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У статті подано сучасні рекомендації з інтенсивної терапії гострої крововтрати в акушерстві. Акушерські кровотечі залишаються провідною причиною материнської смертності в усьому світі. Нові стратегії лікування кровотеч передбачають використання гемостатичної реанімації з визначенням оптимального співвідношення для введення різних компонентів і препаратів крові. Масивні протоколи трансфузії рекомендують раннє використання продуктів крові й обмежують традиційний підхід ранньої масивної інфузійної терапії на основі кристалоїдів. За останні кілька років змінилися дані про гемостатичну реанімацію, і тепер ведуться обговорення щодо оптимальних стратегій інфузійно-трансфузійної терапії. Використання транексамової кислоти, концентрату фібриногену і концентрату протромбінового комплексу стало потенційно новою альтернативною стратегією лікування з поліпшеними профілями безпеки.

Background Reversal of warfarin with prothrombin complex concentrates (PCC) is required in cases of significant bleeding or need for urgent surgery. A weight-based regimen is commonly, but a fixed-dose approach is also feasible with clinically equivalent outcomes. The purpose of this audit is to review the clinical and laboratory outcomes of patients treated in our centre where fixed-dose PCC is used for warfarin reversal. Objectives The primary objective was to evaluate the post-reversal INR. Secondary objectives were the proportion of patients requiring repeat PCC and 30-day complication rates (death, haemorrhage and thrombosis). A subgroup analysis was also performed to compare the outcomes of those who received a dose of ≤15 IU/kg (reduced dose) to those who received >15 IU/kg (standard dose). Methods Patients who received three-factor PCC for warfarin reversal between 1st January and 31st December 2016 were identified and analysed. Clinical data and PCC dosages were extracted from electronic patient records. Results Total of 144 patients were analysed. The median INR pre-reversal was 3.25 (range 1.4-10), which reduced to 1.5 (0.9-3.0) post-reversal. 87% of patients achieved a post-reversal INR of less than 2 and 55% less than 1.5. Sixteen patients required a repeat dose. Complications occurred in 22 patients (15.3%), which consisted of 15 deaths, 7 thrombosis and 2 haemorrhage. No statistically significant differences in the primary and secondary outcomes were noted between reduced-dose and standard-dose subgroups. Conclusion Our results support the use of fixed-dose PCC for warfarin reversal in a day-to-day clinical practice in a hospital setting. This article is protected by copyright. All rights reserved.

Background Patients receiving oral anticoagulation who experience a traumatic intracranial hemorrhage (ICH) should receive anticoagulation reversal. Four factor prothrombin complex concentrate (4FPCC) is indicated for reversal of warfarin, and is frequently used for reversal of direct-acting oral anticoagulants (DOACs). The purpose of this study is to compare the safety and efficacy of 4FPCC reversal for traumatic ICH in DOAC- and warfarin-anticoagulated patients. Methods This was a single-center, retrospective review of adult patients with traumatic ICH who received 4FPCC for reversal of anticoagulation between April 2013 and August 2018. The ICH volume on the pre- and post-reversal head CT scans was measured. The primary endpoint was the incidence of expansion of ICH volume of blood using pre-and post-4FPCC imaging. Results A total of 102 patients meeting inclusion criteria were identified with 75 patients in the warfarin group and 27 patients in the DOAC group. There were no significant differences in baseline characteristics between the groups except DOAC patients had larger ICH volumes at baseline as compared to warfarin patients (23.4 mm3 vs 3.7 mm3, p = 0.0001). There was neither a statistical difference in change in ICH volume pre-and post-4FPCC administration, nor in the rate of >20% ICH expansion between the warfarin and DOAC groups. There was no difference in the rate of adverse events compared between groups. Conclusion There was no difference in the either the change in ICH volume or the rate of >20% ICH expansion in patients receiving 4FPCC for reversal DOAC versus warfarin anticoagulation. Rates of complications were low in both groups.

Direct acting oral anticoagulants (DOAC) are now commonly prescribed medications. Urgent reversal of their anticoagulant effect is sometimes required in emergency situations. In Australia, a specific reversal agent for factor Xa (FXa)-inhibitor DOAC is not available. Instead, two non-specific haemostatic agents, activated prothrombin complex concentrate (aPCC) and 3 factor-prothrombin complex concentrate (3F-PCC), are used off-label despite a paucity of evidence for their effectiveness or safety.To provide further insight into the efficacy and safety of 3F-PCC and aPCC for the reversal of the anticoagulant effect of FXa inhibitor DOACs.We conducted a single-centre retrospective cohort study to investigate the use of aPCC and 3F-PCC for patients on FXa-inhibitor DOAC who present with a significant bleeding event or who require urgent surgery. The primary outcome was haemostatic efficacy according to prespecified criteria. Safety outcomes included the thromboembolic event rate and all-cause mortality during the hospital admission.A total of 51 patients was included in the study (36 patients who had a spontaneous bleeding event and 15 non-bleeding patients who required urgent perioperative management). Thirty-one patients received aPCC and 20 patients received 3F-PCC. Haemostasis was adjudicated as effective in all assessable patients (n = 50; 100%). Thromboembolic events occurred in three patients who received aPCC and one patient who received 3F-PCC. All-cause mortality was 7.8% (four patients).Both aPCC and 3F-PCC are useful adjuncts for the management of patients who require urgent reversal of the anticoagulant effect of FXa-inhibitor DOAC. However, the risk of thromboembolism in this patient group requires careful consideration. Prospective, comparator studies are needed along with the development of guidelines that reflect the availability of haemostatic agents in Australia.

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients ( P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively ( P = .99). Mortality incidence was 12.5% and 31.3%, respectively ( P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

Prothrombin complex concentrates (PCCs) are used to manage bleeding in critically ill children. We performed a repeat cross-sectional study using the Pediatric Health Information System registry to describe PCC utilization in the U.S. children's hospitals over time and determine the relationship between PCC use and specific risk factors for bleeding. We included children

Study Objective: Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages. Methods: A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*. Results: Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent. Conclusion: Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.

In patients following aortic surgery, the prevention and treatment of bleeding requires a multimodal approach that includes targeting fibrinogen and platelet repletion, the use of anti-fibrinolytic agents, and evaluating surgical sources of bleeding. Prothrombin complex concentrates, and fibrinogen concentrates are becoming increasingly important components of treatment algorithms. With major hemorrhage, specific protocols for massive transfusion in conjunction with pharmacologic agents should be considered. Bleeding management algorithms using viscoelastic testing to guide targeted replacement are being used increasingly in complex cardiac surgical patients.

Expert consensus and international guidelines recommend urgent co-administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) to rapidly reverse VKA-related bleeding. This narrative review examined real-world evidence and strategies to optimize international normalized ratio (INR) reversal, hemostasis, and outcomes in patients receiving 4F-PCC in this setting. Key determinants for success include the appropriate use of alternative dosing and administration strategies, such as fixed dosing and increased infusion speed, adherence to institutional guidelines, and removing significant institutional barriers to reduce time to treatment. In the opinion of authors, minimizing the time to treatment with 4F-PCCs is of paramount importance when treating patients with VKA-related bleeding. Practices that safely and feasibly shorten the time to administration should be included in guidelines for institutions responsible for anticoagulant care, and adhered to in centers that perform invasive procedures on patients receiving VKA therapy. Further studies are required to optimize use of 4F-PCC, particularly in relation to the ideal dosing strategy and the role of INR.

Rivaroxaban has the most available data to support the use of prothrombin complex concentrates (PCC) as a reversal agent. However, PCC might increase the incidence of thrombotic events by shifting the haemostatic balance towards hypercoagulability. We assessed the in vitro efficacy and safety of three 4-factor PCCs for reversing rivaroxaban anticoagulant effect. Our in vitro finding indicates that 4-factor PCCs at the dose of 25 U.kg− 1 may be sufficient to reverse rivaroxaban anticoagulant effect.

Thrombosis has proven to be extremely difficult to predict. Measuring the generation of thrombin is a very sensitive method to detect changes in the hemostatic system. We developed a method based on the generation of thrombin to further fingerprint hemostasis, which we have named thrombin dynamics. Via this method we are able to exactly measure the prothrombin conversion and thrombin inactivation, and any change in the coagulation cascade will be reflected in these two processes. In the current study we analyzed the importance of the members of the prothrombin complex on the dynamics of thrombin activation and inactivation. We show that prothrombin conversion is predominantly influenced by factor X and antithrombin, which will provide essential insights in complex thrombosis-related diseases, such as liver cirrhosis and kidney failure.

Anticoagulant-related bleeding carries considerable morbidity and mortality. Major or life-threatening bleeding is among the most severe of these complications. As the number of patients treated with direct oral anticoagulants (DOACs) continues to increase, so does the number of DOAC-related bleeding events. The incidence of CRNM bleeding related to DOAC therapy ranges from 15 to 18% per 100-year patients, while the incidence of major bleeding ranges from 2.71 to 3.6%. Many of these bleeding events can be prevented with tailored dosing regimens or proper peri-procedural management. When unable to be prevented, DOAC-related bleeding can lead to significant long-term disability or death. Management with newer reversal agents such as andexanet alfa and idarucizumab, as well as prothrombin complex concentrates, may improve outcomes for patients with DOAC-related bleeding. The purpose of this review is to explore strategies for preventing and treating bleeding in patients receiving DOACs for anticoagulant therapy.

Obstetrical hemorrhage is the most common cause of maternal mortality worldwide. Together with adequate surgical control and judicious transfusion of blood products, the use of pharmacological agents (e.g., tranexamic acid) and clotting factor concentrates (e.g., fibrinogen concentrates and prothrombin complex concentrates) results in improved hemostasis and decreased bleeding-associated mortality. Guidance in the administration of these agents with the use of viscoelastic testing will likely become standard of care in the near future.

Studies evaluating the use of activated prothrombin complex concentrates (aPCCs) for DOAC-associated bleeding are sparse.We conducted a retrospective study of patients receiving aPCC for DOAC-associated bleeding or for pre-operative optimization of hemostasis prior to urgent surgery. The primary efficacy outcome was hemostatic efficacy, the primary safety outcome was the 30-day thromboembolic complication rate.Eighty-two patients were included in the analysis; 14 patients on dabigatran, 39 patients on rivaroxaban and 29 patients on apixaban. Fifty-four patients received aPCC for major bleeding and 28 patients prior to urgent surgery. Mean aPCC dosing was 2974 IU (SD ± 857 IU). Hemostasis was deemed effective by ISTH criteria in 50% of cases and "Good" or "Moderate" by Sarode criteria in 45.2% and 14.3% of cases, respectively. Surgical hemostasis was rated as "Normal" in 84% of cases pre-operative administration. Median pre-aPCC INR was 1.6 (IQR 0.5) and median post-aPCC INR was 1.2 (IQR 0.2) (p 0.00001). Median pre-aPCC aPTT was 36 s (IQR 12.8), median post-aPCC aPTT was 29 s (IQR 9.8) (p = 0.0001). The 30-day thromboembolic event rate was 6.1%.Further study is needed to characterize the hemostatic effects and thromboembolic risk of aPCC among patients with DOAC-associated bleeding or for attempted normalization of hemostasis prior to urgent surgery.

Prothrombin complex concentrate (PCC) is used as an alternative to fresh frozen plasma (FFP) for emergency bleeding. The primary objective of this study was to compare the time from order to start of administration between 3-factor PCC (PCC3), 4-factor (PCC4), and FFP in the emergency department (ED). The secondary objective was to evaluate the effect of an ED pharmacist on time to administration of PCCs.This was a single center three-arm retrospective cohort study. Adult patients in the ED with bleeding were included. The primary outcome measure was the time from order to administration, which was compared between PCC3, PCC4, and FFP. The time from order to administration was also compared when the ED pharmacist was involved versus not involved in the care of patients receiving PCC.There were 90 patients included in the study cohort (30 in each group). The median age was 69years (IQR 57-82years), and 57% (n=52) were male. The median time from order to administration was 36min (IQR 20-58min) for PCC3, 34min (IQR 18-48min) for PCC4, and 92min (IQR 63-133) for FFP (PCC3 versus PCC4, p=0.429; PCC3 versus FFP, p0.001; PCC4 versus FFP, p0.001). The median time from order to administration was significantly decreased when the ED pharmacist was involved (24min [IQR 15-35min] versus 42min [IQR 32-59min], p0.001).Time from order to administration is faster with PCC than FFP. ED pharmacist involvement decreases the time from order to administration of PCC.

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

Traumatic coagulopathy has now been well characterized and carries high rates of mortality owing to bleeding. A 'factor-based' resuscitation strategy using procoagulant drugs and factor concentrates in lieu of plasma is being used by some, but with little evidentiary support. We sought to evaluate and compare resuscitation strategies using combinations of tranexamic acid (TXA), prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP).Sixty adult swine underwent 35% blood volume hemorrhage combined with a truncal ischemia-reperfusion injury to produce uniform shock and coagulopathy. Animals were randomized to control (n = 12), a single-agent group (TXA, n = 10; PCC, n = 8; or FFP, n = 6) or combination groups (TXA-FFP, n = 10; PCC-FFP, n = 8; TXA-PCC, n = 6). Resuscitation was continued to 6 hours. Key outcomes included hemodynamics, laboratory values, and rotational thromboelastometry. Results were compared between all groups, with additional comparisons between FFP and non-FFP groups.All 60 animals survived to 6 hours. Shock was seen in all animals, with hypotension (mean arterial pressure, 44 mm Hg), tachycardia (heart rate, 145), acidosis (pH 7.18; lactate, 11), anemia (hematocrit, 17), and coagulopathy (fibrinogen, 107). There were clear differences between groups for mean pH (p = 0.02), international normalized ratio (p0.01), clotting time (CT; p0.01), lactate (p = 0.01), creatinine (p0.01), and fibrinogen (p = 0.02). Fresh frozen plasma groups had significantly improved resuscitation and clotting parameters (Figures), with lower lactate at 6.5 versus 8.4 (p = 0.04), and increased fibrinogen at 126 versus 95 (p0.01). Rotational thromboelastometry also demonstrated shortened CT at 60 seconds in the FFP group vs 65 seconds in the non-FFP group (p = 0.04).When used to correct traumatic coagulopathy, combinations of FFP with TXA or PCC were superior in improving acidosis, coagulopathy, and CT than when these agents are given alone or in combination without plasma. Further validation of pure factor-based strategies is needed.

Anesthesiologists managing traumatically injured patients are seeing an increased incidence of patients on direct oral anticoagulants (DOACs). Management of these patients requires an understanding of the pharmacology and pharmacodynamics of these agents in the perioperative setting. With limited reversal options, what are the best options for managing these often complex patients? The reversal agent for dabigatran, idarucizumab, can be useful in the setting of severe hemorrhage. The role of prothrombin complex concentrates is less clear but continues to be recommended in most published guidelines. Management of the DOAC-associated bleeding in the trauma patient requires a stepwise approach taking the severity of bleeding and urgency of surgery/procedures into consideration as well as hemodynamic stability and mortality risk. Frequently, a conservative approach that allows for a drop in plasma DOAC levels is the best option for the patient with minimal to no bleeding. The use of specific reversal agents is limited to dabigatran, but other agents are on the horizon.

Factor X deficiency is one of the rare inherited coagulation disorders. Symptoms vary from mild to severe with the commonest being epistaxis, gum bleeds and menorrhagia. The diagnosis is suspected when both PT and aPTT are prolonged and remains uncorrected following Vitamin K administration. Replacement of Factor X can be accomplished with Fresh Frozen Plasma(FFP) or plasma derived concentrates such as Prothrombin Complex Concentrates(PCC). We report a male child who presented with intracranial haemorrhage at age of 18 months as the presenting manifestation of severe congenital Factor X deficiency.

BACKGROUND Patients on warfarin who present with bleeding or who require an urgent procedure are commonly treated with intravenous (IV) vitamin K, which is supplemented with repletion of the vitamin K factors using either plasma or a prothrombin complex concentrate (PCC). In some such cases, use of vitamin K alone could be adequate to achieve acceptable hemostasis. STUDY DESIGN AND METHODS An algorithm emphasizing the use of vitamin K alone in patients presenting with non–life-threatening bleeding was encouraged, with repeat testing of the international normalized ratio (INR) within 5 hours. Depending on the INR result, patients received no factor repletion or plasma or PCC, as judged by the physician. Leftover samples from a separate cohort of patients with supratherapeutic INRs (INR > 4.0) were studied for clotting factor evaluation. RESULTS A total of 46 pre- and postinfusion INRs were evaluable from 41 patients. Median INR decreased from 5.8 to 2.5, with a median dose of 5 mg after a median time of 4.0 hours postinfusion. A total of 27 of 46 (59%) postinfusion samples showed an INR of 2.5 or less. Samples from patients with the highest INR showed the greatest decline in INR. Samples from supratherapeutic INR patients showed very high Factor VIII:C (200%) and a normal activated partial thromboplastin time in 23 of 50 (46%). CONCLUSION Use of IV vitamin K as sole therapy for urgent partial reversal of warfarin for non–life-threatening bleeding may provide adequate hemostasis within 5 hours, avoiding the need for clotting factor repletion.

Prothrombin complex concentrates (4F-PCC) for anticoagulation reversal pose a risk of thromboembolism although data are limited. This study aims to quantify thromboembolic events (TE) and describe associations.Retrospective, two-center, study of patients receiving 4F-PCC between September 2013 and December 2017 for warfarin or direct oral anticoagulant (DOAC) reversal. Primary outcome was in-hospital TE incidence and secondary outcomes were to describe characteristics associated with TE. Data are reported descriptively and analyzed with bivariate and multivariate analyses.542 patients were included (mean age 73 ± 14 years, 58% male, 76.6% warfarin/23.4% DOAC reversal). Most had intracranial hemorrhage (68.5%) or were undergoing an emergent procedure (13.4%). Fifty patients (9.2%) experienced in-hospital TE and most (62%) occurred within 7 days of 4F-PCC. Younger age (66 vs. 74 years, p 0.01), presence of a hypercoagulable risk factor (46% vs. 26%, p 0.01), indication for anticoagulation (p = 0.008), higher 4F-PCC dose (2148 vs. 2000 units, p 0.01), and longer hospital length of stay (LOS) (21.5 vs. 7 days, p 0.01) were associated with TE following bivariate analysis. Multivariate analysis identified anticoagulation indication of venous thromboembolism or "other" (e.g., antiphospholipid syndrome, Factor V Leiden) were independently associated with higher incidence of TE compared to receiving anticoagulation for atrial arrhythmia (p = 0.05). Hospital LOS ≥ 7 days was associated with threefold greater odds of TE compared to7 days (p = 0.003).In-hospital TE following 4F-PCC was 9.2%, most events occurred within 7 days, and younger age, indication for anticoagulation, and LOS were independently associated with TE which may influence treatment selection.

BACKGROUND:The use of prothrombin complex concentrates in trauma- and surgery-induced coagulopathy is complicated by the possibility of thromboembolic events. To explore the effects of these agents on thrombin generation (TG), we investigated combinations of coagulation factors equivalent to 3- and

The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available.We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed.The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.

Bleeding is a serious complication after pediatric cardiopulmonary bypass (CPB) that is associated with an increase in perioperative morbidity and mortality. Four-factor prothrombin complex concentrates (4F-PCCs) have been used off-label to supplement transfusion protocols for bleeding after CPB in adults; however, data on their use in neonates are limited. In this study, we hypothesized that 4F-PCCs administered ex vivo to neonatal plasma after CPB will increase thrombin generation.Fifteen neonates undergoing complex cardiac repairs requiring CPB were enrolled in this prospective study. Arterial blood was obtained after anesthesia induction but before CPB (baseline), after CPB following heparin reversal, and after our standardized transfusion of a quarter of a platelet apheresis unit (approximately 20 mL·kg) and 3 units of cryoprecipitate. Kcentra (CSL Behring), a 4F-PCC with nonactivated factor VII (FVII), and factor 8 inhibitor bypassing activity (FEIBA; Baxter Healthcare Corporation), a 4F-PCC with activated FVII, were added ex vivo to plasma obtained after CPB to yield concentrations of 0.1 and 0.3 IU·mL. Calibrated automated thrombography was used to determine thrombin generation for each sample.The addition of Kcentra to plasma obtained after CPB resulted in a dose-dependent increase in the median (99% confidence interval) peak amount of thrombin generation (42.0 [28.7-50.7] nM for Kcentra 0.1 IU·mL and 113.9 [99.0-142.1] nM for Kcentra 0.3 IU·mL). The rate of thrombin generation was also increased (15.4 [6.5-24.6] nM·min for Kcentra 0.1 IU·mL and 48.6 [29.9-66.6] nM·min for Kcentra 0.3 IU·mL). The same was true for FEIBA (increase in peak: 39.8 [27.5-49.2] nM for FEIBA 0.1 IU·mL and 104.6 [92.7-124.4] nM for FEIBA 0.3 IU·mL; increase in rate: 17.4 [7.4-28.8] nM·min FEIBA 0.1 IU·mL and 50.5 [26.7- 63.1] nM·min FEIBA 0.3 IU·mL). In the posttransfusion samples, there was a significant increase with Kcentra in the median (99% confidence interval) peak amount (41.1 [21.0-59.7] nM for Kcentra 0.1 IU·mL and 126.8 [106.6- 137.9] nM for Kcentra 0.3 IU·mL) and rate (18.1 [-6.2 to 29.2] nM·min for Kcentra 0.1 IU·mL and 53.2 [28.2-83.1] nM·min for Kcentra 0.3 IU·mL) of thrombin generation. Again, the results were similar for FEIBA (increase in peak: 43.0 [36.4-56.7] nM for FEIBA 0.1 IU·mL and 109.2 [90.3-136.1] nM for FEIBA 0.3 IU·mL; increase in rate: 25.0 [9.1-32.6] nM·min for FEIBA 0.1 IU·mL and 59.7 [38.5-68.7] nM·min for FEIBA 0.3 IU·mL). However, FEIBA produced in a greater median reduction in lag time of thrombin generation versus Kcentra in samples obtained after CPB (P = 0.003 and P = 0.0002 for FEIBA versus Kcentra at 0.1 and 0.3 IU·mL, respectively) and in samples obtained after transfusion (P0.0001 for FEIBA versus Kcentra at 0.1 and 0.3 IU·mL).After CPB, thrombin generation in neonatal plasma was augmented by the addition of 4F-PCCs. The peak amount and rate of thrombin generation were enhanced in all conditions, whereas the lag time was shortened more with FEIBA. Our findings suggest that the use of 4F-PCCs containing activated FVII may be an effective adjunct to the initial transfusion of platelets and cryoprecipitate to augment coagulation and control bleeding in neonates after CPB.

Patients with severe congenital protein (P)C deficiency require long-term anticoagulant management. Recombinant PC concentrates for prophylactic use are not available in Japan; prothrombin complex concentrates (PCC), containing factors (F)II, VII, IX, X, and PC (PPSB-HT®), have been used ‘off-label’ in a few patients. We investigated the combined use of prophylactic PCC and Warfarin (VKA; PT-INR 2.0–2.5) in a severely PC-deficient patient in whom VKA alone did not prevent recurrent purpura. Plasma VKA-dependent factor levels and global PC function (Thrombopath®) were assessed. Plasma activity levels of FII/FVII/FIX/FX post-infusion of PCC (6.3 unit/kg) increased 35/27/27/35 (initial level) to 59/60/38/83 IU/dl, respectively. FVII:C and FIX:C rapidly returned to baseline levels 12–24 h post-infusion, but FII:C and FX:C returned more slowly. PC antigen (

Treatment of microvascular bleeding following cardiac surgery is nowadays based on treatment algorithms and specific monitoring devices. Using these treatment algorithms, specific procoagulant therapies can be initiated to encounter a coagulopathy. Among these therapies are fibrinogen concentrate, prothrombin concentrate, antifibrinolytics, and desmopressin. Specific targeting of parts of the coagulation system may contribute to a reduction in bleeding volumes and transfusion requirements after cardiac surgery.

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.