FFP maintains normal coagulation while Kcentra induces a hypercoagulable state in a porcine model of pulmonary contusion and hemorrhagic shock
Alexandra DixonMarissa BeilingSawyer SmithBrandon BehrensLuisa ApplemanElizabeth A. RickJames MurphyBrianne M. MadtsonBelinda H. McCullyAndrew L. GoodmanAmonpon KanlerdTraci SchallerSarayu SubramanianAlpa TrivediShibani PatiMartin A. Schreiber
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BACKGROUND Moderate injury can lead to a coagulopathy. Fresh frozen plasma (FFP) corrects coagulopathy by means of a balanced array of clotting factors. We sought to compare the late effects of FFP and a prothrombin complex concentrate (PCC) on the coagulopathy of trauma using a porcine model of pulmonary contusion (PC) and hemorrhagic shock (HS) designed to evaluate the organ protective effects of these treatments. METHODS Female Yorkshire swine (40–50 kg) were randomized to receive PC + HS or control (instrumented and uninjured). A blunt PC was created using a captive bolt gun. To induce HS, a liver crush injury was performed. Eighty minutes after injury, swine were treated with 25 U·kg −1 PCC, 1 U FFP, or 50 mL lactated Ringer’s vehicle in a blinded manner. Arterial blood samples were drawn every 6 hours. Swine were euthanized 48 hours postinjury. Data were analyzed by Pearson χ 2 , analysis of variance and Kruskal-Wallis tests with Tukey’s or Mann-Whitney U tests for post hoc analysis. RESULTS Twenty-seven swine received PC + HS, 3 groups of 9 per group received PCC, FFP, or vehicle. Nine were noninjured controls. When compared with control, PC + HS swine had significantly shortened R time at 6 hours, 36 hours, and 42 hours, decreased LY30 at 12 hours, shortened K time at 30 hours and reduced α angle at 42 hours. PC + HS swine showed significant differences between treatment groups in K and α angle at 3 hours, LY30 at 12 hours and 18 hours, and MA at 12 hours, 18 hours, and 30 hours. Post hoc analysis was significant for higher α angle in PCC versus vehicle at 3 hours, higher MA in vehicle versus PCC at 12 hours and 18 hours, and higher LY30 in PCC versus vehicle at 18 hours ( p < 0.012) with no significant differences between FFP and vehicle. CONCLUSION Severe injury with HS induced a coagulopathy in swine. While FFP maintained normal coagulation following injury, PCC induced more rapid initial clot propagation in injured animals.Keywords:
Fresh frozen plasma
Hemorrhagic shock
Clotting time
Prothrombin time
Hemorrhagic shock was produced in anesthetized and unanesthetized dogs by bleeding to fixed arterial pressure levels for specified periods using Wiggers' method. Blood was drawn through an ion exchange resin and at the end of the hypotension was reinfused simultaneously with the removed ions. Early in the hypotension there was usually some shortening of blood coagulation time. In the late hypotension and reinfusion period 75% of the dogs had a distinct prolongation of clotting time. Prothrombin activity and blood platelets showed a marked progressive decline during the shock period. Special tests indicated that the coagulation defect was mainly due to a decrease of labile factor in conjunction with a second deficiency, most likely prothrombin. There was no discernible deficiency of stable factor nor any release of heparinoids during the shock procedure. It is suggested that the hepatic anoxia and the resultant diminished production of labile factor and prothrombin contributes importantly to the clotting defect. Prior administration of heparin (10 mg/ kg) tended to lower mortality and increase survival time but did not afford critical protection against the development of irreversibility.
Hemorrhagic shock
Prothrombin time
Clotting time
Activated clotting time
Clotting factor
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OBJECTIVE: Fresh frozen plasma infusions are commonly used to correct the prolonged prothrombin time in patients with advanced chronic liver disease. The aim of this study was to establish how frequently this treatment is effective in correcting this coagulopathy. METHODS: A split retrospective–prospective study design was employed. In the retrospective series, 80 patients were identified with prolongation of the prothrombin time who received fresh frozen plasma infusions. In the prospective arm, 20 patients were included. All patients had confirmed chronic liver disease and showed no response to vitamin K injections. None of the patients had evidence of disseminated intravascular coagulation. The indications for infusion of fresh frozen plasma, number of units administered, complications, and percentage of patients who corrected their prothrombin time to less than 3 s longer than control time were recorded. RESULTS: The majority of patients (75%) received 2–4 units of fresh frozen plasma. The mean prothrombin time was numerically improved by the infusion of 2–6 units of fresh frozen plasma. However, using correction to less than 3 s longer than control time as an endpoint, only 12.5% of the retrospective and 10% of the prospective study groups respectively had correction of their coagulopathy. Only one complication of infusion of plasma was noted during the course of the study. CONCLUSIONS: Our results reiterate previous observations made more than 45 yr ago, that fresh frozen plasma infusions using the number of units commonly employed in clinical practice infrequently correct the coagulopathy of patients with chronic liver disease. Higher volumes (6 or more units) may be more effective but are rarely employed.
Fresh frozen plasma
Prothrombin time
Liver disease
Prothrombin complex concentrate
Chronic liver disease
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BACKGROUND Moderate injury can lead to a coagulopathy. Fresh frozen plasma (FFP) corrects coagulopathy by means of a balanced array of clotting factors. We sought to compare the late effects of FFP and a prothrombin complex concentrate (PCC) on the coagulopathy of trauma using a porcine model of pulmonary contusion (PC) and hemorrhagic shock (HS) designed to evaluate the organ protective effects of these treatments. METHODS Female Yorkshire swine (40–50 kg) were randomized to receive PC + HS or control (instrumented and uninjured). A blunt PC was created using a captive bolt gun. To induce HS, a liver crush injury was performed. Eighty minutes after injury, swine were treated with 25 U·kg −1 PCC, 1 U FFP, or 50 mL lactated Ringer’s vehicle in a blinded manner. Arterial blood samples were drawn every 6 hours. Swine were euthanized 48 hours postinjury. Data were analyzed by Pearson χ 2 , analysis of variance and Kruskal-Wallis tests with Tukey’s or Mann-Whitney U tests for post hoc analysis. RESULTS Twenty-seven swine received PC + HS, 3 groups of 9 per group received PCC, FFP, or vehicle. Nine were noninjured controls. When compared with control, PC + HS swine had significantly shortened R time at 6 hours, 36 hours, and 42 hours, decreased LY30 at 12 hours, shortened K time at 30 hours and reduced α angle at 42 hours. PC + HS swine showed significant differences between treatment groups in K and α angle at 3 hours, LY30 at 12 hours and 18 hours, and MA at 12 hours, 18 hours, and 30 hours. Post hoc analysis was significant for higher α angle in PCC versus vehicle at 3 hours, higher MA in vehicle versus PCC at 12 hours and 18 hours, and higher LY30 in PCC versus vehicle at 18 hours ( p < 0.012) with no significant differences between FFP and vehicle. CONCLUSION Severe injury with HS induced a coagulopathy in swine. While FFP maintained normal coagulation following injury, PCC induced more rapid initial clot propagation in injured animals.
Fresh frozen plasma
Hemorrhagic shock
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Prothrombin time
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Severe congenital factor V (FV) deficiency is a rare bleeding disorder characterized by very low/undetectable levels of FV. Fresh frozen plasma is the standard treatment for bleeding manifestations. Recently, a novel plasma-derived FV concentrate has been developed.To evaluate the "in vitro" ability of the novel FV concentrate to normalize clotting times and generate normal amount of thrombin in plasma collected from patients with severe FV deficiency.Prothrombin time (PT), activated partial thromboplastin time (aPTT), FV activity and antigen levels and thrombin generation were measured pre- and postspiking of plasma samples of 10 patients with increasing doses of FV concentrate (from 0 to 100 IU/dL).Prothrombin time and activated partial thromboplastin time ratios as well as all thrombin generation parameters were fully corrected by the addition of FV concentrate at a final concentration of 25 IU/dL. However, the addition of FV at a concentration of 1-3 IU/dL was already sufficient to correct peak height and endogenous thrombin potential (but not lag time and time to peak) after activation with 5 pmol/L tissue factor. FV activity and antigen levels showed a linear response to supplementation with the novel FV concentrate.The novel plasma-derived FV concentrate was effective to correct "in vitro" severe FV deficiency in patients. The optimal FV concentration to fully normalize both global clotting times and thrombin generation parameters using the novel plasma-derived FV concentrate was 25 IU/dL.
Thromboplastin
Thrombin Generation
Prothrombin time
Thrombin time
Clotting time
Factor V
Clotting factor
Fresh frozen plasma
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Background: Trauma-induced coagulopathy is associated with an extremely high mortality. We have recently shown that survival can be improved by correction of coagulopathy through early, aggressive infusion of Fresh Frozen Plasma (FFP). However, FFP is a perishable product, and its use is impractical in challenging environments such as a battlefield. Development of shelf-stable, easy to use, low volume, lyophilized, Freeze-Dried Plasma (FDP) can overcome the logistical limitations. We hereby report the development and testing of such a product. Methods: Plasma separated from fresh porcine blood (n = 10) was either stored as FFP, or lyophilized to produce the FDP. For in vitro testing, the FDP was rehydrated with distilled water and the pH, temperature, and osmolarity were adjusted to match the thawed FFP. Laboratory analysis included measurements of prothrombin time (PT), partial thromboplastin time, fibrinogen levels, and clotting factors II, VII, and IX. To test in vivo efficacy, swine were subjected to multiple injuries (femur fracture and grade V liver injury) and severe hemorrhagic shock (60% blood loss associated with "lethal triad" of coagulopathy, acidosis, and hypothermia), and resuscitated with FFP or FDP (n = 6/group; plasma volumes equal to the volume of shed blood). No treatment, and resuscitation with fresh whole blood served as the control groups (n = 6/group). Coagulation profiles (thromboelastography, PT, partial thromboplastin time, international normalized ratio, fibrinogen) were measured serially during the experiment, and for 4 hours posttreatment. Results: In vitro analysis revealed no differences in the coagulation profiles of FFP and FDP. The lyophilization process did not decrease the activity levels of the measured clotting factors. In the swine model, multiple injuries and hemorrhagic shock caused a 50% to 70% increase in PT (p = 0.03), and infusion of FDP and FFP were equally effective in correcting the coagulopathy. Conclusion: Plasma can be lyophilized and freeze-dried to create a logistically superior product without compromising its hemostatic properties. This product may be suitable for use in austere environments, such as a battlefield, for the treatment of trauma-associated coagulopathy.
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Thromboelastography
Prothrombin time
Thromboplastin
Blood product
Coagulation testing
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Background: Hemorrhage and coagulopathy are major contributors to death after trauma. The contribution of red blood cells (RBCs) in correcting coagulopathy is poorly understood. Current methods of measuring coagulopathy may fail to accurately characterize in vivo clotting. We aimed to determine the effect of RBCs on clotting parameters by comparing resuscitation regimens containing RBCs and plasma with those containing plasma alone. Methods: Thirty-two Yorkshire swine were anesthetized, subjected to a complex model of polytrauma and hemorrhagic shock, and resuscitated with either fresh frozen plasma, lyophilized plasma (LP), or 1:1 ratios of fresh frozen plasma:packed RBC (PRBC) or LP:PRBC. Activated clotting time, prothrombin time, partial thromboplastin time, and thrombelastography (TEG) were performed at 1 hour, 2 hours, 3 hours, and 4 hours after resuscitation. Results: Animals treated with 1:1 LP:PRBC had less blood loss than the other groups (p < 0.05). The activated clotting time was shorter in the 1:1 groups when compared with the pure plasma groups at all time points (p < 0.05). The 1:1 groups had shorter TEG R times (time to onset of clotting) at 1 hour, 3 hours, and 4 hours compared with pure plasma groups (p < 0.05). Other TEG parameters did not differ between groups. Partial thromboplastin time was shorter in the pure plasma groups than the 1:1 groups at all time points (p < 0.05). Conclusions: Whole blood assays reveal that RBCs accelerate the onset of clot formation. Coagulation assays using spun plasma underestimate the effect of RBCs on clotting and do not completely characterize clot formation.
Clotting time
Fresh frozen plasma
Prothrombin time
Thromboplastin
Thromboelastography
Polytrauma
Activated clotting time
Hemorrhagic shock
Clotting factor
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In Brief The early and aggressive high-volume administration of fresh frozen plasma, platelet concentrates, and red blood cells (RBCs), using ratio-driven massive transfusion protocols, has been adopted by many for the treatment of trauma-induced coagulopathy and hemorrhagic shock. However, the optimal ratio of RBC: fresh frozen plasma and RBC:platelet concentrate is still under investigation. In some European trauma centers, hemostatic agents such as fibrinogen concentrate, prothrombin complex concentrates, and antifibrinolytics are integral parts of goal-directed massive transfusion protocols. Both a ratio-driven coagulation therapy and a point-of-care–guided coagulation management based on coagulation factor concentrates aim for the same target—the rapid prevention and treatment of shock and coagulopathy to prevent death from traumatic hemorrhage. In this review, we compare the evidence relating to the effectiveness and safety of the ratio-driven and goal-directed approaches to trauma-induced coagulopathy to draw attention to the potential benefits and drawbacks associated with these management strategies. Published ahead of print June 11, 2013.
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Prothrombin complex concentrate
Coagulation testing
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Recombinant human factor VII activated (rFVIIa) is an adjuvant therapy in patients receiving massive transfusion for hemorrhagic shock. We compared patient characteristics and outcomes to determine futility criteria for the administration of rFVIIa in patients receiving massive transfusion for hemorrhagic shock.This was a retrospective cohort analysis of patients who received both massive transfusion and rFVIIa. Consecutive trauma patients were allocated to 1 of 2 cohorts: survivors and nonsurvivors.Seventy-two subjects comprised the study: 27 were survivors and 45 were nonsurvivors. A univariate analysis revealed that nonsurvivors were older and had a more profound coagulopathy as measured by prothrombin time. A stepwise logistic regression revealed an increased odds of death in those patients who were older (odds ratio [OR], 1.048; 95% CI, 1.008 -1.091), had a higher admission prothrombin time (OR, 1.561; 95% CI, 1.152-2.116), and received more fresh frozen plasma (OR, 1.098; 95% CI 1.023-1.179). In addition we saw a protective effect with increased platelet administration (OR, 0.645; 95% CI, 0.446-0.932).The use of rFVIIa for massive transfusion in middle-aged patients with moderate coagulopathy experiencing hemorrhagic shock may be considered futile. However, if rFVIIa is to be used as part of a massive transfusion protocol, adequate administration of platelets should be ensured.
Recombinant Factor VIIa
Fresh frozen plasma
Univariate analysis
Hemorrhagic shock
Prothrombin time
Platelet Transfusion
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