Prothrombin Complex Concentrate Treatment Research Articles

Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants.

Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) use carries extremely high morbidity and mortality. The clinical effectiveness of hemostatic therapy is unclear. To compare the clinical and radiological outcomes of DOAC-associated ICH treated with prothrombin complex concentrate (PCC) vs conservative management. In this population-based, propensity score-weighted retrospective cohort study, patients who developed DOAC-associated ICH from January 1, 2016, to December 31, 2021, in Hong Kong were identified. The outcomes of patients who received 25 to 50 IU/kg PCC with those who received no hemostatic agents were compared. Data were analyzed from May 1, 2022, to June 30, 2023. The primary outcome was modified Rankin scale of 0 to 3 or returning to baseline functional status at 3 months. Secondary outcomes were mortality at 90 days, in-hospital mortality, and hematoma expansion. Weighted logistic regression was performed to evaluate the association of PCC with study outcomes. In unweighted logistic regression models, factors associated with good neurological outcome and hematoma expansion in DOAC-associated ICH were identified. A total of 232 patients with DOAC-associated ICH, with a mean (SD) age of 77.2 (9.3) years and 101 (44%) female patients, were included. Among these, 116 (50%) received conservative treatment and 102 (44%) received PCC. Overall, 74 patients (31%) patients had good neurological recovery and 92 (39%) died within 90 days. Median (IQR) baseline hematoma volume was 21.7 mL (3.6-66.1 mL). Compared with conservative management, PCC was not associated with improved neurological recovery (adjusted odds ratio [aOR], 0.62; 95% CI, 0.33-1.16; P = .14), mortality at 90 days (aOR, 1.03; 95% CI, 0.70-1.53; P = .88), in-hospital mortality (aOR, 1.11; 95% CI, 0.69-1.79; P = .66), or reduced hematoma expansion (aOR, 0.94; 95% CI, 0.38-2.31; P = .90). Higher baseline hematoma volume, lower Glasgow coma scale, and intraventricular hemorrhage were associated with lower odds of good neurological outcome but not hematoma expansion. In this cohort study, Chinese patients with DOAC-associated ICH had large baseline hematoma volumes and high rates of mortality and functional disability. PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality. Further studies on novel hemostatic agents as well as neurosurgical and adjunctive medical therapies are needed to identify the best management algorithm for DOAC-associated ICH.

3-Factor versus 4-Factor Prothrombin Complex Concentrates for the Reversal of Vitamin K Antagonist-Associated Coagulopathy: A Systematic Review and Meta-analysis

Long-term anticoagulation is used worldwide to prevent or treat thrombotic events. Anticoagulant therapy using vitamin K antagonists (VKAs) is well established; however, anticoagulants carry an increased risk of potentially life-threatening bleeding. In cases of bleeding or need for surgery, patients require careful management, balancing the need for rapid anticoagulant reversal with risk of thromboembolic events. Prothrombin complex concentrates (PCCs) replenish clotting factors and reverse VKA-associated coagulopathy. Two forms of PCC, 3-factor (3F-PCC) and 4-factor (4F-PCC), are available. Using PRISMA methodology, we systematically reviewed whether 4F-PCC is superior to 3F-PCC for the reversal of VKA-associated coagulopathy. Of the 392 articles identified, 48 full texts were reviewed, with 11 articles identified using criteria based on the PICOS format. Data were captured from 1,155 patients: 3F-PCC, n = 651; 4F-PCC, n = 504. ROBINS-I was used to assess bias. Nine studies showed international normalized ratio (INR) normalization to a predefined goal, ranging from ≤1.5 to ≤1.3, following PCC treatment. Meta-analysis of the data showed that 4F-PCC was favorable compared with 3F-PCC overall (odds ratio [OR]: 3.50; 95% confidence interval [CI]: 1.88-6.52, p < 0.0001) and for patients with a goal INR of ≤1.5 or ≤1.3 (OR: 3.45; 95% CI: 1.42-8.39, p = 0.006; OR: 3.25; 95% CI: 1.30-8.13, p = 0.01, respectively). However, heterogeneity was substantial (I 2 = 62%, I 2 = 70%, I 2 = 64%). Neither a significant difference in mortality (OR: 0.72; 95% CI: 0.42-1.24, p = 0.23) nor in thromboembolisms was reported. These data suggest that 4F-PCC is better suited than 3F-PCC for the treatment of patients with VKA-associated coagulopathy, but further work is required for a definitive recommendation.

Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.

Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.

Impact of Factor Xa Inhibitor Reversal with Prothrombin Complex Concentrate in Patients with Traumatic Brain Injuries.

Anticoagulant use prior to trauma has been associated with increased incidence of traumatic brain injury (TBI), intracranial hemorrhage (ICH) progression, and mortality. Prothrombin complex concentrates (PCCs) are commonly used as off-label treatments for factor Xa inhibitor-associated life-threatening hemorrhage. At this time, there is no consensus regarding appropriate indication, target dose, or outcomes of PCC administration in patients presenting with traumatic ICH. This study seeks to evaluate the impact of reversal with PCC on hemorrhage progression and outcomes in patients with TBI on preinjury factor Xa inhibitors. This single-center retrospective cohort study included patients ≥ 18years presenting with an acute TBI of any severity on apixaban or rivaroxaban from September 1, 2016, to September 1, 2019. Patients were grouped on the basis of receipt of PCCs for reversal (i.e., reversal or no reversal). Exclusion criteria included spontaneous ICH or known coagulopathy. Propensity score matching was conducted with the following variables: age, Abbreviated Injury Scale (head) score, and Charlson Comorbidity Index score. The primary outcome was hemorrhage stability within 48h. Secondary outcomes included degree of hemorrhage progression, in-hospital mortality, discharge disposition, and incidence of thromboembolic events. Of the 115 patients meeting inclusion criteria, 84 were included in the propensity score matched data set. Baseline characteristics, comorbidities, and TBI severity were similar. The majority of patients in the reversal group (35 [83.3%]) and the no reversal (NR) group (40 [95.2%]) experienced a mild TBI (admission Glasgow Coma Scale score of 14 to 15). In the reversal group, patients received 34.3 units/kg activated PCC, 30.5 units/kg four-factor PCC, or 54.9 units/kg four-factor PCC and activated PCC on average. There was no difference observed in the incidence of hemorrhage progression (10.8% NR vs. 15.0% reversal; p = 0.739) or in median change in ICH volume (0mL NR vs. 1mL reversal; p = 0.2199) between groups. Additionally, reversal did not affect in-hospital mortality (3 [7.1%] NR vs. 4 [9.5%] reversal; p > 0.999). One patient in the reversal group developed a deep vein thrombosis (DVT) during the hospitalization; however, this did not result in a statistically significant difference in the occurrence of DVT (p > 0.999). This study demonstrated that PCC used for the treatment of factor Xa inhibitor-associated ICH related to mild TBI did not significantly impact the incidence or degree of hemorrhage progression, and PCC treatment did not result in increased thromboembolic events.

Healthcare Resource Utilization for Oral Anticoagulant Reversal Therapies in Non-Valvular Atrial Fibrillation/Venous Thromboembolism Patients.

BackgroundThe objective of the study was to describe the healthcare resource utilization (HCRU) and associated costs with hospitalized patients receiving specific versus non-specific oral anticoagulation reversal therapy for life-threatening bleeds and emergency surgeries or urgent procedures.MethodsThis retrospective observational study using the Premier Healthcare Database included adult patients aged ≥ 18 years treated with idarucizumab (IDA) or 3- or 4-factor prothrombin complex concentrates (PCC) to reverse the effects of dabigatran or warfarin, respectively, between October 2015 and February 2018.ResultsMedian ages for IDA (n = 1,232) and PCC (n = 4,939) patients were 78 and 74 years (P < 0.001), respectively. IDA patients had lower bleeding and stroke risk assessment scores (HAS-BLED; P < 0.001 and CHA2DS2-VASc; P = 0.014) and lower prevalence of comorbidities compared with PCC patients. Median hospital length of stay was 6 and 7 days for patients who received IDA or PCC (P < 0.001), respectively. The percentage of patients with an intensive care unit (ICU) admission was lower for IDA patients compared with PCC patients (61.3% vs. 68.7%; P < 0.001). Median total costs per hospitalization were $19,357 for IDA patients and $26,920 for PCC patients (P < 0.001). Median costs per hospitalization for IDA and PCC treatment were $3,277 and $4,424, respectively. When HCRU and costs were examined by cause of reversal and type of bleed, similar trends in hospitalized costs emerged for IDA compared with PCC treatment.ConclusionsThis analysis revealed lower HCRU and total hospital costs in patients administered IDA compared with PCC for reversal of oral anticoagulation, though differences in population characteristics and bleeding events were observed that may have contributed to these findings.

Successful perioperative management using prothrombin complex concentrates in patients with severe congenital protein C deficiency.

Perioperative management of severe congenital protein C deficiency remains unestablished. This deficiency is often treated with anticoagulants, such as warfarin. Although anticoagulants need to be perioperatively discontinued, there are few methods for the management of such patients. We adopted a method for administering prothrombin complex concentrates (PCC), which includes intermittent administration of inactive protein C (PPSB-HT), and examined its outcome as a perioperative management approach for severe congenital protein C deficiency. Three patients underwent our perioperative management six times. We monitored activity levels of protein C, factor IX, and so forth. These patients could be perioperatively managed with PCC treatment.

Prothrombin, alone or in complex concentrates or plasma, reduces bleeding in a mouse model of blood exchange-induced coagulopathy

Prothrombin complex concentrates (PCC) are fractionated plasma protein drugs that reverse warfarin anticoagulation. PCC may control more general bleeding. We sought to identify the dominant procoagulant factor in PCC in vivo. We tested PCC or coagulation factor (F) treatment in CD1 mice made coagulopathic by exchange of whole blood for washed red cells. Anesthetized mice were transfused with murine fresh-frozen plasma (mFFP), PCC, mixtures of human vitamin K-dependent proteins (VKDP) (prothrombin, FVII, FIX, or FX), or purified single human VKDP, immediately prior to tail transection (TT), liver laceration (LL), or intravascular laser injury (ILI). Plasma donor mice were treated with vehicle or control antisense oligonucleotide (ASO-CON) or ASO specific for prothrombin (FII) (ASO-FII) to yield mFFP or ASO-CON mFFP or ASO-FII mFFP. Blood losses were determined spectrophotometrically (TT) or gravimetrically (LL). Thrombus formation was quantified by intravital microscopy of laser-injured arterioles. PCC or four factor- (4F-) VKDP or prothrombin significantly reduced bleeding from TT or LL. Omission of prothrombin from 4F-VKDP significantly reduced its ability to limit bleeding. Mice transfused with ASO-FII mFFP demonstrated inferior haemostasis versus those transfused with ASO-FII following TT, LL, or ILI. Prothrombin is the dominant procoagulant component of PCC and could limit bleeding in trauma.

Prothrombin Complex Concentrates are Superior to Fresh Frozen Plasma for Emergency Reversal of Vitamin K Antagonists: A Meta-Analysis in 2606 Subjects.

Urgent reversal of vitamin K antagonists (VKAs) is required for major bleeding or urgent surgery by intravenous vitamin K with either prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). However, there is lack of consensus regarding the superiority of either reversal agent. We sought to compare the performance of PCC and FFP in urgent reversal of VKA. A meta-analysis was conducted up to November 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Seventeen studies comprising 2606 participants met the inclusion criteria. Compared with FFP treatment, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.60, 95% CI 0.40-0.90, p = 0.01), better reversal of INR (OR 7.36, 95% CI 4.18-12.98; p < 0.00001) and lower risk of at least one treatment-related adverse event (OR 0.45, 95% CI 0.26-0.80, p = 0.006). Among patients with VKA-associated intracranial haemorrhage, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.58, 95% CI 0.35-0.94, p = 0.03) and better reversal of INR (OR 6.52, 95% CI 1.66-25.59, p = 0.007). There were no differences between these two agents in thrombogenicity, requirement for and quantity of red blood cell transfusions, all adverse events, fluid overload or disability on discharge or at 90days. As an agent for urgent reversal of VKA, PCC outperforms FFP in 90-day all-cause mortality including those with VKA-related intracranial haemorrhage, INR reversal and treatment-related adverse events.

Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single-Center, Clinical Experience in 105 Patients.

Patients with liver disease frequently develop coagulopathy, and fresh frozen plasma is traditionally used for correction of coagulopathy to manage and prevent bleeding. Prothrombin complex concentrates (PCCs) offer an attractive alternative because they are more readily available and avoid large‐volume transfusion. This retrospective, single‐center study reviewed clinical use of PCC in patients with acute/chronic liver disease. A total of 105 patients with 194 episodes of PCC administration were reviewed. Data pertaining to indication, dosing, effectiveness, and safety were collected. The effect of PCC on coagulation was analyzed in patients for whom coagulation results were available 7 hours before and after PCC. Data on thromboembolic events and mortality within 4 weeks of PCC administration were captured. Most patients (77%) had chronic liver disease; the remainder had acute liver failure. Indications for PCC were preprocedure prophylaxis and treatment for active/recent bleeding in 48% and 52% of 194 treatment episodes, respectively. The median dose of PCC administered was 22 IU/kg (interquartile range, 16‐29 IU/kg). Before PCC administration, 45% of patients had an international normalized ratio (INR) greater than 2.0, and 36% had fibrinogen levels of at least 1.5 g/L. PCC produced statistically significant reductions in prothrombin time and INR (coadministration with fibrinogen or cryoprecipitate: 3.1 versus 1.9; P < 0.001; no coadministration: 2.3 versus 1.8; P < 0.001). Three patients with multiple risk factors developed thrombotic events (hepatic artery thrombosis, incidental bilateral pulmonary embolism, nonocclusive portal vein thrombosis); there were no cardiovascular or cerebrovascular adverse events. Overall, 46 patients died of causes unrelated to PCC treatment. Conclusion: In patients with liver disease, PCC therapy was effective in improving coagulation test results without an excess of thrombotic events. Further assessment of PCC as hemostatic therapy in this setting is required.

Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial

BackgroundDirect oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent.MethodsPatients with life-threatening bleeding events during rivaroxaban treatment were included and administered 25 U kg−1 of PCC. Blood samples were collected immediately prior to as well as after PCC treatment at predefined time intervals. The primary endpoint was defined as the difference in thrombin generation (TG) parameters ETP (endogenous thrombin potential) and Cmax (peak thrombin generation) prior to and ten minutes subsequent to PCC treatment.ResultsThirteen patients, of whom the majority suffered from intra-cranial haemorrhage (ICH) or subdural haemorrhage (SDH), were included and administered PCC. The results show that the ETP (TG) significantly (p = 0.001) improved by 68% and Cmax (TG) by 54% (p = 0.001) during PCC treatment. In addition, the Quick value (prothrombin time: QuickPT) significantly improved by 28% and the activated partial thromboplastin time (aPTT) was decreased by 7% ten minutes after PCC administration. Cmax was reduced at baseline, but not ETP, aPTT or QuickPT. Lag time until initiation (TG, tlag), thromboelastometry clotting time (CTEXTEM) and time to peak (TG, tmax) correlated best with measured rivaroxaban levels and were out of normal ranges at baseline, but did not improve after PCC administration. In 77% of the patients bleeding (ICH/SDH-progression) ceased following PCC administration. During the study three participants passed away due to other complications not related to PCC treatment. The possibility of thrombosis formation was also evaluated seven days after administering PCC and no thromboses were found.ConclusionsThis study shows that use of PCC improved ETP, Cmax, QuickPT and aPTT. However, of these parameters, only Cmax was reduced at the defined baseline. It can be concluded that CTEXTEM, tlag and tmax correlated best with the measured rivaroxaban levels. The study drug was found to be safe. Nonetheless, additional studies specifically targeting assessment of clinical endpoints should be performed to further confirm these findings.Clinical trial registrationEudraCT trial No. 2013–004484-31.

Adverse Events Following International Normalized Ratio Reversal in Intracerebral Hemorrhage

Background: Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin K antagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited. Methods: Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being ‘related', ‘probably related', ‘possibly related', ‘unlikely related' or ‘not related' to treatment with PCC. To identify factors associated with TEs, log-rank analyses were applied. Results: Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2-3.8) before and 1.3 (IQR 1.2-1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000-2,500) was administered. Nineteen TEs were observed (9.3%); none were classified ‘related' but 9 were classified as ‘possibly' or ‘probably related' to PCC infusion (4.4%). One allergic reaction (0.5%), ‘unlikely related' to PCC, was observed. In the whole cohort, PCC doses >2,000-3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively). Conclusions: Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored.

Efficacy of Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-related Major Hemorrhage

In patients admitted to accident and emergency departments for anticoagulant use-related major hemorrhage and requiring urgent surgery or life-saving invasive intervention, the international normalized ration (INR) value should be rapidly corrected and bleeding should be controlled. With prothrombin complex concentrate (PCC), when used at optimal dose levels, target INR values are achieved within 15 min. In this study, we aimed to discuss the efficacy of the used four-factor PCC in 10 patients who were admitted to the accident and emergency department because of oral anticoagulant use-related major bleeding. Of all the patients to whom PCC treatment was administered, targeted INR levels could not be attained in 2 patients (20%). For our cases with gastrointestinal bleeding, the average baseline INR value was 7.3, while the average INR value after PCC administration was 1.9. For our subdural hematoma cases, the median baseline INR value was 2.5, while the median INR value after PCC administration was 1.3. We believe that PCCs used in eligible patient groups, as in this case series, may provide the desired results at lower doses and that they may be safer with regard to complications. (JAEM 2015; 14: 37-40)

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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.

A Systematic Review On Different Prothrombin Complex Concentrate Strategies To Reverse Vitamin K Antagonist Therapy

▪Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. The aim of this systematic review is to describe the currently used PCC strategies and to present their efficacy in terms of target INR achievement and clinical outcome.MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency reversal of VKA therapy. Additional inclusion criteria were the reporting of PCC dosing strategy, data on target INR or any clinical outcome or safety parameters, prospective patient enrollment, and a full text publication. All PCC studies in non-VKA patients, case-reports (N<5), duplicates, retrospective studies, and studies on activated PCC were excluded. The quality of selected studies was evaluated using two quality assessment tools which are described by Downs (J Epidemiol Community Health, 1998), and Thomas (McMaster University, 2008).A total of 27 studies was included in which the majority was single cohort (N=18, 67%), open label (N=27, 100%), and/or nonrandomized (N=23, 85%). The total number of included patients was 2410, ranging from 5 to 686 patients per study. One of the included studies was scored as having a strong, 12 a moderate and 14 a weak design. The median quality assessment score was 16 out of 26 [range 10-22]. A large heterogeneity in study parameters was observed including 6 different primary endpoints with 12 different definitions.Fifteen PCC protocols were identified in which the PCC dose ranged from 8 to 50 IU of factor IX/kg or a fixed dose protocol of 200, 500, 1000, or 1500 IU of factor IX/patient. These dosing strategies were based on five principals, namely based on bodyweight (BW), bodyweight and initial INR (BW+INRi), bodyweight and initial INR and target INR (BW+INRi+INRt), individual doctors decision (doctor) or a fixed dose (fixed). The actual infused dosage is depicted in figure 1. [Display omitted] [Display omitted] Evaluating the used dosing strategy, target INR was reached in 86%, 81%, 78% and 75% of patient in BW, BW+INRi, BW+INRi+INRt and fixed, respectively and was lower (55%) in doctor strategy. Of note, results of the doctor strategy are based on two studies.Clinical outcome was positive for 75%, 93%, 85%, 88% and 67% of patients in strategy BW, BW+INRi, BW+INRi+INRt, fixed, and doctor strategy respectively. Of note, only one study reported on the clinical outcome in the BW+INRi strategy and two in doctor strategy.While our review shows a great diversity on PCC dosing strategies among published data, the same applies to current PCC guidelines in which the ACCP leaves the dosing to the discretion of the physician, the French guidelines recommend a bodyweight adjusted dosing regardless of the INR, the Canadian guidelines recommend three different fixed doses stratified by initial INR, and the Australian guidelines recommend a range of bodyweight adjusted doses from which the physician should decide.Apart from the different dosing strategies, considerable heterogeneity in assessing the impact of PCC treatment was noticed indicating the lack of consensus regarding different aspects of emergency reversal of VKA treatment e.g. optimal target INR, clinical outcome definition. Furthermore, PCC is predominantly studied in small, single-arm and open label settings using the INR to measure its effect rather than clinical outcome. In addition, results from our quality assessment showed that most study designs were at most moderately robust. Evidence gained from the included studies should therefore be interpreted with caution.In conclusion, this review shows that the worst results are reported when a predefined dosing protocol is absent (doctors strategy), while with the use of any treatment protocol good outcome results of PCC treatment are obtained (target INR reached ³ 75%, positive clinical response ³ 75%). A fixed dose strategy seems to be the most simple treatment, with a high potential for optimal clinical outcome while the lowest PCC dosages are infused. Good quality studies with consistent endpoints are needed to guide clinical use.Actual median dose infused in each study(arm). Dots represent the included studies(cohorts) with large, average and small amount of included patients Disclosures:Khorsand:Sanquin BV, Amsterdam: Research Funding.

Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate

Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers. To quantify bleeding in warfarin-anticoagulated and DE-anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh-frozen plasma (FFP). CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents. PCC (14.3 IU kg(-1) ), but not rFVIIa (3 mg kg(-1) ) or FFP (12 mL kg(-1) ), normalized blood loss and bleeding time in mice with warfarin-induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg(-1) ) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg(-1) DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE-treated mice. Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in DE-induced coagulopathy.

Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding

Prothrombin complex concentrates (PCCs) offer a means for the rapid reversal of warfarin, particularly in the setting of life-threatening bleeding. We evaluated the effectiveness and safety of a PCC-based protocol in patients with warfarin-associated intracerebral hemorrhage (ICH), subdural hematoma (SDH), or subarachnoid hemorrhage (SAH).This was a retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol. Patients with intracranial hemorrhage and known warfarin use with an international normalized ratio (INR)>1.4 received fresh frozen plasma (FFP), vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine® SD) dose based on the initial INR. Demographic and clinical information, the degree of and time to INR normalization, and adverse events were recorded.The thirty study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The mean age was 72.8 (±11) years, including 11 (37%) patients ≥80years old. The median presenting INR was 2.3 (IQR 2–3.3) and post-treatment INR was 1.4 (IQR 1.3–1.5, Z score 6.4, p<0.001). Median time from PCC administration to the first follow up INR was 95 (IQR 50–140) min. No patient's INR increased by more than 0.3 over 72h. Nine patients (30%) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding complication was noted. Adverse events included 3 instances of early hematoma expansion, one ischemic stroke in a patient with endocarditis on post-PCC day 1, one pulmonary embolism 5weeks after PCC treatment, and one coronary in-stent thrombosis 60days after PCC treatment. 6 patients died prior to hospital discharge of anticipated complications of their initial event, and none from identifiable thrombotic complications of PCC.A 3-factor PCC preparation (Profilnine® SD), administered with FFP and vitamin K to patients with acute warfarin-associated intracranial bleeding is a reasonable approach to urgent warfarin reversal. However, randomized, prospective trials are needed to verify the safety and clinical effectiveness of PCC administration in this population.

Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice

IntroductionProthrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008.MethodsAll consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion.ResultsOf 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR.ConclusionsSevere bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.

SAFETY of PROTHROMBIN COMPLEX CONCENTRATES IN PATIENTS REQUIRING RAPID REVERSAL of ANTICOAGULANT TREATMENT with the VITAMIN K ANTAGONISTS: a Systematic Review and a Meta-Analysis of the Literature.

AbstractAbstract 1113▪ Background:Prothrombin complex concentrates (PCCs) are currently recommended by several international guidelines as the treatment of choice in warfarin-related coagulopathy. However, while the efficacy of PCCs is well established, their safety in terms of risk of thromboembolic complications, some of which may be severe or even life-threatening, is still not clear.Thus, we performed a systematic review of the literature with the aim of evaluating the rate of thromboembolic complications in patients on Vitamin K antagonists (VKAs) treated with PCCs for a bleeding event or before an urgent invasive procedure. Methods:MEDLINE and EMBASE databases were searched up to June 2010. Two reviewers performed study selection independently. Studies providing data on incidence thromboembolic complications in patients on VKAs were potentially eligible for the study. Two reviewers independently extracted data on study and population characteristics, type, dose of PCC treatment. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Results:28 studies for a total of 1104 patients were included in our systematic review. Seven studies used 3-factor PCCs, 21 studies used 4-factor PCCs. Concomitant vitamin K was administered in 21 studies, while fresh frozen plasma in 6.Seventeen patients had a thromboembolic complication after PCCs administration (weighted mean 1.9%; 95% CI 1.1–2.9 %). Of the thromboembolic events, 4 were fatal (23%). The incidence of thromboembolic events was 1.9%; (95% CI 1.0–3.1 %) in patients treated for bleeding and 0.8% (95% CI 0.1–2.0 %) in patients treated before urgent surgery or invasive procedures. For 5 of the reported events we were unable to define the subgroup.The incidence of thromboembolic events was 2.3% (95% CI 1.2–3.8) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0–2.4) in patients treated with 3-factor PCCs.One hundred and seven patients died for a mean mortality rate of 11.1% (95% CI 6.4–17.0 %).Only 7 studies for a total 257 patients provided data on the incidence of viral transmission after PCCs administration. In this subgroup of patients there were 4 episode of positivity for parvovirus B19 for a mean incidence of 1.9% (95% CI 0.3–4.9%). Conclusions:The results of our systematic review of the literature show that the treatment with PCCs in patients on VKAs therapy is associated with a low risk of thromboembolic complications providing important information on the safety of this approach. Moreover, also the risk of viral transmission, although evaluated in few studies only, appears to be negligible. The findings of a low thromboembolic risk have been further confirmed by the results of the subgroup analyses separately evaluating treatment with 3 or 4-factors PCCs and different indications for PCCs therapy. Disclosures:Crowther:Pfizer: Consultancy; Leo Pharma: Research Funding; Boehringer Ingelheim: Research Funding.

Successful emergency reversal of phenprocoumon anticoagulation with prothrombin complex concentrate: a prospective clinical study

The present prospective study was designed to evaluate the effectiveness and safety of prothrombin complex concentrate (PCC) for emergency reversal of oral anticoagulation with phenprocoumon, a long-acting coumarin. Patients were eligible for study entry if they required emergency reversal of phenprocoumon anticoagulation because they needed invasive surgical or diagnostic procedures or were actively bleeding. Patients received one or more infusions of pasteurized nanofiltered PCC (Beriplex P/N). Primary study endpoints were changes in International Normalized Ratio, Quick value, factors II, VII, IX and X, and protein C 10, 30 and 60 min following PCC infusion. Eight adult patients were enrolled, seven requiring urgent invasive procedures and one experiencing intracranial bleeding. In the first infusion, patients received a median 3600 IU PCC at median infusion rate 17.0 ml/min. Mean (SD) baseline International Normalized Ratio was 3.4 (1.2). The International Normalized Ratio 10 min after PCC infusion declined to 1.3 or less in seven of eight patients and to 1.4 in one patient. After PCC infusion, the Quick value increased by a mean of 57% [confidence interval (CI), 45-69%], circulating factor II concentration by 85% (CI, 68-103%), factor VII by 51% (CI, 40-62%), factor IX by 61% (CI, 47-76%), factor X by 115% (CI, 95-135%) and protein C by 100% (CI, 82-117%). Clinical effectiveness of PCC treatment was rated 'very good' in seven patients and 'satisfactory' in one. No thromboembolic or other adverse events occurred. PCC treatment rapidly, effectively and safely reversed phenprocoumon anticoagulation in patients undergoing urgent invasive procedures or actively bleeding.

Successful self‐infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor

Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 10-14 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs.