Prothrombin Complex Concentrate Group Research Articles

Fibrinogen and prothrombin complex concentrate in trauma coagulopathy

BackgroundCoagulopathy after injury contributes to hemorrhage and death. Treatment with specific coagulation factors could decrease hemorrhage and mortality. Our aim was to compare fibrinogen and prothrombin complex concentrate (PCC) in a rabbit model of hemorrhagic shock. Materials and methodsNew Zealand white rabbits were anesthetized. Blood was withdrawn to a mean arterial pressure (MAP) of 30–40 mm Hg for 30 min. Animals were resuscitated with lactated Ringer to a MAP of 50–60 mm Hg and randomized to receive 100 mg/kg of fibrinogen, PCC 25 IU/kg, or lactated Ringer. A liver injury was created. A MAP of 50–60 mm Hg was maintained for 60 min. The primary outcome was blood loss, and secondary outcomes were fluid administered and coagulopathy as measured by plasma-based tests. ResultsThere were eight animals in each group. Median blood loss was significantly higher in the fibrinogen group, at 122 mL (95% confidence interval [CI], 75–194), when compared with that in the control group, 35 mL (95% CI, 23–46; 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 (95% CI, 212–309) (P = 0.01). Plasma-based coagulation tests were not different among groups. ConclusionsIn a rabbit model, PCC did not have a significant effect on blood loss. Fibrinogen increased blood loss and fluid requirements.

Prothrombin Complex Concentrates Compared with Frozen Plasma for Urgent Reversal of Vitamin K Antagonists: A Single Centre Retrospective Review

▪Background: Vitamin K antagonists (VKAs) are associated with a risk of major bleeding requiring urgent reversal with frozen plasma (FP) or prothrombin complex concentrates (PCC) and concurrent vitamin K administration. Several treatment guidelines currently recommend PCC over FP for urgent reversal in VKA-associated bleeding. Four-factor PCC (Octaplex®, Beriplex®) has been available in Canada since 2008 with a change in national dosing recommendations in 2012. We conducted a retrospective study to determine the efficacy and safety of PCC in comparison with FP in patients presenting with bleeding and requiring VKA reversal.Methods: We retrospectively reviewed all consecutive bleeding episodes requiring VKA reversal at Vancouver General Hospital (VGH) for 2 cohorts of patients: i) those who received FP (July 28, 2008 to July 27, 2010); and ii) those who received PCC, during two time periods (July 28, 2008 to July 27, 2010; and September 1, 2011 to December 31, 2012) during which Canadian national dosing recommendations had changed. The PCC data however were pooled as no significant differences between the early and later PCC cohorts were found. Details of VKA reversal were reviewed, including patient demographics, bleeding type, indication for VKA therapy, dose of PCC or FP, admission hematologic parameters, INR value subsequent to completion of PCC or FP infusion, time to complete infusion, transfusion requirements, vitamin K dose and route of administration, transfusion reactions, thrombotic events (within 30 days) and mortality during hospitalization. The primary outcome was the proportion of patients achieving a target INR defined as ≤1.5 following the initial order of PCC or FP. Subject characteristics were compared using two-sided t-tests for continuous and Chi-square analysis for categorical variables. Predictors of mortality were analyzed with binary logistic regression.Results: A total of 201 bleeding episodes occurred in 191 patients. PCC was used in 89 episodes (44%). The most common indication for VKA was atrial fibrillation (81%). Mean PCC dose was 1489 U (range 500-3000 U). Mean FP dose was 3.1 U (range 1-10 U). Target INR was achieved in 86% of episodes in the PCC group versus 60% with FP (p<0.001). Mean time to complete the reversal agent was 4.4 hours with PCC versus 8.7 hours with FP (p<0.001). There was no significant difference in thromboembolic events between FP and PCC with 4 thromboembolic events occurring in each treatment group: 2 strokes, 1 myocardial infarction, and 1 recurrent deep vein thrombosis occurred in the PCC cohort. No transfusion-related reactions occurred in the PCC group compared with 12.6% with FP (p<0.001). Mortality was significantly higher in the PCC group (25% vs. 11%, p=0.010); however, intracranial bleeding (ICH) was more common in the PCC group (62% vs. 31%, p<0.001) and was the only independent predictor of mortality. Vitamin K was not administered in 20% of episodes, including 17% of episodes of ICH.Conclusion: PCC is effective in the urgent reversal of VKA with faster and more complete INR reversal, significantly fewer transfusion reactions and no increase in thromboembolic events in comparison to FP. Along with vitamin K, PCC should be the agent of choice for VKA reversal in bleeding patients. DisclosuresChipperfield:Boehringer Ingelheim: Honoraria. Yenson:Octapharma Canada: Unrestricted Education Grant Other; Alexion Pharmaceuticals: Honoraria.

Prothrombin Complex Concentrate in Combination with Fibrinogen Plus Tranexamic Acid Is More Effective Than Mono-Therapy with Prothrombin Complex Concentrate in a Dabigatran Anticoagulation Experimental Polytrauma Model

Background: Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of the direct thrombin inhibitor dabigatran. As no specific reversal agent in situations of life-threatening bleeding with dabigatran is currently available, this study assessed the ability of a four-factor prothrombin complex concentrate (PCC) as mono-therapy as well as PCC in combination with tranexamic acid (TX) and fibrinogen in an experimental polytrauma pig model.Methods: After ethical approval dabigatran etexilate (30 mg/kg p.o. twice daily, n=24) was administered to male pigs for 3 days. On day 4, the pigs were anesthetized and given a 90 min infusion of active dabigatran to achieve consistent, supratherapeutic plasma levels. A standardized polytrauma including bilateral femur fractures and a blunt liver injury was induced. Animals underwent hemorrhagic shock and were resuscitated using Ringer’s solution (1 L). Twelve min after polytrauma, animals received either placebo (control group, n=6); TX, 20 mg/kg plus fibrinogen (80 mg/kg; TX+F group, n=6); PCC alone (PCC group, 50 U/kg, n=6); or TX (20 mg/kg) plus fibrinogen (80 mg/kg) plus PCC (50 U/kg; TX+F+PCC group, n=6) according to randomized group allocation. Coagulation was assessed by thromboelastometry, coagulation parameters and diluted TT. Blood loss (BL) was measured over the observation period of 240 min. Data were analyzed by ANOVA (± SD).Results: Dabigatran levels were 504 ± 171 ng/mL prior to injury and plasma levels remained significantly elevated in all animals throughout the observation period. The degree of injury was similar among animals with comparable BL of 803 ± 46 mL 12 min post injury. Anticoagulation with dabigatran without intervention resulted in a total BL of 3521 ± 600 mL, with 100% mortality and mean survival time of 101 ± 34 min (range: 67 - 148 min; p<0.05 vs PCC-treated groups). In contrast, treatment with 50 U/kg PCC (1712 ± 147 mL) resulted in a significant reduction in BL (p<0.05 vs. controls, TX+F group) and 100% survival. Blood loss was further reduced by adding TX and F with PCC (TX+F+PCC group: 1234 ± 215 mL, p<0.05 vs. all groups). In contrast total BL in animals treated with only TX plus F was 3601 ± 410 mL and comparable to control animals receiving only dabigatran, mortality was 100%, although the onset of bleeding was slightly reduced. Likewise, coagulation parameters improved substantially in animals from PCC and TX+F+PCC groups. Despite a significant increase of fibrinogen after substitution (196 ± 22 mg/dL) in the TX+F group, only moderate effects were measured on coagulation parameters including clot strength and kinetics of clot formation. Clinically and macroscopically no adverse events were observed.Conclusions: This study shows that bleeding in a lethal trauma model can be reduced with mono-therapy using a four-factor PCC. Prior correction of hypofibrinogenanemia with fibrinogen concentrate and tranexamic acid further improves PCC efficacy. Although the effects of PCCs on dabigatran reversal are not well understood, one possible explanation is that by elevating thrombin concentrations through PCC administration, (i.e. PCCs contain prothrombin) this may competitively bind to dabigatran, thereby reducing its anti-thrombin anticoagulant activity. This hypothesis is supported by the lack of effect on blood loss by mono-therapy with TX plus fibrinogen in this study. DisclosuresGrottke:Boehringer Ingelheim: Consultancy, Research Funding; CSL Behring: Research Funding. Honickel:Boehringer Ingelheim: Travel support Other. Spronk:Boehringer Ingelheim: Research Funding. van Ryn:Boehringer Ingelheim Pharma: Employment. Rossaint:CSL Behring: Honoraria.

Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage

Warfarin-associated intracranial hemorrhage is associated with a high mortality rate. Ongoing coagulopathy increases the likelihood of hematoma expansion and can result in catastrophic hemorrhage if surgery is performed without reversal. The current standard of care for emergency reversal of warfarin is with fresh frozen plasma (FFP). In April 2013, the USA Food and Drug Administration approved a new reversal agent, 4-factor prothrombin complex concentrate (PCC), which has the potential to more rapidly correct coagulopathy. We sought to determine the feasibility and outcomes of using PCC for neurosurgical patients. A prospective, observational study of all patients undergoing coagulopathy reversal for intracranial hemorrhage from April 2013 to December 2013 at a single, tertiary care center was undertaken. Thirty three patients underwent emergent reversal of coagulopathy using either FFP or PCC at the discretion of the treating physician. Intracranial hemorrhage included subdural hematoma, intraparenchymal hematoma, and subarachnoid hemorrhage. FFP was used in 28 patients and PCC was used in five patients. International normalized ratio at presentation was similar between groups (FFP 2.9, PCC 3.1, p=0.89). The time to reversal was significantly shorter in the PCC group (FFP 256minutes, PCC 65minutes, p<0.05). When operations were performed, the time delay to perform operations was also significantly shorter in the PCC group (FFP 307minutes, PCC 159minutes, p<0.05). In this preliminary experience, PCC appears to provide a rapid reversal of coagulopathy. Normalization of coagulation parameters may prevent further intracranial hematoma expansion and facilitate rapid surgical evacuation, thereby improving neurological outcomes.

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED

ObjectivesHigh International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare the efficacy of prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP) at lowering the INR level, decreasing active hemorrhages visible by endoscopy, and shortening the length of stay at the emergency department (ED). MethodThis study is a prospective cohort study of consecutive patents with gastrointestinal hemorrhages that received either PCC or FFP. With strict exclusion criteria, only patients over 18 years of age with a high INR level (>2.1) due to warfarin usage were included. ResultsA total of 40 patients (18 female) were included in the study, 20 each in the PCC and FFP groups. For the PCC group, the mean INR levels at the second and sixth hours were lower than those for the FFP group (second hour INR: 1.53 vs 4.50, P < .01, sixth hour INR: 1.52 vs 2.41, P < .01). Seven patients experienced active bleeding (Forrest 1) in the FFP group, whereas no patient experienced active bleeding in the PCC group based on the Forrest classification (35% vs 0%, P < .01), and only 3 patients in the FFP group underwent invasive/surgical treatment (15% vs 0%, P < .01). The ED length of stay was lower for the PCC group (1.62 days vs 3.46 days, P < .01). ConclusionFor patients experiencing a gastrointestinal hemorrhage, INR levels were reversed more quickly, there was less active bleeding on endoscopy, and the ED length of stay was lower in the PCC group than in the FFP group.

Epidemiological features of warfarin overdose and efficacy of prothrombin complex concentrates

The aims of this study were to investigate the epidemiological features of warfarin overdose and evaluate the efficacy of prothrombin complex concentrate (PCC) for overdose treatment. The hospital records of 106 patients admitted to the emergency department (ED) for warfarin overdose during a two-year period were evaluated retrospectively. Demographic and epidemiological data as well as treatments were recorded. The data from 15 patients administered PCC were compared with those of other patients. The patient population consisted of 53 (50%) males and 53 (50%) females with a mean age of 70.2±14.5 years. Forty-five (42.4%) patients were admitted to the ED with bleeding disorders; 61 (57.6%) patients were admitted for other symptoms such as headache, syncope, trauma related injuries. Atrial fibrillation (n=50, 47.1%) was the most common indication for treatment with a vitamin K antagonist (VKA). Other common indications were transient ischemic attack, stroke (n=43, 40.5%) and valvular heart disease (n=17, 16%). Vitamin K was the preferred treatment for VKA reversal in 32 (30.2%) patients. Fresh-frozen plasma (FFP) was preferred in 23 (21.7%) patients. Fifteen (14.1%) patients required acute reversal of VKA with PCC. The anticoagulant drug was discontinued in 58 (54.7%) patients. Erythrocyte suspension (ES) and thrombocyte suspension (TS) transfusion rates were higher in the PCC-administered group; hospitalization rates were also higher in this group. ED length of stay (LOS) was shorter in this group. Initial international normalized ratio (INR) levels were significantly higher in the PCC group (5.68±3.74 versus 13.17±5.15). As the elderly population increases, warfarin and VKArelated complications will be a more significant portion of ED practice.ED physicians should be experienced in acute reversal of VKA with PCC, and be familiar with the possible complications of FFP and PCC. J. Exp. Clin. Med., 2013; 30:327-330

Optimizing the Dose of Three‐Factor Prothrombin Complex Concentrate in Traumatic Brain Injury Patients on Warfarin Therapy

To determine the percentage of patients with correction of their first international normalized ratio (INR)less than1.5 after administration of moderate-dose three-factor prothrombin complex concentrate (PCC), 35 IU/kg compared with low-dose PCC, 25 IU/kg. Retrospective review. Community teaching hospital. A total of 42 adult patients diagnosed with warfarin-associated traumatic brain injury (TBI) presented with an INRof1.5 or more and received at least one dose of PCC during a 19-month study period. The low-dose group received PCC 25 IU/kg from November 2011-July 2012 and the moderate-dose group received PCC 35 IU/kg from August 2012-May 2013. Of the 42 patients, 25 were in the low-dose group and 17 were in the moderate-dose group. Baseline characteristics were similar between both groups in regard to age, sex, weight, creatinine clearance, weekly warfarin dose, initial INR, initial Glasgow Coma Score, and injury severity score. Of the patients in the low-dose group, 12% achieved INR reversal with first measured INR after PCC administration compared with 69% in the moderate-dose group (p<0.001). The median time to INR reversal was 6.9hours in the low-dose PCC group and 1.9hours in the moderate-dose PCC group (p=0.04). There were no differences between the groups in other secondary end points, including stabilization of TBI, days in the intensive care unit, total days of hospitalization, blood product administration, and adverse events. Moderately dosed PCC at 35 IU/kg compared with a lower dosage of 25 IU/kg was associated with a higher percentage of INR reversal and more rapid time to INR normalization in patients with TBI. Future randomized controlled studies to further investigate this novel dose and the impact on potential reductions in the use of fresh frozen plasma are warranted.

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Introduction: It is unclear if administering a 3-factor prothrombin complex concentrate (PCC) with or without fresh frozen plasma (FFP) reverses the international normalized ratio (INR) faster than FFP alone in patients with warfarin-associated intracranial hemorrhage (ICH). Methods: This was an IRB approved retrospective cohort study of adult patients with warfarin-associated ICH and an INR>1.5 who received Profilnine with or without FFP versus FFP alone. Results: Of the 68 patients who met criteria, 32 patients were included in the PCC group and 36 patients were included in the FFP only group. The time to reversal of the INR to ≤1.5 from admission to a hospital was 11.3 hours in the PCC group and 15.4 hours in the FFP group (p=0.023). The time to reversal from treatment administration was 4.2 hours in the PCC group and 9.1 hours in the FFP group (p=0.001). In patients with a pre-treatment INR<3, the mean PCC dose was 34 IU/kg and the time to reversal was 9.2 hours for the PCC group and 15.7 hours for the FFP group (p=0.001). In patients with a pre-treatment INR >3, the mean PCC dose was 34–41 IU/kg and there was no significant difference between groups in time to reversal of the INR. A greater percentage of patients in the PCC group than in the FFP group had an INR ≤1.3 at 24 hours (91% vs 58%, p=0.03). In-hospital mortality was 22% for the PCC group and 8% for the FFP only group (p=0.17). There were 9 patients with documented pulmonary edema after treatment in the FFP only group versus 4 patients in the PCC group (p=0.75). There were 3 thrombotic events documented after PCC treatment (9%). Conclusions: This study demonstrated that a 3-factor PCC administered with FFP corrected the INR faster than FFP alone in patients with warfarin-associated ICH. When stratified by pre-treatment INR, PCC reversed the INR faster for patients with an INR<3, but not for patients with an INR>3. This may be explained by the lower than recommended average PCC dose administered to patients with an INR>4. Significantly more patients in the PCC group had an INR ≤1.3 at 24 hours than in the FFP group.

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Introduction: Subdural hematoma (SDH) affects >100,000 patients/year in the US and leaves >50% of its victims dead or severely disabled. Coagulopathy is an independent predictor for death and disability after SDH. Optimal treatment for coagulopathy-associated SDH remains controversial. Prothrombin complex concentrate (PCC) may rapidly reverse coagulopathy in warfarin-associated SDH (wSDH) but may increase thromboembolic (TE) complications. We hypothesize that PCC use in wSDH may decrease time to surgery from rapid coagulopathy reversal and therefore decrease mortality, but may increase in-hospital TE complications Methods: From a single center prospective database we identified 82 consecutive acute wSDH patients from 2008–2012 with admission INR>1.4. All patients were treated per standardized protocol for rapid warfarin reversal with conventional therapy (FFP+IV vitamin K). Additional 3-factor PCC may be used at treating physician’s discretion. Patients with “do-not-resuscitate” orders within 24 hours of admission, multiple anticoagulant use, chronic SDH, SDH associated with multisystem trauma, and with GCS of 3 and fixed and dilated pupils on presentation were excluded. Primary endpoint was in-hospital and 6-months mortality. Secondary endpoints were time to surgery and incidence of deep venous thrombosis/pulmonary embolism (DVT/PE) and troponin elevation. Propensity scores adjustment was used to reduce confounding. PS for PCC use were modeled using age, gender, mean arterial pressure, admission INR, presence of fixed dilated pupils, GCS, presence of multiple SDH, SDH diameter, SDH location, and midline shift as covariates. Conditional logistic regression models matched on quartiles of propensity score were used to compare in-hospital and 6-month all-cause mortality between PCC-treated and conventional therapy groups. Results: PCC-treated (n=38) and conventional therapy groups (n=44) had similar mean age, gender, baseline hypercoagulable conditions, and median initial INR on presentation. PCC-treated group had lower median GCS on presentation compared with conventional therapy group (14 vs. 15, p<0.0001). PCC-treated group received fewer units of FFP transfusion compared with conventional therapy (median 4 vs. 6 units, p=0.003). Overall in -hospital (OR: 1.61 [0.19–13.62], p=0.66) and 6-month mortality (OR: 3.24 [0.85–12.41], p=0.09) were not different between PCC-treated and conventional therapy group after PS adjustment. PCC use was independently associated with reduced time to surgery (-1.92 [(-2.70)–(-1.20)] after PS adjustment. Univariate analysis showed PCC group had higher incidence of DVT/PE (16% vs. 0%, p=0.006) and troponin elevation (32% vs. 14%, p=0.04) compared to conventional therapy. However, after PS adjustment there were no between-group differences in the incidence of DVT/PE or troponin elevation. Conclusions: Warfarin reversal with PCC reduced time to surgery and decreased the number of FFP transfusion needed but did not reduce in-hospital or 6-month mortality in wSDH. PCC use was not independently associated with increased TE complications in wSDH. Future prospective randomized studies are necessary to determine the risk versus benefit of PCC use in wSDH, and to determine whether rapid correction of coagulopathy leads to better neurological outcome and decreased mortality in wSDH.

Prothrombin complex concentrate: Urgent anticoagulation reversal

Prothrombin complex concentrate: Urgent anticoagulation reversal

Prothrombin complex concentrate

Coagulopathy in patients with traumatic brain injury (TBI) is a well-studied concept. Prothrombin complex concentrate (PCC) has been shown to be an effective treatment modality for correction of TBI coagulopathy. However, its use and effectiveness compared with recombinant factor VII (rFVIIa) in TBI has not been established. The purpose of this study was to compare PCC and rFVIIa for the correction of TBI coagulopathy. All patients with a TBI and an induced or acquired coagulopathy whom received rFVIIa or PCC at our Level I trauma center during a 4-year period were reviewed. Data collected included demographics, changes in international normalized ratio and blood products transfusion, craniotomy rates, and time to neurosurgical intervention, thromboembolic complications, and mortality differences. The study was composed of 85 TBI patients, of whom 64 patients received PCC while 21 patients received rFVIIa. PCC group were more likely to be on coumadin (44% vs. 14%, p = 0.01). There was a significant decline in packed red blood cell transfusion and fresh frozen plasma after PCC administration (p < 0.01). There was no statistically significant difference in the craniotomy rate (28% vs. 10 %, p = 0.1) or the mean time to intervention between the two groups (201 [33] vs. 230 [10], p = 0.9). Mortality rates were lower in the PCC group compared with rFVIIa (67% vs. 47%, p = 0.02). Subsequent thromboembolic event was seen in one patient on rFVIIa. Mean cost of treatment per patient on PCC was $1,007 compared with $5,757 for rFVIIa (p < 0.01). PCC is safe and effective for treating coagulopathy in TBI patients, while reducing costs and resource use. PCC should be considered as an effective therapy to treat both acquired and induced coagulopathy in TBI with or without prehospital coumadin use. Therapeutic study, level IV.

Recombinant Activated Coagulation Factor VII and Prothrombin Complex Concentrates Are Equally Effective in Reducing Hematoma Volume in Experimental Warfarin-Associated Intracerebral Hemorrhage

Based on an experimental model of warfarin-associated intracerebral hemorrhage, we investigated whether the rapid reversal of anticoagulation using prothrombin complex concentrates (PCC) or recombinant activated coagulation factor VII (rFVIIa) reduces hematoma volume. Mice were orally pretreated with warfarin (2 mg/kg). Intracerebral hemorrhage was induced by collagenase injection into the right striatum. Forty-five minutes later, PCC (100 IE/kg), rFVIIa (1 mg/kg), or an equal volume of saline was administered intravenously. Hematoma volume after 24 hours was quantified using a photometric hemoglobin assay. International normalized ratio was 4.3±0.4 in saline-treated mice, 0.9±0.1 in rFVIIa mice, and 1.4±0.2 in PCC mice. Intracerebral hemorrhage volume was 29.0±19.7 μL in the saline group (n=7), 8.6±4.3 μL in the rFVIIa group (n=6), and 6.1±1.8 μL in the PCC group (n=7; analysis of variance between-group differences P=0.004; post hoc rFVIIa versus saline P=0.021; PCC versus saline P=0.007). No significant difference was found between PCC- and rFVIIa-treated animals. Our results suggest that PCC and rFVIIa are equally effective in restoring coagulation and preventing excessive hematoma growth in acute warfarin-associated intracerebral hemorrhage.

Prothrombin Complex Concentrate Versus Standard Therapies for INR Reversal in Trauma Patients Receiving Warfarin

Prothrombin complex concentrate (PCC) is recommended as a therapy to be considered for the reversal of warfarin's effects. Few published data are available on the use of PCC for this indication in traumatically injured patients. To determine whether the addition of PCC to standard approaches to warfarin reversal more rapidly corrects the international normalized ratio (INR) in injured patients. A retrospective analysis was performed in trauma patients who were on warfarin preinjury from January 2007 to September 2009 at North Memorial Medical Center. Data were collected from medical records and the trauma registry. Patients were separated based on whether or not they received PCC. The groups were compared on the basis of demographics, units of fresh frozen plasma (FFP), vitamin K use, units of PCC, number of patients achieving an INR of 1.5 or less, time to an INR of 1.5 or less, mortality, intensive care unit (ICU) and hospital length of stay, and the incidence of thromboembolic events during hospitalization. Thirty-one patients were included in the analysis; 13 patients who received a total mean (SD) dose of 2281 (1053) units (25.6 [12.2] units/kg) of PCC (Profilnine SD) were compared to 18 patients who did not receive PCC. There was no significant difference between groups in FFP units received or the number of patients who received vitamin K. Most patients in both groups achieved an INR of 1.5 or less (92% PCC vs 89% no PCC). However, the mean time to achieve an INR of 1.5 or less was 16:59 (20:53) hours in the PCC group versus 30:03 (23:10) hours in the no PCC group (p = 0.048). There were 3 deaths in the PCC group and no deaths in the no PCC group (p = 0.06). ICU and hospital length of stay and number of thromboembolic events did not differ significantly between the 2 groups. PCC, when added to FFP and vitamin K, resulted in a more rapid time to reversal of the INR.

Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia

Although prothrombin complex concentrate (PCC) is increasingly used for the treatment of trauma-induced coagulopathy, few studies have investigated the impact and safety of PCC for this indication. The present study was performed to assess PCC for treatment of coagulopathy after blunt liver injury under severe hypothermia. Coagulopathy in 14 anaesthetised pigs was induced by haemodilution. Subsequently, standardised blunt liver injury was induced under severe hypothermia (32.8-33.2°C). Animals were randomised to receive either PCC (35 IU kg⁻¹) or saline (control). Coagulation was assessed over the following 2 hours by thromboelastometry and thrombin generation. Internal organs were examined to determine presence of emboli. The administration of PCC showed a significant reduction in blood loss (p=0.002 vs. controls) and a significant increase in the rate of survival (p=0.022 vs. controls). Plasma thrombin generation in the PCC group increased considerably above baseline levels, with significant increases in peak thrombin levels and endogenous thrombin potential versus controls throughout the follow-up period. In addition, PT decreased significantly in the PCC group versus the control group. However, only slight improvements in thromboelastometry variables were observed. Histology showed an equal degree of liver injury in both groups, and no thromboembolism. In severely hypothermic pigs, the application of PCC corrected trauma-induced coagulopathy and reduced blood loss. Thus, the infusion of PCC might be a reasonable approach to reduce the need for blood cell transfusion in trauma. Furthermore, the impact and safety of PCC application can be monitored through thrombin generation and thromboelastometry under hypothermia.

Effect of Prothrombin Complex Concentrate on Hematoma Enlargement and Clinical Outcome in Patients with Anticoagulant-Associated Intracerebral Hemorrhage

Background: The present study was carried out to determine the effect of prothrombin complex concentrate (PCC) on hematoma enlargement (HE) and the early clinical outcome of intracerebral hemorrhage (ICH) patients on long-term warfarin treatment. Methods: Themedical records and computed tomography (CT) images of 50 consecutive ICH patients on long-term warfarin treatment (35 men, 15 women; 69 ± 12 years old) were reviewed. International normalized ratio (INR) values, frequency of HE and clinical outcome were compared between patients treated with and without PCC. Results: INR values on admission were above 2.0 in 37 patients, of whom 19 were given PCC (PCC group) and 18 were not given PCC (control group). In these 37 patients, the frequency of HE (p = 0.017), the number of patients with a poor clinical outcome (modified Rankin Scale score ≧3 at 30 days or at discharge; p = 0.045) and in-hospital mortality (p = 0.042) were significantly higher in the control than in the PCC group. On multivariate logistic regression analysis with adjustment, PCC administration was independently associated (odds ratio 0.03, 95% confidence interval 0.00–0.63; p = 0.023) with a reduction in poor clinical outcome in ICH patients whose INR values were >2.0 on admission. Conclusions: Immediate INR reversal with PCC may prevent HE and subsequent poor outcome.

Suboptimal effect of a three‐factor prothrombin complex concentrate (Profilnine‐SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose

Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.

Rapid Reversal of Anticoagulation Reduces Hemorrhage Volume in a Mouse Model of Warfarin-Associated Intracerebral Hemorrhage

Warfarin-associated intracerebral hemorrhage (W-ICH) is a severe type of stroke. There is no consensus on the optimal treatment for W-ICH. Using a mouse model, we tested whether the rapid reversal of anticoagulation using human prothrombin complex concentrate (PCC) can reduce hemorrhagic blood volume. Male CD-1 mice were treated with warfarin (2 mg/kg over 24 h), resulting in a mean (+/-s.d.) International Normalized Ratio of 3.5+/-0.9. First, we showed that an intravenous administration of human PCC rapidly reversed anticoagulation in mice. Second, a stereotactic injection of collagenase was administered to induce hemorrhage in the right striatum. Forty-five minutes later, the animals were randomly treated with PCC (100 U/kg) or saline i.v. (n=12 per group). Twenty-four hours after hemorrhage induction, hemorrhagic blood volume was quantified using a photometric hemoglobin assay. The mean hemorrhagic blood volume was reduced in PCC-treated animals (6.5+/-3.1 microL) compared with saline controls (15.3+/-11.2 microL, P=0.015). In the saline group, 45% of the mice developed large hematomas (i.e., >15 microL). In contrast, such extensive lesions were never found in the PCC group. We provide experimental data suggesting PCC to be an effective acute treatment for W-ICH in terms of reducing hemorrhagic blood volume. Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH.

Efficacy of Prothrombin Complex Concentrate (PCC) for Reversal of Warfarin Effect.

In the United States supratherapeutic INRs are typically reversed with fresh frozen plasma (FFP). This requires transfusion of large volumes (10–15 ml/kg) with therapeutic delay, volume overload, risk for TRALI (transfusion related acute lung injury) and multiple donor exposures. Our Blood Utilization Review Committee recommends PCC as the preferred product for warfarin reversal. Profilnine (Alpha Therapeutic Corp, Los Angeles, CA) is PCC containing vitamin-K dependent clotting factors and dosed by FIX content. FII, VII and X content is no more than 150%, 35% and 100% of the FIX amount, respectively. The manufacturer's suggested dose for warfarin reversal is 15–50 U/kg. The dose of PCC and need for vitamin K or FFP is determined by the clinician after consultation with the transfusion service. Sixty-five patients received PCC; 25 for reduction of INR prior to surgery or other interventions and 40 for treatment of a supratherapeutic INR (>5.0) with bleeding or risk of bleeding. Twenty-three patients with supratherapeutic INRs received low dose PCC (mean 25 U/kg) and 17 received high dose (mean 50 U/kg). The average admission INR was 9.0 (5.2–15.0) for the low-dose group and 8.6 (5.3–15) for the high-dose group. Repeat INR measurements occurred after PCC and again if FFP was transfused. Twenty patients had samples frozen for analysis of FII, VII, IX and X with a mean time between PCC infusion and sample draw of 2 hours (0.5–8.1). Ten of these were stable at the time of PCC infusion and were used to calculate relative factor recovery. The INR corrected (decreased to ≤3) in 55%(6/11) of cases following treatment with low-dose PCC, while high-dose PCC corrected the INR in 43%(3/7). Combination of PCC and FFP (mean 2 units, ~5–7 mL/kg) corrected the INR in 89% (16/18) and 87%(13/15) of cases for low and high-dose PCC, respectively. PCC dose, with or without FFP, had no effect on the likelihood of INR correction (Chi-square, p> 0.05). The addition of low dose FFP, however, significantly increased the response rate (Chi-square, p<0.05) for both doses. The average factor increment is summarized in Table 1. Differences in factor levels between the PCC and PCC plus FFP groups were not significant(ANOVA, p>0.05). Based on PCC dose the median recovery of factor IX was 100% with a median recovery for FII, VII and X of 168%, 32%, and 100% of the factor IX increment. When FFP was added to the treatment regimen the recovery of factor IX was 106% of the PCC dose. FII, VII, and X were 182%, 46%, and 119% of the FIX increment. Only FVII recovery was significantly higher in the PCC plus FFP group (Mann-Whitney, p< 0.05). In conclusion, treatment with Profilnine increases factor levels compatible with the manufacturer's insert, but PCC plus FFP causes a larger FVII increment. Treatment with low or high dose PCC results in similar rates of INR correction. However, addition of FFP increases the rate of INR correction for both doses. Profilnine alone is, therefore, unable to reliably correct a supratherapeutic INR, and supplementation with small amounts of FFP is necessary to provide additional FVII. A PCC product with a higher content of FVII is a better therapeutic option but is not readily available in the United States.Factor increments following PCC infusionINRF II(%)F VII(%)F IX(%)F X(%)PCC onlyPre8.3±4.511±107±710±106±3Post2.6±1.453±2114±1028±1931±12PCC plus FFPPre12.2±5.05±11±112±1912±19Post1.9±0.876±2820±1245±2253±19mean±SD