Initiation of a fixed-dose four-factor prothrombin complex concentrate protocol.

Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to weight and initial INR. Our institution implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units. We evaluated the frequency with which the initial fixed dose 4F-PCC was inadequate, as defined by need for supplemental dosing. As part of the protocol, if the initial fixed-dose 4F-PCC is administered and does not achieve INR goal, then the remainder of the standard weight- and INR-based dosing can be given. During the study period, 63 patients on warfarin received 4F-PCC using the fixed-dose protocol. Based on the INR following 4F-PCC administration, 11 patients (17%) were eligible to receive a supplemental dose based on failure to achieve their specified INR goal. Two of the 11 patients eligible for supplemental 4F-PCC dosing received the second dose, both with initial supratherapeutic INRs > 3.5. We found that most patients given an initial fixed-dose 4F-PCC achieved their INR goals, and of those who did not, most did not receive supplemental dosing, suggesting that clinical providers felt that adequate hemostasis had been achieved. In addition, fixed-dose 4F-PCC was able to be given rapidly, with few dosing errors, suggesting that this is a reasonable option for 4F-PCC delivery.

Safety and effectiveness of a prothrombin complex concentrate in approved and off-label indications.

OBJECTIVE: To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. BACKGROUND: PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. METHODS: This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (<1·5) and (ii) clinical efficacy as bleeding cessation and/or decreased number of transfused blood components and 24-h mortality in bleeding coagulopathy. The safety end-point is the incidence of thromboembolic events. RESULTS: A total of 328 patients were included (51·8% male, median age 78 years old). Indications were as follows: VKA reversal (66·6%), bleeding coagulopathy (30·5%) and direct anticoagulant (DOAC) reversal due to bleeding (2·5%). VKA reversal was effective in 97·1% of patients, and 76·5% demonstrated complete reversal (INR < 1·5); only 34·3% patients needed hemoderivatives. Prior to emergency procedures, PCCs achieved global responses in 83% of patients, with no bleeding complication during intervention. DOAC reversal was effective in 88·9% of patients. Bleeding cessation was associated with the dose administered (P = 0·002). In coagulopathy bleeding, haemorrhage cessation, established by the International Society of Thrombosis and Haemostais (ISTH) definition, occurred in 56·7% of massive bleeding events and in 42·5% of other coagulopathies; 24-h mortality was 30%, mainly related to active bleeding. Ten thrombotic episodes were observed (3·1%). CONCLUSION: 4F-PCC was effective as adjuvant treatment with an acceptable safety profile, not only for the emergent reversal of VKAs but also for refractory coagulopathy associated with major bleeding.

Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants.

OBJECTIVE: Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event. DESIGN: Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event. SETTING: Academic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 ±â€¯3.6 units/kg) and 26 received moderate dose (mean 24.3 ±â€¯2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions. CONCLUSIONS: Low (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events.

Rapid response to intravenous vitamin K may obviate the need to transfuse prothrombin complex concentrates.

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.

[EMERGENCY TREATMENT OF BLEEDING IN PATIENTS TAKING WARFARIN].

Anticoagulant therapy with vitamin K antagonists (AVK) is an effective treatment and prevention of thrombosis. One of the major disadvantages of the AVK is a risk for serious bleeding. Prothrombin complex concentrates (PCC), fresh frozen plasma (FFP) and vitamin K1 are available for control of these situations. The experience of special team ofthe Scientific Center for Hematology was the basis for presented retrospective study. Three regimens of warfarin-related bleeding were compared: PCC+ VK for several bleeding, FFP+ VK for different clinical situations and VKfor light bleeding. PCC showed himself as effective and safe hemostatic agent. Transfusions of FFP were sometimes not effective, sometimes led to TACO. Supplementation of vitamin K1 for patients of I and II groups provided more stable control of hemostasis. In III group VK vas effective to stop bleeding. Two impotent sings for conclusion: necessary of laboratory monitoring, TEG first of all; individual balance of hemostasis base of bleeding or thrombotic risks.

Strategies for urgent reversal of target-specific oral anticoagulants.

The direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are US Food and Drug Administration (FDA)-approved target-specific oral anticoagulants (TSOACs) that have emerged onto the market for use in some indications similar to those for warfarin; in addition, edoxaban is seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for all 3 agents, for the prevention of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing hip or knee surgery for rivaroxaban and apixaban, and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. As anticoagulants, they are all associated with a risk of bleeding, and, unfortunately, there are no approved antidotes for reversal of these agents. A number of small studies in human subjects and in human/animal models exposed to TSOACs have evaluated the use of activated charcoal, hemodialysis for dabigatran, or clotting factor concentrates for their ability to neutralize the anticoagulant effects or reduce drug concentrations of TSOACs. Clotting factor concentrates that have been used include prothrombin complex concentrates and recombinant factor VII. This review examines studies and case reports evaluating these strategies for expedited or emergent reversal of TSOACs.

A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal.

INTRODUCTION: Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage. METHODS: We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs). RESULTS: A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups. CONCLUSIONS: Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality. TRIAL REGISTRATION: Eudra CT number 2007-000602-73.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations.

Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra-articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti-inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB).

Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation.

BACKGROUND: Prothrombinex-VF (a three-factor prothrombin complex concentrate) contains little factor VII. Therefore, the Warfarin Reversal Consensus Guidelines from 2004 published by The Australasian Society of Haemostasis and Thrombosis recommend that it be administered with fresh frozen plasma to reverse warfarin anticoagulation. AIM: To evaluate the efficacy and safety of Prothrombinex-VF used alone in warfarin reversal. METHODS: Adult patients requiring urgent reversal of warfarin anticoagulation were defined as having achieved complete (target international normalized ratio (INR) <1.4) or partial reversal (target INR 1.4-2.0) of their anticoagulation. Prothrombinex-VF was given at doses of between 25 and 50 IU/kg based on the intent of reversal and an INR was obtained 30min post infusion. RESULTS: A total of 50 patients (mean age 72years, range 32-85years) was included. The median initial INR in the complete reversal arm (n= 35) was 3.5 (range 1.7-20) with 91% achieving the target INR (mean 1.1, range 0.9-1.4). In the partial reversal arm (n= 15) the mean initial INR was 5.6 (range 2.5-12) with 93% achieving the target INR (mean 1.6, range 1.4-2.2). There were no adverse effects attributed to Prothrombinex-VF. CONCLUSIONS: Prothrombinex-VF is very effective and safe when used alone to reverse warfarin anticoagulation. The supplementary use of fresh frozen plasma in these patients is not required. A review of the current Warfarin Reversal Consensus Guidelines is needed.

Unfractionated heparin dose requirements targeting intermediate intensity antifactor Xa concentration during pregnancy.

STUDY OBJECTIVE: To describe unfractionated heparin (UFH) dosing requirements and monitoring parameters to achieve target antifactor Xa concentrations in pregnant women receiving intermediate-dose UFH therapy. DESIGN: Retrospective cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: Twenty-five pregnant women (who had 27 pregnancies) who received intermediate-dose UFH between January 1, 1998, and March 31, 2005. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were retrieved by using an integrated electronic medical, pharmacy, and laboratory records system. The primary outcome was the required UFH dose at the time of first target antifactor Xa level achieved. Antifactor Xa levels were measured at the mid-dosing interval for UFH. An antifactor Xa assay concentration of 0.1-0.3 unit/ml was used as the target range for intermediate-dose UFH for antithrombotic management of pregnant women as described in the American College of Chest Physicians clinical practice guidelines. The mean UFH dose required to achieve this target antifactor Xa range was 236.9 units/kg/day. The UFH doses required to achieve target antifactor Xa levels correlated significantly with patient weight (r = 0.682, p<0.001). The final UFH dose/kg required at the end of pregnancy was similar to that at the first target level (p>0.05) when adjusted for weight. However, the total daily amount of UFH did increase by the end of pregnancy (21,889 vs 19,320 units, p=0.02). There was an average of 7.9 antifactor Xa determinations and 3.1 dosage modifications during the mean of 19 weeks of antenatal UFH therapy. Most (62%) antifactor Xa levels were within the target range. No thromboembolic events, heparin-induced thrombocytopenia, or osteopenic fracture occurred. There was one hemorrhagic complication that resolved with temporary withdrawal of UFH. CONCLUSIONS: Pregnant women required a mean UFH dose of 236.9 units/kg/day to achieve the targeted antifactor Xa level of 0.1-0.3 unit/ml. The required UFH doses correlated with patient weight, and most antifactor Xa levels were within the desired target range. These findings may assist clinicians in more precisely initiating and monitoring intermediate-dose UFH in pregnant patients.

Haemophilic factors produced by transgenic livestock: abundance that can enable alternative therapies worldwide.

Haemophilia replacement factors, both plasma-derived and recombinant, are in relatively short supply and are high-cost products. This has stymied the study and development of alternative methods of administration of haemophilia therapy even in the most economically advanced countries, owing to the large amounts of material needed because bioabsorption and bioavailability of haemophilic factors can be less than 10% when using non-intravenous routes of delivery. There is therefore a need to increase access to therapy worldwide by decreasing the cost and increasing the abundance so that therapy can be achieved through simplified, alternative delivery methods. Transgenic livestock have been used to produce haemophilic factors in milk. Only the pig mammary gland has been shown to carry out the post-translational processing necessary to enable both the biological activity and long circulation half-life needed for therapeutic glycoproteins. Furthermore, the large amounts of recombinant protein that can be produced from pig milk make feasible the use of alternative delivery methods such as oral, intratracheal, subcutaneous, and intramuscular administration.

The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation.

Bleeding events are a common adverse effect in oral anticoagulation that frequently depend on the duration and intensity of treatment. Major bleeding events, particularly intracerebral hemorrhages, are a serious complication in cases that require the rapid reversal of anticoagulation. Urgent correction of the coagulation defect is also indicated when major emergency surgery is necessary. In addition to vitamin K supplementation, the administration of prothrombin complex concentrates is the most effective measure for the rapid reversal of anticoagulation. Due to the time-consuming administration and increased risk of volume overload, the administration of fresh frozen plasma is less advisable in such instances. The application of prothrombin complex concentrates requires a precautious risk-benefit evaluation, including an estimation of contraindications and repeated laboratory monitoring for dose adjustment.

Indications for prothrombin complex concentrates in massive transfusions.

A major hemorrhagic insult may require massive transfusions to maintain oxygen transport and hemostasis. Thus an adequate transfusion budget must consider losses, patient's blood volume, critical levels of laboratory parameters, replacement rates of coagulation factors from the extravascular space, and the efficacy of blood products. The substitution of large quantities of blood or red cell concentrates can induce and aggravate a complex haemostatic disorder. Some patients develop generalized microvascular bleeding. A transfusion regimen is described, which in our hands can reduce complications of massive transfusion. For hemostatic support, platelet concentrates and fresh frozen plasma are the treatment of choice. Localization and persistence of bleeding, hepatic disease, and vitamin K deficiency due to medication or intestinal malabsorption may require the supplementary use of prothrombin complex concentrates. Furthermore, antithrombin and fibrinogen concentrates may be indispensable.

Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models.

The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animals studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given s bolus injections 5 min and 3.0 mg/kg neutralized the r-hirudin-induced prolongation and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

Haemophilia home therapy.

Within the past 20 years, home therapy has become an accepted treatment for the majority of people with severe haemophilia in the developed world. The intravenous administration of blood products by suitably trained patients or their relatives has proved to be safe and effective. It allows for the early treatment of bleeding episodes before the appearance of physical signs. It results in reduced morbidity, especially in terms of reduction in long-term arthropathy, and in reduced socio-economic handicap. It is cost effective both in terms of savings in time previously lost from school or work and reduction of reliance on expensive hospital facilities. Home therapy forms a vital part of the overall comprehensive care of people with haemophilia and their families.

[Home treatment in hemophilia]. / Die Heimtherapie der Hämophilie.

88 patients with severe haemophilia (66 with haemophilia A without inhibitor, 12 with haemophilia A and inhibitor, 10 with haemophilia B) currently receive comprehensive care at the Vienna haemophilia centre. Data available at the centre and a questionnaire answered by the hemophiliacs were used in order to evaluate the current situation of home care. At present, 62 (70%) out of 88 patients receive home treatment (51 with haemophilia A without inhibitor, 5 patients with haemophilia A and inhibitor and 6 with haemophilia B). For treatment of joint and muscle bleeding mean dosages of 15.3 units/kg body weight of factor VIII concentrate, 17.0 units/kg of factor IX concentrate and 30 units/kg of FEIBA were administered by the hemophiliacs. Children and young patients required higher doses (30 and 17.4 units/kg F VIII, respectively). Two thirds of the bleeding episodes were successfully treated by a single infusion. No severe side effects were observed during home treatment. Home treatment has been widely accepted by the patients. It is regarded as a practical and safe therapy and has improved the life quality of haemophiliac patients.