inhibitors protein C (150–450 IU) and protein S (130–260 IU) (quantities are for one vial of Beriplex P/N 250).14 The product is currently available in several European countries.

METHODS

The study was performed according to German Animal Welfare law and was approved by the appropriate government authorities.

Surgical Preparations
Forty-five pigs were obtained from a local breeding farm. Pigs were fasted overnight but had free access to water. The animals were 3–4-mo-old and weighed 25–35 kg. They were premedicated IM with a mixture of 2 mg/kg azaperone (Stresnil, Janssen), 15 mg/kg ketamine (Ketavet, Pharmacia & Upjohn), and 0.02 mg/kg atropine sulfate (Atropinsulfate, B. Braun). Anesthesia was induced by 10 mg/kg thiopental-sodium via an ear vein. Tracheal intubation was performed, and the pigs' respiration was facilitated using a Heyer Access ventilator. Inhaled anesthesia was maintained by isoflurane (Forane, Abbott) at a concentration of 1%–2%, depending on the status of anesthesia.

A 14-gauge catheter was advanced into the carotid artery for the collection of blood samples, and a 20-gauge catheter was placed into the femoral artery for continuous arterial blood pressure measurements. A 14-gauge catheter was introduced into the external jugular vein for blood withdrawal and administration of erythrocytes, plasma expander, and test substances. Basic fluid requirement was achieved by IV administration of lactated Ringer's solution (4 mL/kg x h). Body temperature was measured by a rectal thermometer.

Experimental Protocol
The study design is shown in Figure 1. After assessing baseline hemodynamic and coagulation values (t = 0), a hypothermic, normotensive dilutional coagulopathy was induced by stepwise withdrawal of 350 mL blood and initial volume replacement with 350 mL of 6% hydroxyethyl starch (HES) (Infukoll 6%, MR 200,000, substitution 0.45–0.55, Schwarz Pharma). For the reinfusion of erythrocytes, blood was centrifuged (800g, 10 min), and erythrocytes were resuspended in NaCl to achieve the initial volume. After resuspension, erythrocytes were centrifuged again, resuspended in lactated Ringer's solution (half of the initial volume, 175 mL) and reinfused into the animal. After withdrawal of about 65%–70% of blood, 650 mL of 6% HES at room temperature was infused IV. Arterial blood pressure was normal after dilutional coagulopathy, and hemodynamic variables were similar in all groups (legend of Fig. 4).


Figure 17
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  		Figure 1. Study design for the porcine model of dilutional coagulopathy. HES, hydroxyethyl starch; PCC, prothrombin complex. Blood samples were taken at baseline (t = 0), after dilution (t = 80 min), and after substitution (t = 120 min). Time to hemostasis and blood loss were measured for 2 h after wounding (until t = 240 min).

 

Figure 47
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  		Figure 4. Time to hemostasis (A; Kaplan–Meier plot) and blood loss (B; box plot) in pigs after spleen incision injury. Mean arterial blood pressure (mm/Hg) at baseline/after substitution was 53.5 ± 5.0/51.4 ± 3.8 (negative control); 53.5 ± 4.2/61.7 ± 8.4 (dilution); 50.9 ± 4.3/55.7 ± 5.0 (PCC). Rectal temperature (°C) at baseline/after substitution was 38.3 ± 0.5/37.1 ± 0.8 (negative control); 38.0 ± 0.8/35.9 ± 1.3 (dilution); 38.2 ± 0.4/36.2 ± 0.7 (PCC). Time is given in minutes postwounding. {diamondsuit} mean, + median, the box represents the 25%–75% quantile.

 

Blood samples were taken again after HES infusion (t = 80 min) and the animal was allowed to stabilize for 35 min. PCC was administered at 115 min, after which the third blood sample was withdrawn (t = 120 min). Assessment of time to hemostasis and blood loss was performed from the time of injury until 120 min postinjury. No blood samples were taken during this period to avoid interfering with the hemostatic process. The prospective primary outcome variable was time to hemostasis, and blood loss was the secondary variable.

For the arterial injury tests, a standardized spleen incision (8 cm length, 1 cm depth) was performed with a scalpel blade. Blood was suctioned out of the abdomen and pooled in a collection jar where the total blood loss was measured. The time to hemostasis was defined as the point in time when blood ceased leaking from the wound. For the venous injury tests, a 3-mm hole was drilled into the neck of the femur, at a depth as to penetrate the bone marrow. Blood was suctioned from the wound area between bone and muscle and pooled in a collection jar. Time to hemostasis was determined as for the arterial injury.

Substitution Therapy
For preparation of the PCC (Beriplex P/N; CSL Behring), the lyophilized powder was dissolved to provide a solution of 30 U (factor IX) per milliliter. This was administered fresh (i.e., not previously frozen) at a volume of 1.15 mL/kg, providing a dose of 35 U/kg. For the spleen injury study, 26 pigs were randomized to the following groups: untreated (n = 5), dilution + placebo (n = 16), or dilution + 35 U/kg PCC (n = 5). For the bone injury study, 19 pigs were randomized to the following groups: untreated (n = 5), dilution + placebo (n = 7), or dilution + 35 U/kg PCC (n = 7). Study medication was administered blind by an investigator not involved in any other aspects of the study.

Blood Analytical Methods
Platelet aggregation was measured in whole blood in a Multiplate Impedance Aggregometer (Instrumentation Laboratory, Kirchheim, Germany) with a standardized platelet count. Aggregation was induced with collagen, and the measurement time was 6 min. Adhesion of platelets in whole blood samples under flow conditions was tested using Impact R (DiaMed AG, Cressier s/Morat, Switzerland). Thromboelastometric measurements were performed in a ROTEM® (Pentapharm, Aesch, Switzerland); the assessed variables were maximal clot firmness (MCF), coagulation time (CT), clot formation time (CFT), and maximum velocity (MaxVel), which is the first deviation of the clot formation curve. Prothrombin time (PT) was measured with a Schnitger & Gross coagulometer (Amelung, Germany) using the Thromborel reagent (Dade Behring, Marburg, Germany). Coagulation factors were measured in deficient plasma (Dade Behring) with a Schnitger & Gross coagulometer (Amelung). Coagulation factors VIII, IX, XI, and XIII were measured in deficient plasma with activated partial thrombin time, whereas factors II, VII, V and X were measured with PT. Ristocetin cofactor activity was measured with von Willebrand Reagent in a Behring coagulation timer (Dade Behring), whereas von Willebrand Factor (vWF) antigen was measured using an Asserachrom vWF Ag ELISA (Boehringer, Mannheim, Germany). Fibrinogen measurements were performed with a Schnitger & Gross coagulometer (Amelung), and factor XIII was measured with the Berichrom FXIII test kit (Dade Behring). Hematology variables (red blood cells, hematocrit, and platelets) were measured with a Sysmex F-820 Analyzer (Sysmex GmbH, Norderstedt, Germany). Arterial blood pressure was measured using apparatus from Foehr Medical Instruments (Seeheim, Germany).

Statistical Analysis
Time to hemostasis was analyzed by the log-rank test, and the observation period lasted 120 min after wounding. Data recorded at times beyond 120 min were regarded as censored observations. Blood loss was analyzed by the Wilcoxon test. Differences in PT were evaluated by a Student's t-test (on the basis of normal distribution).

RESULTS

Pigs undergoing the dilution procedure had a mild hypothermia (temperature decreased from 38°C to 36°C); this was attributable to administration of HES. The mean rectal temperature was similar in all of these animals (legends of Figs. 4 and 5). Arterial blood pressure decreased after blood withdrawal, but returned to baseline values after substitution with HES and remained constant until the spleen or bone injury was performed (legends of Figs. 4 and 5). Before the injury, the hematocrit had decreased to 60% of its baseline value (not shown).


Figure 57
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  		Figure 5. Time to hemostasis (A; Kaplan–Meier plot) and blood loss (B; box plot) in pigs after bone injury. Mean arterial blood pressure (mm/Hg) at baseline/after substitution was 54.5 ± 8.5/61.1 ± 9.2 (negative control); 54.4 ± 7.2/53.2 ± 6.6 (dilution); 53.2 ± 7.2/54.3 ± 5.5 (PCC). Rectal temperature (°C) at baseline/after substitution was 38.0 ± 0.7/36.7 ± 0.7 (negative control); 37.5 ± 0.7/35.2 ± 0.8 (dilution); 38.3 ± 0.7/36.3 ± 1.0 (PCC). Time is given in minutes postwounding. {diamondsuit} mean, + median, the box represents the 25%–75% quantile, * denotes an outlier.

 
Characterization of the Coagulation Deficit
The dilutional coagulopathy affected all aspects of the coagulation system: the enzymes, coenzymes, and inhibitors of the coagulating cascade, fibrinogen, and platelets. The concentrations of coagulation factors 120 min after initiation of the dilution are shown in Figure 2; all were decreased to 25%–45%, relative to baseline values.


Figure 27
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  		Figure 2. Coagulation factor concentrations after dilutional coagulopathy. vWF, von Willebrand factor. Levels of coagulation factors were determined at 120 min and expressed as percentage of their baseline levels. Values are mean; error bars indicate standard deviation. Baseline values (U/mL) were as follows: vWF antigen 0.35 ± 0.09; vWF ristocetin cofactor 0.56 ± 0.09; antithrombin III 0.92 ± 0.13; factor XIII 0.49 ± 0.06; factor XII 0.96 ± 0.44; factor XI 0.66 ± 0.15; factor X 0.58 ± 0.07; factor IX 2.3 ± 0.42; factor VIII 5.2 ± 0.9; factor VII 0.48 ± 0.06; factor V 6.38 ± 1.3; factor II 0.50 ± 0.04; and fibrinogen (g/L) 2.9 ± 0.8.

 

The decrease in coagulation factors led to a pathological thromboelastogram. As shown in Table 1 (dilution group), the MCF was decreased, whereas CT and CFT were increased. Concomitantly, a lower MaxVel was found. In contrast, in the negative control group, thromboelastic variables remained unchanged versus baseline. The response to PCC was manifested by decreases in both CT and CFT in comparison with dilutional control, although these differences did not reach statistical significance. Platelet number and function were also affected (data not shown). The number of platelets was around 400,000/µL at baseline and remained constant over time in normal, anesthetized pigs (negative control). In animals undergoing dilutional coagulopathy, the platelet number gradually decreased to about 100,000/µL, whereas treatment with PCC had no effect on platelet count or function. Collagen-induced platelet aggregation was decreased under the conditions of a dilution: both the area under the curve and the maximal aggregation were decreased by about a factor of two (data not shown). Platelet adhesion was measured in a circular flow chamber; surface coverage was 15.1% ± 15% at baseline and 7.6% ± 2.5% under the conditions of a dilutional coagulopathy. PT was prolonged from approximately 14 s at baseline to over 20 s after blood dilution (Fig. 3).


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  		Table 1. Thromboelastometry (ExTEM) Variables in Pigs Undergoing a Dilutional Coagulopathy

 

Figure 37
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  		Figure 3. Influence of prothrombin complex concentrate (PCC) on prothrombin time and prothrombin plasma levels. Results are taken from the PCC bone injury group (n = 7) and the placebo control (n = 7). Values are mean; error bars indicate standard deviation.

 

Hemorrhage and Substitution Therapy with PCC
The coagulopathy led to a delayed hemostasis and increased blood loss after spleen incision injury and bone injury. Time to hemostasis after spleen incision injury increased approximately three-fold in the dilution group (median, 82.5 min) compared with untreated pigs (median, 19 min; between-group difference, 55 min; P < 0.0001), whereas blood loss increased from a median of 40 mL in untreated animals to 589 mL (P = 0.001) in animals that underwent dilution (Fig. 4). After bone injury, time to hemostasis increased from 25 min in untreated pigs to 97 min in the dilution group (between-group difference, 72 min; P = 0.0032); at the same time, blood loss increased from 120 to 589 mL (P = 0.0045, Fig. 5).

PCC significantly (P < 0.02) reduced PT compared with the dilutional control, and effectively normalized the prolonged PT. In addition, PCC restored the plasma concentration of prothrombin to a level slightly above normal (P < 0.001, Fig. 3). A significant decrease in time to hemostasis after spleen injury was obtained with PCC compared with the dilutional control group (median, 35 vs 82.5 min; P < 0.0001; Fig. 4) and there was a trend towards reduced blood loss in the PCC group (mean, 275 vs 589 mL), although this did not reach statistical significance (P = 0.16). After bone injury (Fig. 5), PCC also significantly reduced time to hemostasis (median, 27 vs 97 min; P < 0.0011) and blood loss (mean, 79 vs 589 mL; P < 0.0017), when compared with the dilutional control group.

DISCUSSION

This study demonstrated that porcine dilutional coagulopathy affected all elements of the coagulation system. Coagulation abnormalities were detected by thromboelastometry, including increased CT and CFT, and decreased MCF and MaxVel. Platelet function (aggregation and adhesion) was impaired; this may have been related both to coagulopathy and decreased platelet count. PT was also prolonged, indicating deficiencies in the extrinsic clotting pathway and/or deficiencies in levels or polymerization of fibrinogen. Dilutional coagulopathy led to massive blood loss and increased time to hemostasis after spleen incision (arterial) and bone (venous) injury. The administration of PCC normalized PT. In both the venous and arterial bleeding models, PCC significantly reduced time to hemostasis, and thus met the primary end-point of the study. PCC also significantly reduced blood loss (the secondary end-point) in the venous model; in the arterial model, the corresponding reduction did not reach statistical significance. The present study therefore indicates that PCC can improve coagulation in both venous and arterial bleeding.

Dilutional coagulopathy is associated with decreased levels of all coagulation factors. The administration of a multicomponent therapeutic drug such as PCC restored the key enzymes of the coagulation cascade, providing sufficient levels for both the tissue factor (extrinsic) and contact activation (intrinsic) pathways. This may be preferable to administering a single factor, which has a more specific effect on the extrinsic pathway. In the context of anticoagulation reversal, preclinical studies have indicated that PCC is superior to recombinant activated factor VII (rFVIIa) in terms of thrombin generation15 and restoring hemostatic function.16 The administration of any PCC would restore levels of several proteins of the prothrombin complex, factors II, VII, IX, and X. Some PCCs, notably Beriplex P/N, also contain the vitamin K-dependent coagulation inhibitors proteins C and S.16 These constituents are important from a safety perspective, as they ensure that any risk of thrombosis is minimized. A number of studies have indicated little or no risk of thrombosis among patients treated with Beriplex P/N.11,17–20

The principal task of the coagulation system is the establishment of hemostasis. Thrombin is pivotal to this process, although ineffective without fibrinogen, factor XIII, and platelets. Thrombin has multiple functions in the coagulation system: the formation of fibrin from fibrinogen, the activation of the cofactors V and VIII, the activation of factor XIII, and the activation of platelets via the thrombin receptor. The generation of thrombin from the prothrombinase complex, which contains the activated form of factor X as the acting serine protease, requires sufficient prothrombin (factor II) as a substrate. The activated form of factor IX is the enzyme of the tenase complex which, together with factor VIII, converts factor X to factor Xa. In recent years, attempts have been made to substitute with a single component of the prothrombin complex, namely the activated form of factor VII, which is available as a recombinant protein (rFVIIa).21 rFVIIa is able to bind directly to activated platelets and initiate the conversion of factor X to factor Xa while bypassing the tenase (factor IXa/VIIIa) pathway. This is the basis for the well-known efficacy of rFVIIa in treating patients with hemophilia A and B who have inhibitors to FVIII or FIX.22 Although these patients have sufficient factor X and prothrombin, this is unlikely to be the situation in a patient with a severe dilutional coagulopathy. If factor X decreases below a critical concentration, rFVIIa will lack its substrate, and our data suggest that it is important to supply enough prothrombin complex factors to initiate the thrombin burst. Studies with rFVIIa in porcine models of dilutional coagulopathy and liver trauma have shown inconsistent results, with some reporting a beneficial effect and others reporting no benefit.23–25 Comparative studies of rFVIIa and PCC would be of value in determining the potential roles of these products in managing patients with dilutional coagulopathy.

Fibrinogen has been proposed as the first critical factor in dilutional coagulopathy.26 Recent studies in a severe pig liver injury model have also indicated a beneficial outcome of substitution therapy with a fibrinogen concentrate or the combination of PCC and fibrinogen concentrate.27,28 The administration of fibrinogen might therefore be beneficial in maintaining hemostasis. Nevertheless, in our hands, PCC alone improved coagulation after both arterial and venous injuries. Coagulation in the venous vasculature depends predominantly on fibrin formation, whereas arterial coagulation is mainly dependent on platelet function.29 Thrombin has an important role in both fibrin formation and platelet-mediated primary hemostasis; therefore, a functional coagulation cascade must generate sufficient amounts of thrombin if hemostasis is to be achieved in both settings.

The dose of PCC administered in the current study, 35 U/kg, was chosen because it is the established dosing for humans. Depending on the pretreatment International Normalized Ratio, the dose for anticoagulation reversal may range between 25 and 50 U/kg.11 Optimal PCC dosing for dilutional coagulopathy in humans is yet to be determined. A further aspect of interest would be the duration for which PCC is effective in this setting.

A potential limitation of this study is that induction of hemodilution and administration of PCC occurred before arterial and venous injury; in a traumatized patient, injury occurs before hemodilution. Nevertheless, as the hemodynamic situation in pigs is similar to that in humans, the results may be considered applicable to the clinical setting. The mild hypothermia observed in the animals undergoing hemodilution also supports the clinical applicability of the present results, since trauma patients generally have reduced body temperature. The model used in this study is original and has not been described previously. The fact that it involved only localized bleeding is a possible limitation, as this is not directly comparable with the hemostatic system impairment that occurs after major operations or trauma.

In conclusion, impaired coagulation was significantly improved by substitution therapy with PCC in the present porcine model. Monotherapy with PCC was able to significantly reduce hemorrhage in venous and arterial bleeding. This is in agreement with data from retrospective clinical audits of PCC use, which indicate improved outcomes in patients with refractory bleeding during or after surgery.17,30 Clinical studies are needed to confirm whether PCC use may be effective in reversing dilutional coagulopathy in humans.

ACKNOWLEDGMENTS

The authors thank Wilfried Krege, Elmar Raquet, and Stefan Bliss for their skilful technical assistance and Petra Schorge for her excellent work in preparing the manuscript.

Footnotes

Accepted for publication November 29, 2007.

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G. Dickneite and I. Pragst
Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model
Br. J. Anaesth., March 1, 2009; 102(3): 345 - 354.
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