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Four-factor prothrombin complex concentrates (4FPCCs) are emerging as the standard of care for emergent warfarin reversal due to their ability to rapidly and effectively achieve hemostasis. The ideal dose of this medication is not known. Recently, our hospital instituted a protocol where all doses of 4FPCC were a fixed dose of 1500 IU. This protocol provides 4FPCC rapidly and precludes delay waiting for international normalized ratio (INR) values. The purpose of this study was to evaluate our experience with this fixed dose protocol.This is a retrospective review of patients who received 1500 IU of 4FPCC for emergent warfarin reversal between March 2014 and January 2015. Demographic and clinical data regarding administration, efficacy, and safety were collected and analyzed.A total of 39 patients met inclusion criteria. The most common indication for treatment was intracranial hemorrhage (28, 71.8%). The median INR at presentation was 3.3, and the median INR after a single dose of 1500 IU was 1.4 (P.001). A total of 36 patients (92.3%) achieved successful reversal with a target INR of less than 2.0, and 28 patients (71.8%) achieved successful reversal with a target INR of 1.5 or less. There were no thrombotic adverse events within 7 days.Administration of a fixed dose of 1500 IU of 4FPCC leads to high rates of successful INR reversal and no related thrombotic adverse events within 7 days, and there was no need to wait for INR at presentation. These findings suggest good efficacy and safety when using 1500 IU of 4FPCC for emergent warfarin reversal.

In cardiovascular surgery, hemostatic complexities require the provision of blood products to control bleeding as well as the use of a number of hemostatic agents, some of which cause significant morbidity. Among these agents is prothrombin complex concentrates (PCC), however there is no clear consensus on PCC use in cardiovascular surgery. To investigate the safety of PCC in patients undergoing left ventricular assist device (LVAD) placement, we reviewed our single institution experience to examine the incidence of thromboembolic events and a variety of hospital markers including morbidity and mortality. A retrospective review was conducted of patients who underwent LVAD placement between January 2010 and October 2012. Patients who received intraoperative PCC constituted the PCC group (n = 41) and those who did not constituted the non-PCC group (n = 27). The overall incidence of thromboembolic events at 3 months postoperative was 12 (29.3%) in the PCC group compared with six (22.2%) in the non-PCC group, respectively (p > 0.05). Morbidity did not differ between groups and one patient in the PCC group died. The intraoperative use of PCC in LVAD insertion does not appear to be associated with a significant increase in thromboembolic events; however, larger randomized trials are needed to confirm these findings.

Oral factor Xa inhibitors are an attractive class of anticoagulants expected to have broad application. Rapid and reliable reversal of the anticoagulant effect is important for patients with bleeding complications or those in need of urgent reversal for procedures. While no specific reversal agent is yet available, multiple published clinical guidelines suggest that four-factor prothrombin complex concentrates (PCC) should be considered when urgent reversal is desired. This presentation updates prior reviews on this topic (Crit Care, 17, 2013, 230; Thromb Haemost, 111, 2014, 189; J Thromb Thrombolysis, 2015, 39, 395); and summarizes more recent evidence in human studies indicating that four-factor PCCs available in North America do not reverse oral factor Xa-inhibitor anticoagulants. New agents on the horizon appear to be far more promising as therapies for reversal or oral factor Xa inhibitors.

There is increasing interest in prothrombin complex concentrates as therapy for perioperative and trauma-related bleeding. A suitable point-of-care test is needed to guide such therapy, and randomized controlled trials are needed for robust, evidence-based recommendations.

The high incidence of trauma, especially in elderly people anticoagulated with new oral anticoagulants (NOAs), has become a major challenge, particularly in critical situations with life-threatening bleeding. Under these circumstances, urgent NOA reversion becomes mandatory. Prothrombin complex has become a frequent indication in critical situations in which rapid reversal of anticoagulation is needed and where the use of fresh frozen plasma is limited. This study offers our point of view regarding the usefulness of NOAs, not only in the prevention of cardioembolic events but also as regards their emergent reversion in cases of severe bleeding associated to trauma.

The high incidence of trauma, especially in elderly people anticoagulated with new oral anticoagulants (NOAs), has become a major challenge, particularly in critical situations with life-threatening bleeding. Under these circumstances, urgent NOA reversion becomes mandatory. Prothrombin complex has become a frequent indication in critical situations in which rapid reversal of anticoagulation is needed and where the use of fresh frozen plasma is limited. This study offers our point of view regarding the usefulness of NOAs, not only in the prevention of cardioembolic events but also as regards their emergent reversion in cases of severe bleeding associated to trauma.

Objectives Antibodies to phosphatidylserine/prothrombin complex (aPS/PT) detectable in sera of some patients with antiphospholipid syndrome (APS) have been shown to correlate with thrombosis. However, associations of aPS/PT antibodies with APS related disorders remain unclear. Aim To evaluate whether there are any associations between aPS/PT antibodies and Raynaud phenomenon, migraine and/or valvular lesions in primary thrombotic APS (PAPS). Methods We enrolled 67 consecutive patients (56 women) with thrombotic PAPS (VTE in 80.6%), aged 46.2 ± 13.5 years. The exclusion criteria were: acute coronary syndromes or stroke within preceding 6 months, cancer, severe comorbidities and pregnancy. The IgG and IgM aPS/PT antibodies were determined by ELISA with the cut-off of 30 units. We recorded Raynaud phenomenon, migraine and valvular lesions. Results Positive IgM or/and IgG aPS/PT antibodies were observed in 29 patients (43.3%), with a higher prevalence of IgM antibodies ( n = 27, 40.3%) compared with IgG isotype ( n = 12, 17.9%, p = 0.014). aPS/PT antibodies were observed most commonly in patients with triple aPL ( n = 12, 85.7%) compared with those with double ( n = 5, 35.7%) or single aPL antibodies (n = 12, 30.8%, p = 0.03), with no association with demographics, the ANA titre, the type of thrombotic events or medications. Raynaud phenomenon, migraine and valvular lesions were observed in 15% ( n = 10), 30% ( n = 20) and 18% ( n = 12) of the patients, respectively. Raynaud phenomenon and migraine, but not valvular lesions, were markedly more frequent in PAPS patients presenting with positive aPS/PT antibodies ( n = 10, 34.5% vs. n = 0, 0%; p = 0.0001). Conclusions In PAPS patients aPS/PT antibodies are related to the occurrence of both Raynaud phenomenon and migraine.

Damage control resuscitation has been increasingly adopted and practiced over the last decade. The concepts used are not new to this era of medicine but are novel in combination. This chapter will focus on adjuncts to damage control resuscitation (DCR) including massive transfusion protocols, the “other” tenets of damage control resuscitation, hypertonic saline, tranexamic acid, pharmacologic resuscitation, Factor VIIa, and prothrombin complex, and viscoelastic testing.

Warfarin är ett läkemedel som används för att förhindra att högriskpatienter såsom de med förmaksflimmer får tromboembolism. Denna verkan uppnås genom att hämma de K-vitaminberoende faktorerna VII, X och protrombin och på så sätt minska blodets förmåga att koagulera. Att hitta rätt dosering av läkemedlet för warfarinbehandlade patienter har visat sig vara svårt eftersom det kräver regelbunden provtagning och påverkas av mat- och levnadsvanor. Det vanligaste sättet att mäta protrombinkomplexhalten är med venös plasma men det är även möjligt att använda sig av kapillär plasma. Helblod kan användas för mekaniska metoder som inte använder sig av optisk detektion. Fördelen är att helblod inte kräver centrifugering. Studiens syfte var att undersöka om det fanns en signifikant skillnad (p≤0,05) mellan helblod och plasma som används i den nuvarande metoden för kapillära prover och om det finns en skillnad i stabiliteten av dessa prov. Dubbla prover togs från 30 warfarinbehandlade patienter och 5 icke warfarinbehandlade individer. Ett av proven centrifugerades och analyserades på plasma, det andra analyserades på helblod. Resultaten visade att det fanns en signifikant skillnad (p≤0,05) mellan metoderna. Bland-Altman diagrammet visade att 95 % av helblodsproverna inte var högre än 0,25 INR och lägre än 0,14 INR. Detta har en låg klinisk inverkan. 4 Proverna förvarades i rumstemperatur i upp till 24 timmar och analyserades sedan om. Ingen förändring över 10 % kunde observeras i hållbarheten. Studien visade att trots att det finns en signifikant skillnad är det möjligt att ersätta den nuvarande metoden med plasma och använda helblod istället., Warfarin is a drug used to prevent high-risk patients such as those with atrial fibrillation from thromboembolisms. This effect is achieved by suppressing vitamin-K dependent factors VII, X and prothrombin and therefore decreasing the bloods ability to clot. Finding the right dosage of the drug for warfarin treated patients has proven difficult, as it demands regular blood draws to monitor their prothrombin complex level, which is affected by dietary and living habits. The most common way to measure prothrombin complex levels is by using venous plasma but it is also possible to use capillary plasma. Whole blood can be used for mechanical methods, which don’t use optical detection. The benefit is that whole blood doesn’t require centrifugation. The aim of this study was to investigate if there was a significant difference (p≤0,05) between using whole blood and plasma which is the existing method for capillary sample and also if there is any differences between the stability of these samples. Double samples from 30 warfarin treated patients and 5 non-treated persons were taken. One of the samples were centrifuged and analyzed on plasma and the other analyzed on whole blood. The results showed that there was a significant difference (p≤0,05) between the methods. Bland-Altman plot comparison showed that 95 % of the whole blood samples would not be higher than 0,25 INR and lower than 0,14 INR. This has low clinical impact. The samples were stored at room temperature for up to 24 hours and reanalyzed. No changes over 10 % in INR values were observed. This study showed that even though there is a significant difference, it is possible to replace the existing method which using plasma with the whole blood instead.

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)

Рассмотрены способы получения полного протромбинового комплекса методом анионообменной хроматографии с использованием различных сорбентов. Изучен способ получения PPSB анионообменной хроматографией на DEAE- и QAE-Sephadex А50batch методом. Показано влияние массы геля, взятого для хроматографии, на выход и удельную активность ф. II, ф. VII, ф. IX, ф. X. Предлагаются новые способы получения протромбинового комплекса с высоким содержанием ф. VII методом колоночной хроматографии. Изучена статическая емкость по ф. VII системы гемокоагуляции ряда сорбентов, а также динамическая емкость TOYOPEARL GigaCap Q-650M и Capto Q.

Введение. Прогрессирование атеросклеротического процесса в системе внутренней сонной артерии (ВСА) часто сопровождается развитием острых церебральных эпизодов и происходит на фоне стойкого ухудшения гемореологических и гемостазиологических показателей, несмотря на регулярный прием антиагрегантных препаратов. Цель исследования: оценка вклада ряда гемореологических и гемостазиологических параметров в прогрессирование атеросклероза сонных артерий и развитие аспиринорезистентности, в том числе с учетом фармакокинетики салициловой и ацетилсалициловой кислоты (АСК) у пациентов с атеросклерозом на фоне постоянного приема препаратов АСК. Материалы и методы. Обследовано 93 пациента с атеросклеротическим поражением ВСА и 50 практически здоровых добровольцев. Обследование проводилось до начала терапии и по истечении не менее чем шестимесячного регулярного лечения (препараты АСК в дозе 100 мг/сутки). Средний период наблюдения составил 10,1±3,5 месяцев. Результаты. Выявление у пациентов с церебральным атеросклерозом склонности к повышенному тромбообразованию имеет важное прогностическое значение при подборе лекарственных средств, направленных на снижение тромбогенного потенциала крови и достижение стойкого антитромботического эффекта. Заключение. Разработанный подход, сочетающий мониторинг содержания салицилатов при одновременном измерении агрегации тромбоцитов, является более информативным, поскольку дает клиницисту возможность персонифицировать аспиринотерапию., Introduction. Atherosclerosis progression in the internal carotid artery (ICA) is often accompanied by the development of acute cerebral episodes and associated with refractory worsening of hemorheological and hemostasiological parameters despite the regular antiaggregant medication. Aim: to estimate the role of some hemorheological and hemostasiological parameters in the progression of carotid atherosclerosis and development of aspirin resistance taking into account the pharmacokinetics of salicylic and acetylsalicylic acid (ASA) at patients with atherosclerosis under continuous administration of ASA drugs. Materials and methods. We examined 93 patients with ICA atherosclerotic lesion and 50 healthy volunteers. Patient’s examination was carried out before treatment onset and after not less than six months of regular treatment (ASA drugs at dose 100 mg/day). Average follow-up period was 10,1±3,5 months. Results. Identifi cation of predisposition for increased thrombus formation in patients with cerebral atherosclerosis has an important prognostic value in drugs selection aimed at reducing blood thrombogenic potential and achieving of stable antithrombotic effect. Conclusion. Developed approach that combines monitoring of salicylates content with simultaneous measurement of platelet aggregation is more informative because it gives the clinician the opportunity to personalize aspirin therapy., №3(72) (2017)

International audience; BackgroundAccording to the International Society on Thrombosis and Haemostasis (ISTH), intramuscular hematoma without other severity criteria is not considered a major bleeding. Objectives: In a large cohort of reversed vitamin K antagonist (VKA) patients admitted to the emergency unit for muscular hematoma, we assess frequency, severity, and anticoagulation management based on whether ISTH criteria were met or not.Materials and methodsWe performed a retrospective single-center study involving patients admitted to an emergency unit for VKA-induced intramuscular hematoma whose bleeding was reversed with prothrombin complex concentrates.ResultsDuring the study period, 631 VKA-induced bleeding events occurred in our emergency unit, of which 73 (11.6%) were intramuscular hematomas and half met ISTH criteria. The mean age was 75.5years (95% CI=72.6–78.3). Admission blood tests showed that patients with ISTH criteria had higher international normalized ratio (7.0±4.6 vs. 4.1±3.0, p=0.002) and lower hemoglobin (8.1±1.8 vs. 11.9±2.2, p

The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to

Diagnosis of antiphospholipid syndrome (APS) lies in the recognition of antiphospholipid antibodies (aPL). As standardization of tests for the detection of aPL is far from being optimal and reference material is not available, inappropriate diagnoses of APS are not unusual. In the last few years, the concept of triple test positivity has emerged as a useful tool to identify patients with APS. Clinical studies on patients and carriers of triple positivity clearly show that these individuals are at high risk of thromboembolic events and pregnancy loss. Moreover, triple positivity arises from a single (probably pathogenic) antibody directed to domain 1 of β2-glycoprotein I, a protein whose function is still unknown. Studies on homogenous group of patients with single or double positivity are scant, and uncertainties arise on their association with clinical events. Promising but undetermined results come also from the determination of antibodies directed to phosphatidylserine/prothrombin complex. Interpretation of laboratory profile in APS is challenging, and the collaboration between clinical pathologists and clinicians is highly desirable.

Background and aims To explore utility of Antibodies to Phosphatidylserine/Prothrombin Complex (aPSPT), in Indian Anti phospholipid Syndrome (APS) patients. Methods Data of 372 subjects whose sera was tested for aPSPT by ELISA (AESUKU,GERMANY), was retrospectively analysed. Performance of various APLs was compared using non-parametric tests. To ascertain additional utility of aPSPT, patients with suspected APS were categorised into 2 groups i.e. i) those with any one of criteria antibodies positive ii) those with any one APL positivity including anti- PSPT positivity. Results In 46 patients of APS, 38 (82.60%) had thrombotic events (21 arterial , 26 venous) and 11 ( 23.91%) had obstetric events. Lupus anticoagulant was present in 37/46 (80.43%) ,anticardiolipin antibody in 19/46 (41.33%), aPSPT in 17/46 (36.95%), anti-β2glycoprotein1 (β2GP1) IgG and IgM in 13/46 (28.26%) and 7/46 (15.21%) patients of APS respectively. aPSPT tested positive in 9/60 (15%) patients with seronegative APS (SNAPS). aPSPT did not differ from other criteria APLs in any clinical parameter except compared to those with IgM B2GP-1 positivity. aPSPT was numerically more sensitive and specific than IgM B2GP1 for thrombotic, non-criteria events but less sensitive for detecting obstetric events (Table 2). Inclusion of aPSPT test in patients with suspected APS increased sensitivity marginally but with concomitant decrease in specificity. Conclusions In our study, aPSPT was third most common antibody in APS patients, displaying higher sensitivity and specificity in comparison to IgM anti-β2 GP1 for all APS manifestations except obstetric ones. SNAPS patients may test positive for aPSPT, thus endorsing its inclusion in classification criteria of APS.

I was pleased to read the letter by Zhang, et al 1 regarding our November 2017 published work, “Closing the Serological Gap in Antiphospholipid Syndrome: The Value of ‘Non-criteria’ Antiphospholipid Antibodies.”2 There are several valuable points that Zhang, et al bring up in their letter that I would like an opportunity to highlight and expand upon. First, their results show significant clinical value for the IgG and IgM antiphosphatidylserine/prothrombin complex (aPS/PT) test for both diagnosing antiphospholipid syndrome (APS) and helping in risk stratification (thrombotic vs non-thrombotic). Their results showed the combination of IgG or IgM aPS/PT with lupus anticoagulant (LAC) … Address correspondence to N. Zohoury. E-mail:nzohoury{at}inovadx.com.

Background Prothrombin complex concentrates (PCCs) can be used instead of frozen plasma (FP) transfusion to reverse the effect of warfarin. Audits have demonstrated over usage of FP transfusions even before the introduction of PCC. The objective of this study was to determine the appropriateness of current FP transfusion practice in the current era since the introduction of PCCs. Methods A retrospective cohort study of consecutive patients receiving FP over 3 months was carried out. Each episode of FP use over a 24-h period was adjudicated independently by two reviewers as appropriate (consistent with Canadian/AABB guidelines), appropriate but inconsistent with guidelines or inappropriate. Discrepancies were resolved by a third reviewer. Use of FP to reverse warfarin was considered inappropriate. FP usage from previous years was assessed as baseline. Results During the study period, 111 FP transfusions were administered. 74·8% of FP usage occurred in the ICU. The proportion of FP transfusions that were deemed appropriate, inconsistent yet appropriate or inappropriate were 33/89 (37·1%), 16/89 (18·0%) and 40/89 (44·9%), respectively, when use of FP for therapeutic plasma exchange was excluded. The most common reasons for inappropriate use were the absence of bleeding with an increased INR or warfarin reversal. Conclusion Our study is the first to audit FP transfusions in the post-PCC era in Canada. FP usage remains inappropriately high in INR prolongation without another indication or to reverse warfarin. Targeted interventions to reduce FP usage in the future should focus on the ICU and on education about warfarin reversal.

Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ∼50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ∼60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

Antibodies to prothrombin can be detected by ELISA using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have been both related with the clinical manifestation of APS. Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient. This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of APS.

Although new oral anticoagulants (NOACs) represent an advance in anticoagulant therapy over vitamin K antagonists (VKAs), they nevertheless have a low, but significant risk for bleeding complications. Reversal agents for VKAs, such as prothrombin complex concentrates (PCCs), are currently being evaluated in preclinical studies for NOAC reversal. This article reviews the preclinical data for the most extensively studied PCC for NOAC reversal, Beriplex, a 4-factor PCC. The results from the Beriplex studies are also compared with those obtained with other reversal agents, including different nonactivated PCCs, activated PCCs, and recombinant activated factor VII.

Aim. To evaluate the prevalence of accomplished goal in laboratory clotting parameters for the anticoagulant therapy in deep vein thrombosis (DVT).Material and methods. The study is performed as one-stage, descriptive, analytic, pharmacoepidemiologic investigation. The material for the study were 200 case histories of DVT from Volgograd hospitals. The analyzed were: structure of anticoagulant prescription, coagulogrammes with APTT, prothrombin complex and INR.Results. Direct acting anticoagulants were prescribed in 91% cases. High-molecular heparin was used in 84,5% prescriptions, low-molecular heparins — in 6,5%. Monitoring of APTT was done only in 36% patients. The target values of APTT (1,5–2,5 times higher than upper limit) was reached only in 6% cases. Of the indirect anticoagulants warfarin was used in 75,5%. Although laboratory control of warfarin was done in 97% cases, only in 28% of patients INR at discharge was in the range 2,0–3,0.Conclusion. The data witnesses a variety of drawbacks in anticoagulant therapy of DVT patients. High dosages of HMW heparin and warfarin, not enough rigourous control and dosage titration led to the absence of the desired therapeutic diapasone of hypocoagulation.

Patients presenting to the emergency department with acute bleeding and a history of clotting or platelet disorder present a unique challenge to the emergency physician. The severity of bleeding presentation is based on mechanism as well as factor levels: patients with factor levels greater than 5% can respond to most minor hemostatic challenges, whereas those with factor levels less than 1% bleed with minor trauma or even spontaneously. Treatment should be initiated in consultation with the patient's hematologist using medications and specific factor replacement, except in rare, life-threatening, resource-poor situations, when cryoprecipitate or activated prothrombin complex may be considerations.

High 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).This 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.A 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).For 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.

Introduction: Direct oral FXa inhibitors (DOACs, e.g., apixaban [Apix] and rivaroxaban [Riva]) exert their anticoagulant activity by specifically targeting FXa with subnanomolar affinities. Reversal of DOAC-induced anticoagulation can be achieved by immediate and effective sequestration of the inhibitors to relieve inhibition of FXa activity and restore normal thrombin generation (TG). Andexanet alfa (AnXa) is a modified human FXa protein approved in the US and EU for patients treated with Apix or Riva, when reversal of anticoagulation is needed due to life-threatening bleeding. Factor replacement therapies (e.g., 4 factor-PCCs [4F-PCCs]) have demonstrated clinical benefit for vitamin K antagonist-anticoagulated patients by replacing factors II, VII, IX, and X rendered deficient by the anticoagulant. In contrast, the effectiveness and clinical benefit of 4F-PCCs are unclear for reversing DOACs because PCCs do not affect anti-FXa activity. In the present study, we evaluated the effect of individual coagulation factors (FIX, FX, FII), as well as 4F-PCCs on TF-initiated TG (TF-TG) in human platelet poor plasma (PPP), with or without Apix or Riva, and compared it with AnXa under the same conditions. Methods: TF-TG was measured using a calibrated automated thrombogram (CAT, 5 pM TF, Diagnostica Stago). Purified plasma proteins (FIX, FX, FII), PPP, and a commercially available 4F-PCC (Kcentra/Beriplex) were used. 4F-PCC was used with or without pretreatment with the heparinase cup (Haemonetics Corporation) at room temperature for 30 minutes. TF-TG was measured in PPP spiked with purified plasma proteins, 4F-PCC (0-1.0 IU/mL), 4F-PCC + Riva or Apix (0-250 ng/mL), or PPP with AnXa (0-4 μM) + Riva or Apix (0-2000 ng/mL). For comparison, reversal of warfarin anticoagulation by 4F-PCC was performed under similar conditions using individual plasma from warfarin-treated patients (INR = 1.5-6.9) spiked with 4F-PCC (0-1.0 IU/mL). Five CAT parameters were collected, and the endogenous thrombin potential (ETP) and Peak thrombin (Peak) were used for the comparisons. Results: In normal PPP, addition of FX (up to 1.0 IU/mL) had minimal effect on TF-TG parameters, whereas FIX (1.0 IU/mL) mainly increased Peak (~60%). In contrast, FII (1.0 IU/mL) increased both the ETP (~2x) and Peak (~50%). These observations are consistent with the relative plasma concentration and affinity of these coagulation factors as the substrate for the respective enzyme complexes, demonstrating the predominant role of prothrombinase activity in the TF-TG. Addition of 4F-PCC (1.0 IU/mL, equivalent to the therapeutic dose of 50 IU/kg) to PPP caused similar increases of ETP (~2.4x) and Peak (~40%). However, individual plasma protein (FIX, FX, FII) or 4F-PCC up to 1.0 IU/mL was unable to restore normal ETP or Peak in the presence of Apix or Riva (75-250 ng/mL). ETP and Peak increased only when the inhibitor concentrations were sufficiently low ( Conclusions: Specific reversal agents are effective for restoration of TF-TG by either direct sequestration of the FXa inhibitor and restoration of FXa activity (in the case of AnXa with FXa inhibitors) or by replacement of inactive factors due to warfarin treatment (in the case of 4F-PCCs). Addition of coagulation factors or use of 4F-PCCs had limited effect on restoration of normal TG in the presence of a FXa inhibitor. These data demonstrate that AnXa can normalize TF-TG over a wide range of FXa inhibitor concentrations (0-2000 ng/mL), in particular over the range observed in bleeding patients in the ANNEXA-4 study, where 77% of bleeding patients had inhibitor levels ≥75 ng/mL at baseline. In contrast, 4F-PCCs were only able to restore normal TF-TG at low inhibitor levels (90% immediate reversal of anti-FXa activity and >80% hemostatic efficacy with a wide range of FXa inhibitor levels and multiple bleed types. Disclosures Lu: Portola Pharmaceuticals: Employment, Equity Ownership. Lin:Portola Pharmaceuticals, Inc: Employment, Equity Ownership. Bui:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership.

SummaryNewer oral anticoagulants offer several advantages over traditional agents (e.g. warfarin), but they are still associated with a bleeding risk and currently there is no validated reversal treatment for them. While there is little support for the use of fresh frozen plasma, and limited data available on the effects of activated recombinant factor VII, preclinical data suggest that prothrombin complex concentrates (PCCs) may have potential in this setting. PCCs are currently used to successfully reverse warfarin-induced anticoagulation; however, clinical evidence for their use with new oral anticoagulants is lacking, with most of the available data coming from preclinical animal studies. Furthermore, there appears to be variation in the ability of different PCCs to reverse the coagulopathy induced by the new anticoagulants, and a lack of correlation between the reversal of laboratory test results and the reversal of anticoagulant-induced bleeding. Although there have been encouraging results, care must be taken in generalising findings from animal models and nonbleeding human subjects to the situation in bleeding patients. Ultimately, more evidence supporting anticoagulation reversal for new anticoagulants is needed, particularly regarding the treatment of bleeding in human patients in a clinical setting. According to the current evidence, use of PCCs may be considered a reasonable approach in dire clinical situations; however, a consensus has not yet been reached regarding PCC use or dosing, due to lack of clinical data.

espanolEl control de la hemorragia es uno de los pilares de la medicina militar. El shock hemorragico es la primera causa tratable de muerte en combate y supone un reto dentro de la logistica sanitaria. El objetivo de este estudio es analizar el concepto y fisiopatologia de la hemorragia, describir los componentes sanguineos (concentrado de hematies, plaquetas, sangre completa, plasmaferesis y componentes sanguineos congelados), farmacos (fibrinogeno, complejo protrombinico, factor VII activado recombinante y acido tranexamico) y procedimientos (control de la hemorragia a nivel tactico, cirugia del control del dano, resucitacion del control del dano y tromboelastometria) que se pueden emplear para el control de la hemorragia en ambiente militar. EnglishThe bleeding control is one of the topics in military medicine. Hemorrhagic shock is the leading cause of preventable death in combat and is a challenge in medical logistics. The objective of this study is to analyze the concept and physiopathology of the hemorrhage, describing blood components (packed red blood cells, platelets, whole blood, blood components and frozen blood components), medications (fibrinogen, prothrombin complex, recombinant activated factor VII and tranexamic acid) and procedures (tactical hemorrhage control, damage control surgery, damage control resuscitation and thromboelastometry) that can be employed to control bleeding in the military environment.

Inhibitor antibodies to factor VIII arise in a substantial minority of patients with hemophilia A treated with replacement therapy; factor IX inhibitors in treated hemophilia B patients are considerably less common. As replacement therapy is not feasible in most such patients, hemostasis can generally only be achieved with “inhibitor bypassing agents”, namely (activated) prothrombin complex concentrates and recombinant factor VIIa. These agents are widely used to treat active bleeding in inhibitor patients but they have been used relatively infrequently as prophylactic agents to prevent bleeding and its consequences, mainly progressive joint damage. This is in contrast to hemophilia patients without inhibitors, in whom prophylactic replacement with concentrates of factor VIII or IX has become widely accepted as the optimal strategy to prevent these adverse outcomes. This review addresses the current experience and evidence and the future prospects regarding prophylaxis in inhibitor patients.

For emergent warfarin reversal, four-factor prothrombin complex concentrates (4FPCCs) are recommended by many international guidelines. We surveyed international clinical sites including members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Most sites have emergent warfarin reversal protocols (53% use PCC, 25% use PCC+ plasma and 2% use plasma alone); however, variation between adjusted dosing and fixed dosing was observed.

Intro: There have been case reports of ischemic infarcts after treatment with prothrombotics for anticoagulation reversal following spontaneous intracerebral hemorrhage (ICH), though there have been no systematic studies evaluating MRI infarction following prothrombin complex concentrate (PCC) or factor eight inhibitor bypassing activity (FEIBA) administration. We evaluated the prevalence of ischemic infarcts on diffusion-weighted imaging (DWI) in ICH patients who received prothrombotics compared to those who did not. Methods: We performed a retrospective review of patients admitted with ICH between January 2013 and April 2016 in whom MRI brain with DWI imaging was performed within 2 weeks of admission and prior to digital subtraction angiography. PCC (4-factor Kcentra, weight, and INR based dosing) was administered to patients on warfarin at the time of ictus with a INR≥1.4 and FEIBA (50 u/kg) was given to patients exposed to an oral Factor Xa inhibitor or direct thrombin inhibitor if ICH occurred within 3-5 half lives of the last dose. Acute ischemia was defined as DWI hyperintensity with corresponding apparent diffusion coefficient hypointensity. Perihematoma lesions, and procedure-related infarctions were excluded from analysis. Groups were compared using chi-square and Wilcoxon Rank Sum tests. Results: A total of 254 patients were enrolled. Of these, 41 (16%) received either 4-factor PCC (n=33) or FEIBA (n=8). Comparing those who received prothrombotics to those who did not, there was no difference in age (median 68 with prothrombotics and without; p=0.724), sex (44% female in both groups; p=0.977), initial NIH Stroke Scale (median 6 versus 8, p=0.838), or hematoma volume (median 15ml versus 10ml; p=0.207). Patients who received prothrombotics were more likely to have lobar ICH than deep ICH (71% versus 47%; p=0.005). DWI infarctions were found in 16% of patients who receive PCC or FEIBA compared with 22% who did not (p=0.404). Conclusions: Our data suggests prothrombotics do not increase the risk of acute ischemic infarcts within two weeks of administration.

WOS: 000395347700002 PubMed: 27553841 Recombinant factor VIIa (rFVIIa) is used in the management of bleeding in patients with hemophilia. A generic biosimilar version of NovoSeven is also developed (AryoSeven). To compare the activation profile of NovoSeven and AryoSeven, 2 commercially available protein complex concentrates (PCCs) were used. Profilnine activated by RecombiPlasTin 2G resulted in conversions of prothrombin to prethrombin and thrombin at 5 to 30 minutes. However, addition of rFVIIa at final concentration range of 0.25 to 0.5 mu g/mL to the same mixture resulted in total conversion of prothrombin to thrombin with a doublet at 36 kDa. Recombinant factor VIIa alone did not generate thrombin in native Beriplex, and the addition of rFVIIa to Beriplex failed to generate thrombin. Beriplex activated by RecombiPlasTin 2G resulted in complete conversion of prothrombin to thrombin. Both NovoSeven and AryoSeven exhibited similar activation profiles. These studies indicate that the activation of PCCs by both rFVIIa preparations results in comparable generation of thrombin.

Supplemental Digital Content is available in the text. Published ahead of print August 24, 2017., Prothrombin complex concentrates (PCCs) have been associated with a possible risk of thromboembolic complications, potentially attributable to an increased ratio of the plasma concentration of factor II (FII) to antithrombin (AT). We developed a mathematical model to examine the relationship between amounts of PCC or therapeutic plasma administered, and plasma levels of FII and AT. The model showed that PCC produces substantial increases in plasma levels of FII but only small changes in AT, increasing the FII:AT ratio. Therapeutic plasma was shown to have only modest effects on levels of FII or AT, unless high doses are used.

Background Warfarin-related intracerebral haemorrhage (WRICH) has high mortality. Haematoma expansion is prolonged in WRICH and independently predicts worse outcomes. Guidelines recommend prompt reversal of the warfarin coagulopathy, but evidence of benefit is lacking. Aims To determine whether the introduction of a WRICH reversal protocol (late 2008), which includes prothrombin complex concentrates (PCC), improves outcomes Methods All patients presenting with WRICH between January 2004 and July 2010 were included. Retrospective case note and radiology review was performed, collecting data on intracerebral haemorrhage (ICH) severity, degree and timeliness of reversal, and patient outcomes. Cox's proportional hazards analysis was used to compare outcomes associated with and without PCC after controlling for ICH severity. Results Eighty-eight patients were included (27 treated palliatively). Mean international normalised ratio was 2.9. Vitamin K, PCC and fresh frozen plasma were given alone or in combination to 68, 23 and 44 patients, and mean time from computed tomography scanning to administration was 2.2, 3.3 and 3.1 h respectively. Four patients received PCC pre-protocol (none before 2007), two during development and seventeen patients post-protocol. Those who received PCC had improved survival (P < 0.001). After controlling for ICH score, hazard ratio for death was 0.27 (P < 0.01) for use of PCC. Survival tended to be greater with earlier administration of PCC (P = 0.053). Despite improved survival, discharge domicile and function were not significantly worse. Conclusions PCC reversal was associated with improved survival without worsened disability. Delays in administration may have reduced the potential benefits.

Introduction Prothrombin complex concentrates (PCCs) are recommended as first-line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients. Method We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards. Results During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs. Conclusions In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care.

Hemostasis involves complex processes meaning blood not to extravasate. It's temporary cessation is necessary to perform cardiac surgery procedure with cardiopulmonary bypass. In heart transplantation, standard procedures of heparine neutralization are insufficient. We present results obtained from the group of 10 patients (8 men and 2 women) in mean age of 41 ± 15 years, who underwent heart transplantation procedure with Lower-Shumway technique in moderate hypothermia (28°C). Mean cardiopulmonary bypass time was 218 ± 20 min, cross clampling aortic time was 114 ± 18 min and organ cold ischemia time was 221 ± 16 min. Postoperative human prothrombin complex was given after INR result (2.2 ± 0.3) was obtained followed by normalized activated clotting time (ACT) 124 ± 17 seconds. In high risk patients undergoing cardiac surgery procedure, standard international normalized ration (INR) measurements following ACT results are required to obtain more detailed information concerning plasma hemostasis disturbances. Prothromplex Total NF (Baxter International Inc, USA) is a safe option to correct the problem without risk of overloading the patients circulatory system.

Background: Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol. Methods: We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment. Results: Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively). Conclusion: Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy.

The vitamin K antagonists (VKAs) are associated with a significant rate of major and fatal bleeding complications. The new direct oral anticoagulants (DOACs), even though having a better bleeding profile than the VKAs, are still associated with serious bleeding. The anticoagulation induced by the VKAs can be reversed with both vitamin K and prothrombin complex concentrates, whereas the DOACs were developed without specific reversal agents. Although there is controversy around the necessity of a reversal agent, most clinicians agree that having a reversal agent for the DOACs would be beneficial. Three reversal agents are currently in development.

Purpose Prior to the Food and Drug Administration approval of 4-factor prothrombin complex concentrate (4F-PCC), only 3-factor PCC (3F-PCC) products were available in the US. There is limited data comparing the safety and efficacy of 3F-PCC versus 4F-PCC. The purpose of our study, therefore, was to compare the safety and efficacy profiles of 3F-PCC versus 4F-PCC for the emergent reversal of warfarin. Methods A single-center, retrospective cohort analysis compared patients who received 3F-PCC or 4F-PCC for the emergent reversal of warfarin due to life-threating bleeding from January 2013 to September 2015. The primary objective of this study was the percentage of patients whose international normalized ratio (INR) reversed to ≤ 1.5 within 8 h of PCC administration. The secondary safety objective was incidence of thromboembolic events at 7 days post PCC. Results A total of 137 patients were included. The median baseline INR was 3.15 in the 3F-PCC group and 3.1 in the 4F-PCC group. The median post-PCC INR was 1.4 in the 3F-PCC group and 1.3 in the 4F-PCC group. INR ≤ 1.5 was achieved in 45/58 (78%) patients in the 3F-PCC group and 46/58 (79%) patients in the 4F-PCC group (p = 0.61). The thromboembolic event rate between the two groups at 7 days was similar, 4/68 (5.9%) for 3F-PCC versus 4/69 (5.8%) for 4F-PCC (p = 1.0). Conclusions There was no significant difference in the percentage of patients who achieved an INR ≤ 1.5 between the 3F-PCC and 4F-PCC groups for emergent reversal of warfarin.

Transfusion of blood products can be life saving when used appropriately. It carries however at the same time a potential for morbidity and mortality, depending on the patient, the product or the setting. Numerous strategies have been elaborated to minimize these risks, and in recent years, transfusion has no longer been regarded as essential for the management of a wide range of diseases. Uncomplicated surgeries in well-prepared patients can now be conducted without the use of transfusions. Questions about transfusion safety and shortage have led to extensive research on alternatives to blood transfusion, ranging from non-pharmacological to pharmacological solutions. Restrictive transfusion therapies, preoperative autologous blood donations, perioperative red cell salvage, acute normovolaemic haemodilution techniques or patient blood management are potential solutions where prothrombin complex or fibrinogen concentrates, synthetic anti-fibrinolytic agents, desmopressin, rFVIIa, or erythropoiesis stimulating agents may play a complementary pharmacologic role.

Insufficiency fractures are a common cause of morbidity among geriatric patients worldwide. Improved outcomes are known to result from decreased delay to definitive operative fixation and mobilization. Use of warfarin is an important potential cause of delay. The ideal mode of warfarin reversal is currently unknown. Prothrombin complex concentrates (PCCs) offer rapid correction with small infusion volume, both of which are important for elderly patients with multiple comorbidities. The authors present 2 cases of insufficiency fractures occurring in geriatric patients receiving warfarin therapy reversed with a 3-factor PCC. Both patients were independent, community ambulators without significant functional disability and returned to their prior level of functioning. There were no significant bleeding or venous thromboembolic complications. To the authors' knowledge, no previous reports have described the use of PCC in geriatric patients with fractures. Nonetheless, its potential is well documented in emergency and trauma surgery literature. The use of PCC could potentially allow surgeons and hospitals to avoid complications related to immobility and the associated costs of treatment, extended hospital stay, and readmission. The authors' limited experience suggests 3-factor PCC preparations may provide adequate correction to allow expeditious surgical treatment. [ Orthopedics. 2017; 40(2):e367–e369.]

Intracerebral haematoma expansion independently predicts poor functional outcome and mortality. Therefore, it is important to act quickly to arrest this expansion. Whilst a direct antidote to dabigatran remains in development, the use of factor VIII inhibitor bypassing activity may offer a practical strategy for arresting haemorrhage in individuals taking direct thrombin inhibitors.

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.

Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available.

SummaryUrgent reversal of warfarin is required for patients who experience major bleeding or require urgent surgery. Treatment options include the combination of vitamin K and coagulation factor replacement with either prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP). However, the optimal reversal strategy is unclear based on clinically relevant outcomes. We searched in MEDLINE, EMBASE and Cochrane library to December 2015. Thirteen studies (5 randomised studies and 8 observational studies) were included. PCC use was associated with a significant reduction in all-cause mortality compared to FFP (OR= 0.56, 95 % CI; 0.37–0.84, p=0.006). A higher proportion of patients receiving PCC achieved haemostasis compared to those receiving FFP, but this was not statistically significant (OR 2.00, 95 % CI; 0.85–4.68). PCC use was more likely to achieve normalisation of international normalised ratio (INR) (OR 10.80, 95 % CI; 6.12–19.07) and resulted in a shorter time to INR correction (mean difference –6.50 hours, 95 %CI; –9.75 to –3.24). Red blood cell transfusion was not statistically different between the two groups (OR 0.88, 95 % CI: 0.53–1.43). Patients receiving PCC had a lower risk of post-transfusion volume overload compared to FFP (OR 0.27, 95 % CI; 0.13–0.58). There was no statistically significant difference in the risk of thromboembolism following administration of PCC or FFP (OR 0.91, 95 % CI; 0.44–1.89). In conclusion, as compared to FFP, the use of PCC for warfarin reversal was associated with a significant reduction in all-cause mortality, more rapid INR reduction, and less volume overload without an increased risk of thromboembolic events.Supplementary Material to this article is available online at www.thrombosis-online.com.