On-label compared to off-label four-factor prothrombin complex concentrate use: a retrospective, observational study.

BACKGROUND: Four-factor prothrombin complex concentrate (4F-PCC) is US Food and Drug Administration approved for the urgent reversal of coagulation factor deficiency induced by a vitamin K antagonist complicated by acute major bleeding or in situations in which invasive procedures are urgently needed. Although recent evidence suggests the superiority of 4F-PCC over plasma for on-label indications, the off-label use of 4F-PCC has not been rigorously studied. STUDY DESIGN AND METHODS: Eighty-nine patients receiving 4F-PCC at a single institution from July 2016 to December 2017 were retrospectively analyzed. Two cohorts, "On-Label" and "Off-Label" uses of 4F-PCC, were evaluated, comparing patient characteristics, blood utilization, and clinical outcomes including in-hospital mortality. RESULTS: Patients receiving 4F-PCC for off-label reasons (n = 46) were younger and sicker compared to those receiving 4F-PCC for on-label reasons (n = 43). Notably, the mortality rate for off-label use was approximately twofold greater than the mortality rate for on-label use (26 of 46 [56.5%] vs. 12 of 43 [27.9%]; p = 0.006). Patients receiving 4F-PCC for off-label reasons received more units per patient of each blood component than their on-label counterparts. The average cost estimate per patient for 4F-PCC was similar (approx. $4300) in each cohort. CONCLUSION: 4F-PCC is an effective but expensive treatment option for those requiring urgent reversal of vitamin K antagonist-induced coagulopathy. However, providers should be conscious of the high costs and questionable efficacy when using 4F-PCC off-label.

Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors.

Current unmet needs in haemophilia A patients with inhibitors include the need for intravenous infusion of replacement therapy and the high burden of treatment associated with prophylaxis. Emicizumab is a humanised bispecific monoclonal antibody designed to address these unmet needs and has completed phase III clinical trials in adolescents/adults (HAVEN 1) and paediatric (HAVEN 2) inhibitor populations. In HAVEN 1, there was an 80% bleed reduction across all bleeds, 89% reduction in treated joint bleeds, 92% reduction in treated spontaneous bleeds, and 95% reduction in treated target joint bleeds on emicizumab compared with no prophylaxis. In HAVEN 2, there was a 63% reduction in all bleeds, 94.7% reduction in treated bleeds, 94.7% reduction in treated spontaneous bleeds, 100% reduction in treated joint bleeds, and 100% reduction in treated target joint bleeds on emicizumab prophylaxis when compared with no prophylaxis. For patients on bypassing agent prophylaxis, emicizumab resulted in a 68% reduction in bleeds in HAVEN 1 and a 100% reduction in bleed rates in HAVEN 2. In HAVEN 1, three patients developed thrombotic microangiopathy (TMA) and two developed thrombosis when emicizumab was used together with an activated prothrombin complex concentrate (aPCC) at high or frequent doses. When the combination was avoided in HAVEN 2, no patient developed TMA or thrombosis. In both studies, no anti-emicizumab antibodies developed and the pharmacokinetic profile of emicizumab was similar. Emicizumab use is currently being explored in haemophilia A patients without inhibitors as well as in combination with other haemophilia A replacement therapies. The role of emicizumab in combination with current factor VIII replacement therapies and evolving non-replacement therapies remains to be established.

A decade-long clinical experience on the prophylactic use of activated prothrombin complex concentrate in acquired haemophilia A: a case series from a tertiary care centre.

: In acquired haemophilia A (AHA), risk for recurrent bleeding exists until the inhibitor is detectable. Thus, patients with persisting inhibitor may benefit from prophylaxis with activated prothrombin complex concentrate (aPCC). Potential thromboembolic complications and cost are also factors to consider. Today, no high level evidence or clear recommendations are available on aPCC prophylaxis in AHA. Recently, a small prospective study demonstrated a favourable outcome with short-term, daily administered aPCC infusion. Here we report a retrospective case series of 19 patients with AHA to demonstrate our practice on aPCC prophylaxis. In our practice, clinical bleeding tendency guided our decision on the initiation of aPCC prophylaxis. In patients with serious bleeding tendency, aPCC infusion was prolonged beyond bleeding resolution in a twice-weekly or thrice-weekly regimen. Serious bleeding phenotype included a single episode of life-threatening bleeding or recurrent, severe haemorrhages. Patients who did not present such events were treated on-demand. The preventive dose of aPCC was equal with the lowest effective therapeutic dose. Prophylaxis was continued until the inhibitor disappeared. Eleven patients received aPCC prophylaxis. In nine cases, prophylaxis lasted beyond two months. No severe bleeding developed spontaneously and no thromboembolic complication occurred in the median 16 weeks (interquartile range 9-34) duration of prophylaxis. Eight patients of the nonprophylaxis group did not present any severe haemorrhage. According to our experience, we consider prophylaxis with aPCC effective and well tolerated for patients with AHA and serious bleeding tendency, until the acquired inhibitor persists.

Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis.

Published literature suggests that a fixed-dose 4-factor prothrombin complex concentrate (4FPCC) may be efficacious in managing warfarin-associated hemorrhage, however the ideal dose is still unclear. The purpose of this evaluation was to determine the efficacy of fixed-dose 4FPCC in reducing the International Normalized Ratio (INR) to ≤ 1.5 among warfarin patients with need for urgent or emergent anticoagulation reversal. Starting October 2016, our institution changed from standard 4FPCC FDA-labeled dosing based on the patient's presenting INR and weight, to a fixed-dose of 1500 units for all patients requiring urgent or emergent warfarin reversal. We conducted a retrospective evaluation, after implementation, with the primary outcome being the proportion of patients who achieved an INR ≤ 1.5 with a single fixed-dose of 1500 units of 4FPCC. Secondary outcomes assessed included: medication turnaround times, attainment of target INR ≤ 2 or clinical hemostasis (as judged by the prescribing provider), use of rescue doses, thrombotic events, and cost savings. A total of 37 patients were included in the analysis. Almost 75% of patients achieved an INR ≤ 1.5 after a single fixed dose of 1500 units, and 100% of patients achieved an INR ≤ 2. The median pre- and post-dose INRs were 3.06 and 1.32 respectively. Based on this evaluation, the administration of a fixed dose of 1500 units 4FPCC, was shown to be effective in adequately reversing the INR in the majority of patients with minimal thrombotic risks.

Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.

The immune response to infused factor concentrates remains a major source of morbidity and mortality in the treatment of patients with hemophilia A and B. This review focuses on current treatment options and novel therapies currently in clinical trials. After a brief review of immune tolerance regimens, the focus of the discussion is on preventing bleeding in patients with hemophilia and inhibitors. Recombinant factor VIIa and activated prothrombin complex concentrates are the mainstays in treating bleeds in patients with inhibitors. Both agents have been shown to reduce bleeding episodes to a similar degree when infused prophylactically; however, individual patients may respond better to one agent over the other at any given time. The international immune tolerance trial revealed that a high-dose factor VIII regimen provided significantly better bleeding protection than the low-dose regimen. Given the high cost of treatment and the potential for a high-dose immune tolerance regimen to prevent bleeding in some patients, we discuss how we treat patients to maximize the prevention of bleeds while minimizing cost. Novel approaches to treatment of these patients are in development. These include agents that mimic factor VIII or augment thrombin generation by bypassing the inhibitor, as well as agents that inhibit the natural anticoagulants.

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy.

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered.

[Indications and use of prothrombin complex in cardiac surgery]. / Indicaciones y usos del complejo protrombínico en cirugía cardiaca.

On of the most common, and serious, complications in cardiac surgery is postoperative bleeding. According to the majority of studies, between 10% and 92% of patients subjected to elective surgery require transfusions of blood products and blood derivatives. Transfusions and reinterventions are associated with longer stays in critical care units and a decrease in survival rates. There have been some important changes in the treatment of changes in haemostasis and post-surgical bleeding in the last few years, particularly with the introduction into clinical practice of working procedures backed up by clinical guidelines, as well as the appearance of new drugs. The aim of this work is to describe the main characteristics and update the use of prothrombin complexes that are currently available in Spain, with special emphasis on their use in cardiac surgery.

Current challenges of pharmacovigilance in bleeding disorders: converting the burden to benefit.

SUMMARY: Safety surveillance studies have proven essential in research and development of new biological therapies for bleeding disorders as well as other diseases. Although product safety regarding HIV, hepatitis, and other blood-borne infections is currently excellent, potential new infectious agents require continued vigilant monitoring. Inhibitor development is the most common serious side effect of haemophilia replacement therapy. Several aetiological factors associated with inhibitors have been identified, but their true impact is still largely unknown. Moreover, whether plasma-derived and recombinant factor products differ in their immunogenic profiles is an unresolved issue. Coagulation factor products under development and those currently on the market require uniform, long-term surveillance. The European Haemophilia Safety Surveillance (EUHASS) project was recently established to meet these goals. The pharmaceutical industry and clinicians face common challenges complying with these requirements. In rare diseases like haemophilia, obtaining adequate patient numbers poses a challenge. Another challenge is a lack of methods for assessing disease severity, a surprising deficiency in the era of modern medical and laboratory technology. National and international registries can be used to gather required safety surveillance information. Simultaneously, clinicians benefit from well-organized registry data in their daily practice and harmonize the quality of comprehensive haemophilia care by homogeneous follow-up platforms. Experience with such registries comes, for example, from Europe (PEDNET), the USA (CDC/UDC), the UK (UKHCDO), and Sweden (Malmö). It is important to commit to future pharmacovigilance efforts, aiming at high-quality safety surveillance programmes at both the pharmaceutical research community and clinical levels.

Prophylaxis in 10 patients with severe haemophilia A and inhibitor: different approaches for different clinical situations.

The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Therapeutic decision-making in inhibitor patients.

A panel of hematologists met to discuss treatment choices in patients with hemophilia A and inhibitors. The group agreed that the management of bleeding episodes is complicated by a variable response to bypassing therapy, uncertainties regarding optimal dosing of NovoSeven, and concerns about the combined use of NovoSeven and FEIBA. Thrombotic risk was rated very low for both agents, and there was consensus that product selection should not be restricted to recombinant products. Cost considerations in therapeutic decision-making were also discussed.

Developing a tracking system for coagulation factor concentrates in southern Ontario.

BACKGROUND: In response to the transfusion- transmitted AIDS epidemic, Canadian authorities recommended the development of tracking systems and improved reporting of adverse events. This study describes the development of a verifiable and comprehensive regional tracking system for coagulation factor concentrates. STUDY DESIGN AND METHODS: The Hamilton- Niagara Regional Hemophilia Program received distribution and utilization data from Canadian Blood Services, 26 regional hospitals, and 70 individuals with bleeding disorders on home-based therapy. Purpose-specific software, the Canadian Hemophilia Assessment and Resource Management System (CHARMS), was used to store, monitor, analyze, and validate data. RESULTS: During a 1-year period (2001), all factor concentrates distributed in this region were accounted for. A higher proportion of FVIII and FIX concentrates (88 vs. 12%) was infused at home than in hospitals, and a higher proportion (63 vs. 28%) was used to prevent than to treat bleeds. During a period of shortage, a 5-percent reduction in utilization of both FVIII and FIX concentrates was documented. One recall was managed swiftly and efficiently. Two patients reported allergic skin reactions. CONCLUSION: A verifiable tracking system has been developed that can provide ongoing data for both clinical and administrative purposes. Data collection from patients needs to be made more efficient and real-time recording is an important future objective. Such a system can be instituted locally for less than 1.5 percent of the cost of the factor concentrate used.

Inactivation of parvovirus B19 in coagulation factor concentrates by UVC radiation: assessment by an in vitro infectivity assay using CFU-E derived from peripheral blood CD34+ cells.

BACKGROUND: Nonenveloped and thermostable viruses such as parvovirus B19 (B19) can be transmitted to patients who are receiving plasma-derived coagulation factor concentrates treated by the S/D method for inactivating enveloped viruses. Therefore, it is important to develop and validate new methods for the inactivation of nonenveloped viruses. STUDY DESIGN AND METHODS: Suspensions of B19 in coagulation factor concentrates (FVIII) were irradiated with UVC light. B19 infectivity was determined by an indirect immunofluorescence assay using CFU-E, as a host cell, derived from peripheral blood CD34+ cells. The effects of catechins on B19 infectivity and on FVIII activity after UVC illumination were also examined. RESULTS: The indirect immunofluorescence assay estimated the B19 infectivity of samples containing virus copies of 10(5) to 10(11) per 10 microL to be a median tissue culture-infectious dose of 10(0.3) to 10(5.4) per 10 microL. B19 was inactivated by 3 log at 750 J per m(2) of UVC radiation and was undetectable after 1000 or 2000 J per m(2) of irradiation. However, FVIII activity decreased to 55 to 60 percent of pretreatment activity after 2000 J per m(2) of UVC radiation. This was inhibited in the presence of rutin or catechins. Epigallocatechin gallate could maintain FVIII activity at almost 100 percent of pretreatment activity after 2000 J per m(2) of UVC radiation, while B19 infectivity was decreased to undetectable levels, which resulted in >3.9 log inactivation. CONCLUSION: UVC radiation in the presence of catechins, especially epigallocatechin gallate, appears to be an effective method of increasing the viral safety of FVIII concentrates without the loss of coagulation activity.

Prions and haemophilia: assessment of risk.

Based on information accumulated to date, it is still difficult to assess the risk of Creutzfeldt-Jakob disease (CJD) and blood transfusion with any degree of confidence. However, it is reasonable to conclude that CJD is produced by a transmittable agent which is probably contained in low titer in the blood of infected people and animals. From the present clinical and epidemiological studies, transmission by blood or blood products appears to be a rare or non-existent cause of current and past cases of CJD in humans. Since blood products are necessary to prevent the immediate risk of death or significant morbidity in many clinical conditions, therapeutic decisions should be made after consideration of the known risk in these situations vs the theoretical long-term risk of the rare occurrence of CJD.

Settlement accepted.

AIDS: A $640 million settlement that would pay $100,000 to each U.S. hemophiliac who contracted HIV from blood-clotting products has been approved by U.S. District Judge John F. Grady. Grady will conduct a hearing to determine whether the four clotting product manufacturers will withdraw the offer if individual hemophiliacs or their survivors opt to continue their own lawsuit. Grady will also determine whether claimants will have to turn over their awards to reimburse Medicaid, Medicare, Social Security, and private health insurance companies. This settlement was intended for persons who would not have filed individual suits.^ieng

Human coagulation factor IX: assessment of thrombogenicity in animal models and viral safety.

Thromboembolic complications associated with prothrombin complex concentrate treatment may be related to the high levels of factors II and X in these products. We report here results from preclinical safety studies with a human coagulation factor IX product (AlphaNine; Alpha Therapeutic Corp., Los Angeles, Calif.) that contains no detectable factor II or VII and less than 10 units of factor X/100 units of factor IX. This product was manufactured from virally inactivated factor IX complex with a barium citrate adsorption step followed by affinity chromatography yielding factor IX concentrate with a specific activity of about 86 factor IX units/mg protein. Electrophoresis and immunoblot analysis indicated that the factor IX represents about 65% of the protein in this product. The virus inactivation step incorporated into the manufacturing process (incubation with n-heptane at 60 degrees C for 20 hours) was shown to inactivate at least 8.6 logs of type 1 human immunodeficiency virus. The barium citrate adsorption and affinity chromatography steps were found to remove 2.0 logs of the marker virus, vaccinia, and the DEAE ion-exchange chromatography used to produce factor IX complex was found to remove 1.4 logs of the marker virus, Sindbis. Analysis of three separate manufacturing lots with the polymerase chain reaction revealed no evidence of hepatitis C virus. The purified factor IX was nonthrombogenic when tested at doses of 450 units/kilogram in a rabbit stasis (Wessler) model, whereas the prothrombin complex concentrates were found to be thrombogenic at doses of less than 50 units/kg. There was no evidence of DIC in a porcine model after infusion of 200 units/kg of coagulation factor IX, as manifested by negative fibrin monomer tests, the absence of fibrin in blood vessels at autopsy, little or no change in prothrombin times and partial thromboplastin times, and only moderate decreases in platelet levels after infusion.

Financial assistance for HIV-infected persons with haemophilia worldwide.

In many countries we could note the dramatic developments in regard to financial assistance of HIV-infected haemophiliacs and their families since we distributed the first overview on this to all World Federation of Hemophilia member countries. As a result of the untiring efforts of the National Haemophilia Societies, infected persons and their families receive essential assistance in 15 member countries. It is hoped that this development will sway more and more member countries to consider demands for financial support and provide them with the arguments to succeed.