Use Of APCC Research Articles

A Single Center Experience of 13 Episodes of Acquired Hemophilia A (2019 - 2023)

Background: Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by neutralizing autoantibodies to factor VIII (FVIII). Treatment of AHA involves immunosuppression to eliminate the autoantibody and hemostatic management involving bypassing agents (BPAs). While the use of BPAs, including activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa), is primarily derived from studies of congenital hemophilia with inhibitors, registry studies of AHA have also demonstrated the efficacy of rVIIa ( Baudo et al., Blood, 2012) and aPCC ( Borg et al., Haemophilia, 2015) ( Zanon et al., Br J Haem 2019) in this population. Given the changing treatment landscape, low incidence of AHA, and high morbidity and mortality associated with the disease, our study aims to describe a single institution's experience with treating AHA. Methods: We retrospectively reviewed the records of adult patients diagnosed with AHA at a single academic medical center between January 1, 2019, and June 30, 2023. Results: Eleven patients were treated for 13 distinct episodes of AHA, with one patient admitted for three discrete episodes of AHA with responses to therapy followed by relapses once lost to follow-up. The patients were predominantly white (63.7%, n=7) and female (63.7%, n=7), with a median age of 74 years and weight of 87 kg on admission (Table 1). One patient (9.1%) had concomitant autoimmune disease. No patients presented peripartum or with active malignancy, liver disease, or a family history of bleeding disorders. The median FVIII level on admission was 1% (IQR=1%, 3.5%), with a median anti-FVIII antibody titer of 27 BU (IQR=4.5 BU, 47 BU). Given mild bleeding presentation, Patient 2 was treated as an outpatient with immunosuppression only. All patients received aPCC as the first-line BPA. Patient 5 developed uncontrolled bleeding from an arterial line despite receiving aPCC and was transitioned to rFVIIa for two days before resuming aPCC once hemostasis was achieved. The median duration of aPCC therapy was eight days. The use of aPCC (FEIBA) instead of rFVIIa (NovoSeven) as the first-line BPA led to total estimated cost avoidance of $13.5 million (calculated using average wholesale price). No patients had thrombotic events after the diagnosis of AHA. Six episodes (46.1%) were treated with prednisone and rituximab. Six episodes (46.1%) were treated with prednisone and oral cyclophosphamide. One episode (7.7%) was treated initially with prednisone and cyclophosphamide but was eventually transitioned to rituximab following a lack of response and bleeding complications after two weeks. This patient was also subsequently treated with emicizumab for five months until FVIII activity was recovered. P neumocystis jirovic i i pneumonia prophylaxis was prescribed in eight episodes (61.5%), and antiviral prophylaxis was prescribed in one episode (7.7%). No infections were noted during the follow-up period, other than two documented cases of COVID-19, one of which required admission. The median time to achieve FVIII >50% was 5.1 weeks, with a median of 8.6 months of follow-up (Figure 1). Patient 11 relapsed twice, as described in Table 1. No other patient relapsed during the follow-up period. No patient deaths occurred during the follow-up period. Conclusions: We describe 13 episodes of AHA successfully treated at a single academic medical center between 2019 and 2023. aPCC was the first-line BPA administered in all patients, with significant cost savings relative to rFVIIa. Immunosuppression, including prednisone and either cyclophosphamide or rituximab, was used to successfully eliminate autoantibodies in all patients. One patient received emicizumab for ongoing hemostatic control until achieving improvement in FVIII activity. No significant infections, thrombotic events, or deaths were noted in this cohort.

Efficacy and Safety of Activated Prothrombin Complex Concentrate for Reversal of the Anticoagulant Effect of Apixaban and Rivaroxaban in Patients with Major Bleeding.

The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited. We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization. A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%). The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

Prothrombin complex concentrates for the urgent reversal of apixaban and rivaroxaban: an Australian retrospective cohort study.

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.

Evaluation of the Safety of Emicizumab Prophylaxis in Persons with Hemophilia A: An Updated Summary of Thrombotic Events and Thrombotic Microangiopathies

▪Background: Emicizumab is indicated for routine prophylaxis in persons with congenital hemophilia A (PwcHA) with/without factor (F)VIII inhibitors in >100 and >80 countries, respectively. Emicizumab has been used by >11,400 persons across the globe (data cut-off 15 May 2021). The pivotal HAVEN 1-4 trials established the efficacy and safety of emicizumab prophylaxis; however, the HAVEN 1 trial identified an increased risk of thrombotic events (TEs) and thrombotic microangiopathies (TMAs) when used in conjunction with >100 U/kg/24 hours activated prothrombin complex concentrate (aPCC) for ≥24 hours (Oldenburg, et al. New Engl J Med 2017). Here we report an updated safety evaluation of emicizumab prophylaxis focusing on TEs and TMAs.Methods: All individual safety reports for emicizumab from clinical trials, registries, expanded access programs, compassionate use and the post-marketing setting were collated with a cut-off date of 15 May 2021 and analyzed for TEs and TMAs. Number of TEs/TMAs, clinical factors (indication, age, FVIII inhibitor status, comorbidities) and drug factors (co-exposure to medications affecting coagulation) are presented in aggregate. Individual case reports (cases) were reviewed to exclude non-TEs and any duplicate reports. TEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA) search strategy: ‘Embolic and Thrombotic Events’ Standardized Medical Query ([SMQ] Wide) and Preferred Term ‘Acute Coronary Syndrome’. TMAs were defined as hemolytic uremic syndrome, microangiopathic hemolytic anemia, microangiopathy, thrombotic microangiopathy and thrombotic thrombocytopenic purpura.Results: In total, 52 cases (56 events) meeting the search criteria were identified on the Roche Global Safety Database as of 15 May 2021 (Figure). After review, 39 cases were reported in PwcHA and 10 cases were determined to be off-label (acquired hemophilia A, n=7; or unknown indication, n=3). Two additional cases were determined to be duplicates. One case of ‘hemiparesis’ was identified through SMQ review, but did not fit the clinical definition of a true TE. Six cases occurred with concomitant aPCC use, of which four were TMAs. In total, 33 cases were not associated with concomitant aPCC use, and these comprised 37 TEs and no TMAs in PwcHA. No new TEs or TMAs associated with aPCC were reported since the last update (Lee, et al. Haemophilia 2020).For the 37 TEs reported in PwcHA and not associated with aPCC, the median age (range) at time of event was 49 years (0.42-84) and the median (range) emicizumab treatment duration at time of event was 330 days (0-1076). In total, 36 (97.3%) TEs were medically confirmed and one (2.7%) was patient reported. Seventeen (45.9%) TEs occurred in PwcHA with FVIII inhibitors. Seven (18.9%) TEs were associated with central venous access devices (CVADs), of which four were reported to be resolving/recovering at last report. All except for two (with limited information) non-aPCC associated TEs in PwcHA were associated with ≥1 cardiovascular (CV) risk factors (e.g. previous myocardial infarction, ischemic heart disease, coronary artery disease, hypertension, hyperlipidemia, smoking, advanced age) or other risk factors for thrombosis (e.g. sepsis/bacteremia, device use, coinciding injury, hepatitis C).Of the non-aPCC and non-CVAD associated events reported, six (20.0%) TEs led to the discontinuation of emicizumab. Across all non-aPCC associated events, an evaluation of latency or duration of treatment did not reveal any patterns or trends. In total, four TEs were fatal: two myocardial infarctions, both in medically complex patients; and two disseminated intravascular coagulation events in patients >70 years of age with pneumonia. Where reported, 20/31 (64.5%) TEs were recovered/resolving at the time of this analysis, with the majority of these cases reporting no change to emicizumab prophylaxis as a result of the event.Conclusions: The reporting rate for TEs without concomitant aPCC remains low as exposure increases. Notably, all cases with adequate information available were associated with CV risk factors and/or risk factors for thrombosis. All TMAs were associated with concomitant use of aPCC. This post-marketing analysis does not support TEs and TMAs without concomitant aPCC as an identified risk for PwcHA receiving emicizumab prophylaxis. The risk-benefit profile of emicizumab remains unchanged. [Display omitted] DisclosuresHoward: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McKinley: Pro Unlimited: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure:The enclosed analysis of the Roche Hemlibra internal database was produced by submitted safety reports, including reports of off-label use. These data will be discussed in aggregate, and not individually described.

Incidence of Thrombo-Embolic Events in Relation to Activated Prothrombin Complex Concentrate Exposure: A Literature Meta-Analysis

IntroductionThe development of factor VIII (FVIII) inhibitory antibodies is one of the major challenges of the treatment of hemophilia, because it hinders FVIII replacement for the treatment and prevention of bleeding events (Leissinger 2015). Two products are currently available to control bleeding in patients with inhibitors: the activated prothrombin complex concentrate (aPCC; FVIII inhibitor bypassing activity, FEIBA VH; Shire plc, USA) and recombinant activated factor VII (rFVIIa; NovoSeven, Bagsvaerd, Denmark). Both agents have shown similar efficacy, with some patients responding better to one over the other (Astermark 2007). Both agents have been associated with the development of thromboembolic events (TEEs) (Aledort 2004). Aim of this study was to estimate TEE incidence in patients with congenital hemophilia with inhibitors and acquired hemophilia exposed to aPCC, by using a meta-analytic approach based on published scientific literature.MethodsA systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The incidence rate of TEEs was estimated via a meta-analytic approach by using a Generalized Linear Mixed Model based on a Poisson distribution.Stratified analyses according to study design (prospective vs. retrospective), hemophilia type (congenital vs. acquired) and treatment modality (on-demand, prophylaxis and surgery) have been conducted.ResultsWe identified a total of 144 papers through the electronic literature search and out of the 61 fully evaluated articles, 39 studies with TEE data related to the use of aPCC in patients with congenital hemophilia with inhibitor or acquired hemophilia were included in the meta-analysis. The studies included were published from 1980 to 2016, providing information on safety related to 678,447 aPCC infusions (7,291 infusions as on-demand treatment, 77,203 in prophylaxis, 3,296 in surgery and 590,657 in unspecified treatment modalities).In the 39 studies included overall, 46 TEEs were reported: 13 disseminated intravascular coagulation (DIC), 11 ischemic coronary syndrome (ICS), 4 pulmonary embolism (PE), 3 thrombotic cerebrovascular accidents (CVA), 3 deep vein thrombosis (DVT), 3 superficial vein thrombosis (SVT), 6 unspecified thrombosis (unreported location) and 3 fibrinogen reduction. No thrombotic microangiopathic events have ever been reported. Out of the 39 studies included, 31 (79%) reported no TEEs.The estimated pooled TEE incidence rate was 2.87 (95% CI 0.32-25.40) per 100,000 aPCC infusions. When stratifying for retrospective and prospective studies, 35 TEEs in 649,343 aPCC infusions (pooled incidence rate, 5.42 per 100,000 infusions), and 11 TEEs in 29,104 infusions (pooled incidence rate, 1.09 per 100,000 infusions) were respectively reported. TEE incidence rate in patients treated with aPCC on-demand was 5.09 per 100,000 infusions, while in patients treated with prophylaxis, no TEEs were reported. Five TEEs were reported in 11 studies in hemophilia patients with inhibitors undergoing surgery, being the pooled TEE incidence rate 112.03 per 100,000 aPCC infusions. Finally, pooled TEEs incidence rate in acquired hemophilia patients was 287.79 per 100,000 infusions, but less than 0.01 per 100,000 infusions in congenital hemophilia patients.ConclusionsThe pooled incidence rate was lower than 3 TEEs per 100,000 aPCC infusions, demonstrating a relatively low risk and confirming previous figures reported (Erlich 2002, Aledort 2004). Stratified analysis showed that the incidence is even lower in patients with congenital hemophilia and no TEE in prophylaxis. These findings provide robust evidence of safety of aPCC over almost 40 years of published studies. DisclosuresRota:ASHLEY COMMUNICATIONS ON BEHALF OF SHIRE FOR SHIRE SYMPOSIUM PARTICIPATION AS A SPEAKER AT THE ISTH 2017 CONGRESS: Honoraria. Cortesi:Shire: Research Funding. Crea:Shire: Employment, Equity Ownership. Gringeri:Shire: Employment. Mantovani:Daiichi Sankyo: Consultancy; Shire: Research Funding; Bayer AG: Consultancy; Boehringer Ingelheim: Research Funding; Janssen-Cilag: Research Funding.

Use of Bypassing Agents Prior to and Post Bypassing Agent Dosing Guidance during Emicizumab Prophylaxis: Analyses from the HAVEN 1 Study

Use of Bypassing Agents Prior to and Post Bypassing Agent Dosing Guidance during Emicizumab Prophylaxis: Analyses from the HAVEN 1 Study

Successful Treatment of Bleeding in Acquired Hemophilia A with Activated Prothrombin Complex Concentrate in Spain

INTRODUCTION. Acquired hemophilia A (AHA) is a rare autoimmune disorder characterized by development of autoantibodies against coagulation factor VIII (FVIII). Bypassing agents are recommended as first-line for the treatment of bleeding episodes in patients with AHA. Due to the low incidence of AHA, available clinical data on efficacy and safety of the activated prothrombin complex concentrate (aPCC) in patients with AHA are limited. The objective of this retrospective multicenter study was to detail AHA management in patients treated with aPCC in real life in Spain.METHODS. Data from patients with AHA, treated in any moment with aPCC, in five reference centers for coagulopathies disorders, between June 2012 and June 2017, have been collected.Bleedings were classified as initial (first episode after AHA diagnosis or relapse), concurrent (new bleeding at the same time but at a different anatomical location), subsequent (a new bleed recurring 72 hours after the resolution of the previous bleed) or re-bleed (same anatomical location within 72 hours of the resolution of the previous bleeding). Severity of the bleed was evaluated according the Word Health Organization scale. Hemostatic efficacy was assessed as bleeding cessation and pain control. Safety was evaluated during bypassing agent treatment and until 30 days after discontinuation.RESULTS . Ten patients (6 males), 40% idiopathic AHA, median aged 70 years (64-84, IQR) at diagnosis. Seven patients out of 10 had at least 1 thrombotic risk factor, but no history of thrombotic events previous AHA. The median baseline residual FVIII level was 1% (0-1%, IQR), the median inhibitor titer was 24 BU (9-40, IQR).In all cases the suspected diagnosis of AHA was precipitated by a bleeding event (combined with a prolonged aPTT in 7 patients). Suspected diagnosis came from hematology (80%), emergency room (10%) and internal medicine (10%). The diagnosis was made promptly by hematology after the suspicion at a median of 1 day (0-7, IQR). 10 patients presented 19 bleedings (13 initial, 4 subsequent, 1 concurrent, 1 re-bleed) (WHO severity: grade 1, n=1; grade 2, n=5; grade 3, n=12; grade 4, n=1) that were recorded. 84% of these bleedings arose spontaneously, 44% of them manifested primarily as muscle hematomas. There was emergency surgery because of acute abdominal surgey complication. Seventeen bleedings were treated with aPCC as first line (n=11) or second line after rFVIIa (n=6), achieved bleeding cessation and pain control in the 100% of the evaluated bleeding episodes. The mean initial dose per infusion was 54.4 (± 12.9 SD) U/kg, the median total dose was 48000 U (32000-68000 U, IQR), the initial dosing interval was 8 hours (8-12, IQR), the median duration of treatment was 5.5 days (3.5-10.5 days, IQR), and the median number of injections was 15 (7.5-21, IQR). No adverse events, including thromboembolic events, were described during aPCC treatment. A 75-years-old female patient died due to a severe respiratory insufficiency after 19 days of aPCC discontinuation. The reasons to change from rFVIIa to aPCC were non bleeding control in 2 patients and necessity to reduce the number of infusions per day for ambulatory management in the rest. All patients received first line immunosuppressive therapy: prednisone 1 patient, corticosteroids plus cyclophosphamide 7 patients, rituximab plus other immunosuppressive drug 2 patients. Patient with prednisone alone and one with rituximab plus esteroides needed a second line treatment for no response after more than 4 weeks. Median time to response in the group of corticosteroids plus cyclophosphamide was 56.5 days (40-108, IQR), rituximab plus other immunosuppressive drug 56.5 days (50-56.5 days, IQR).CONCLUSIONS . This is the first study providing information on the daily use of aPCC in the treatment of AHA in Spain. With a hemostatic efficacy rate of 100% and a good safety profile, in line with other published real-life data. This multicenter Spanish experience supports the role of aPCC as first-line treatment for bleedings in AHA. DisclosuresNo relevant conflicts of interest to declare.

Comparison of bypassing agents in patients on emicizumab using global hemostasis assays.

Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A with and without inhibitors. Management of breakthrough bleeding in patients with inhibitors on emicizumab involves episodic treatment with bypassing agents (BPA), activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Thrombotic events and thrombotic microangiopathy were reported when patients on emicizumab received concomitant aPCC at relatively high doses yet such events were not reported with rFVIIa. We studied the effect of spiking various concentrations of BPA on plasma taken from patients on emicizumab. Eleven patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Blood samples drawn from patients were spiked in vitro with varying concentrations of aPCC and rFVIIa. All samples were tested utilizing global haemostasis assays, thromboelastography and thrombin generation assay. Thrombin generation increased with higher concentrations of spiked BPA with a normalized endogenous thrombin potential at a concentration of 0.05IU/ml and 4 mcg/ml for aPCC and rFVIIa, respectively. Concentrations of aPCC in the range of licensed dosing led to excessive thrombin generation. Thromboelastography was not sufficiently sensitive. Due to the known thrombotic complications when emicizumab is used in conjunction with aPCC, there has been a large-scale abandonment of the use of aPCC in patients on emicizumab. However, it is possible that aPCC can be used safely with emicizumab albeit with lower doses than are typically prescribed. It would be important to test this hypothesis in a clinical study.

In Vitro Evaluation of Thrombin Generation of Eptacog Beta (Factor VIIa, Recombinant) and Emicizumab in Congenital Hemophilia Α Plasma with and without Inhibitors

In Vitro Evaluation of Thrombin Generation of Eptacog Beta (Factor VIIa, Recombinant) and Emicizumab in Congenital Hemophilia Α Plasma with and without Inhibitors

Comparison of Bypassing Agents in Patients on Emicizumab Using Global Hemostasis Assays

Introduction: Management of breakthrough bleeding events in patients on emicizumab involves episodic treatment with the bypassing agents (BPA), activated prothrombin complex concentrate (aPCC) and recombinant activated FVII (rFVIIa). A concomitant drug reaction between emicizumab and aPCC resulting in thrombotic events was noted in the HAVEN clinical trials resulting in a black box warning recommending avoiding treatment with high and prolonged doses of aPCC in patients on emicizumab. There have been a few reports where hemophilia plasma was spiked with emicizumab and then various concentrations of BPA which have demonstrated a synergistic effect of emicizumab with aPCC and an additive effect with rFVIIa using thrombin generation assays (TGA), however studies using in vivo emicizumab blood samples have not been performed. In addition, spiking with very low concentrations of aPCC and rFVIIa have not been done. With this in mind, we elected to assess the effect of spiking various concentrations of BPA on plasma taken from patients on emicizumab on thrombin generation. Methods Patients with severe hemophilia A (HA) with inhibitors who are currently on emicizumab and who achieved steady state were recruited to participate. Blood samples were drawn in the non-bleeding state and with no recent use of BPA and TGA was performed using the calibrated automated thrombogram with platelet poor plasma (PPP) using the PPP reagent low for aPCC and with platelet rich plasma (PRP) using the PRP reagent for rFVIIa. Eight concentrations of aPCC and rFVIIa ranging from zero (baseline) to very low (sub-therapeutic) to therapeutic concentrations were spiked in vitro into patient samples. Table 1 describes the concentrations of the bypassing agents and descriptive statistics are provided for the different TGA parameters. Results Eleven patients with severe HA and inhibitors currently on emicizumab for at least 6 weeks were enrolled in the study. The TGA parameters assessed include lag time (min), ETP (nM*min), Peak thrombin (nM), time to peak (min), Vel index (nM/min) and start trail (min). The summary statistics are provided in tables 2a and 2b. The in vitro TGA spiking with aPCC demonstrated normalization of both the ETP and peak thrombin at a concentration of 0.05 IU/mL and 0.1 IU/mL comparable to a dose of ~5 IU/kg and ~10 IU/kg, respectively, however above this concentration, aPCC spiking demonstrated a very high ETP and peak thrombin (Table 2a). The in vitro TGA spiking with rFVIIa demonstrated normalization of ETP and peak thrombin at up to a concentration of 3 mcg/ml comparable to a dose of ~180 mcg/kg (Table 2b). Discussion Due to the known thrombotic complications when emicizumab is used in conjunction with aPCC, there has been a large-scale abandonment of the use of aPCC in patients on emicizumab leaving these inhibitor patients with only one BPA for management of bleeding and surgery which is not ideal. However, it is possible that aPCC can be used safely with emicizumab albeit with lower doses than may typically be used and below the doses in the prescribing information. While only clinical studies can answer this question, before this is attempted, a study of in vitro spiking of in vivo emicizumab samples should be performed. Thus, in this study we set out to determine what concentrations of BPA (in patients on emicizumab) could result in normalization of the TGA parameters ETP and peak thrombin. This, in turn, could suggest which doses of both rFVIIa and especially aPCC could be studied in a trial (or even used safely) when managing breakthrough bleeding or surgery in patients on emicizumab. The results demonstrate that at rather low concentrations of aPCC equating doses of ~5 and ~10 IU/kg, the ETP and peak thrombin reach normal levels, i.e. not excessive. We also note that most concentrations of rFVIIa result in normal ETP and peak thrombin as has been reported before. In conclusion, we have demonstrated that lower doses of aPCC could potentially be used safely and effectively in inhibitor patients on emicizumab. It would be important to test this hypothesis in a clinical study. Disclosures Young: Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria.

Pre-Analysis for Hemostatic Effect of Bypassing Agents in Hemophilia a Patients with Inhibitors Under the Emicizumab Prophylaxis By Global Assays

Introduction: Emicizumab (Emi) is an anti-factor (F)IXa/FX bispecific antibody that mimics FVIIIa cofactor function. The clinical trials on Emi prophylaxis for hemophilia A patients with inhibitor (HA-Inh) demonstrated marked reduction in bleeding rates. However, Emi at clinically relevant plasma concentrations (~50 mg/ml) corresponding to ~15% of FVIII equivalent activity may not provide enough hemostasis at severe bleeding or major surgical intervention. In these circumstances, additional infusions of bypassing agents (BPAs) may be needed for hemostatic management. In the HAVEN 1 study, thrombotic events/ thrombotic microangiopathy occurred in Emi-treated HA-Inh receiving consecutive infusions of aPCC in higher doses. After these reports, guidance was provided to avoid the use of aPCC as first choice during Emi prophylaxis. If aPCC is the only available BPA, use of the lowest dose expected to achieve hemostasis with the initial dose ≦50 U/kg was recommended. To further support these recommendations, more investigation is required for the use of BPAs under Emi prophylaxis. Objective: We examined the coagulation effects by spiking BPAs to whole blood or plasma samples from Emi-treated HA. Methods: Samples from eight Emi-treated HA-Inh and two hemophilia A patients without inhibitors (HA-Inh(-)) in phase 1/2 and HAVEN 1 were tested. The Emi doses were 0.3-3.0 mg/kg/w or 1.5 mg/kg/w, respectively. Either aPCC or rFVIIa was spiked to patients' whole bloods or plasmas, and assessed by rotational thromboelastometry (ROTEM; Ca2+ trigger) and clot waveform analysis (CWA; ellagic acid/tissue factor-mixed trigger; Nogami, JTH2018). Furthermore, samples in Emi-treated HA-Inh of phase 1/2 (n=1) or HAVEN 2 (n=2) receiving BPAs infusion for hemostatic management were assessed by both assays. Results and Discussion: The baseline levels, before spiking BPAs, in ROTEM parameters, such as clot time (CT) and clot formation time (CFT), of Emi-treated HA were 1,380/521sec(s) (reference range 762-1,127/207-511s), respectively. Spiking aPCC markedly shortened CT/CFT to 167/81.5s and 148/78.0s at 0.65 and 1.3 U/mL corresponding to 50 and 100 U/kg infusion, respectively. Even at 0.13 U/mL (10 U/kg), CT/CFT shortened to 290/92.6s, which was shorter than that of reference range. Its effect was dose-dependent. Spiking rFVIIa also improved CT/CFT to 726/179s, 551/141s at 32.3 and 112 μg/mL (90 and 270 μg/kg). In CWA, the baseline levels of adjusted-|min1| (ad|min1|), indicative of maximum coagulation velocity, in Emi-treated HA were 5.53 (normal control 7.98±0.24). Ad|min1| was improved to 6.48 and 8.04 by spiking aPCC (10 and 100 U/kg), or 7.11 and 7.12 by spiking rFVIIa (90 and 270 μg/kg), respectively. For rFVIIa its effect was not dose-dependent. According to the investigation for in vivo effect by BPAs infusion in a total of 9 treatment events of Emi-treated HA-Inh, CT/CFT (1,812/553s) was improved to 1,151/346s, of which was within normal range. Ad|min1| (5.7) was improved to 6.6 30 min(m) after aPCC infusion (44-74 U/kg). By rFVIIa infusion (90-119 μg/kg), CT/CFT (1,962/758s) improved to 912/207s, and ad|min1| (4.9) also improved to 6.5 30m after infusion, of which improvement remained within normal range. The hemostasis effects were clinically satisfying and no thrombosis occurred in all cases. The ROTEM parameters by spiking aPCC were apparently hypercoagulant relative to those by infusion at same dose, supporting our previous report (Furukawa JTH2015). The shortening effect on the ROTEM parameters by spiking aPCC 100 U/kg in Emi-untreated HA seemed to be similar to that by spiking aPCC 10 U/kg in Emi-treated HA. In addition, ad|min1| by spiking aPCC 10 U/kg with Emi also improved as well as ~100 U/kg without Emi in our previous report (Nogami JTH2018). Taken together, it is suggested that the hemostatic effect of aPCC infusion (10 U/kg) to Emi-treated HA could be comparable to that of 100 U/kg to Emi-untreated HA-Inh, though there is a limitation to predicting the hemostatic effect of aPCC in a clinical setting from these ex vivo results. Conclusion: Spiking tests in Emi-treated HA-Inh by ROTEM and CWA are useful to evaluate clinical coagulation potentials and dose finding of BPAs in Emi-treated HA receiving BPAs. Additionally, under Emi prophylaxis, a lower dose of aPCC infusion might be a possible option to treat breakthrough bleed in Emi-treated HA-Inh. DisclosuresFurukawa:CSL Behring: Research Funding. Nogami:Bayer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Sysmex: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies, Research Funding, Speakers Bureau. Matsumoto:Shire Japan Co. Ltd: Research Funding. Kasai:Chugai Pharmaceutical Co., Ltd: Employment. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau.

Clinical and economic analysis of different strategies for the treatment of hemophilia A

Although hemophilia A is a rare disease, its treatment is costly, and expenses are mainly related to the cost of factor VIII concentrates. Aim. To evaluate the clinical and economic feasibility of rFVIIa (NovoSeven®) for the treatment of patients with hemophilia A compared to the schemes based on the use of APCC (Feiba). Matherials and methods. Clinical and economic analysis was conducted by the “total cost of illness” method using modeling by building a “decision tree”. This study identifies only the direct costs of pharmacotherapy. The cost of a vial of each of the concentrates analyzed meets the declared value as of December 2016. Results. The analytical model of the “decision tree” was designed to calculate the costs for the outpatient treatment of mild and moderate bleedings. Due to higher clinical efficacy the use of rFVIIa as the first-line therapy saves 32 % to 42 % in the treatment of a patient; in the conditions of the modern Ukrainian pharmaceutical market it is from UAH 170,326.4 to UAH 252,990.4 (with an adapted variant of therapy) and UAH 291,743.1 in the basic variant. When using rFVIIa as the first-line therapy the costs for life appeared to be lower by approximately 10 % than when taking APCC. Conclusions. The use of NovoSeven® is more feasible economically and allows both to improve outcomes and to spend financial resources more efficiently to treat these patients.

Four Decade Cumulative Review of Thrombo-Embolic Events Reported with the Use of Activated Prothrombin Complex Concentrate in Congenital Haemophilia

Introduction and Objectives: The use of bypassing agents have contributed to a better management of bleeding (prevention and treatment) of persons with haemophilia (PWH) and inhibitors. One of these, an activated prothrombin complex concentrate (APCC - FEIBA - FVIII inhibitor bypassing activity, Shire) became commercially available 40 years ago in 1975. While bypassing therapy has been proven effective, it introduced a potentially increased risk of treatment-associated thrombo-embolic events (TEEs). The small size of clinical trials and post-authorization surveillance studies in PWH with inhibitors limits the capability to ascertain risk factors for APCC-associated TEEs. The present review provides an overview of clinical details of all spontaneous and literature cases TEEs reported with the use of APCC in congenital haemophilia, documented in the Company's global safety database.Materials and Methods: The global safety database was reviewed for all spontaneous and literature adverse events reports of APCC received from 1975 through July 2016, addressing patient demographics, dosing regimens, confounding and risk factors deemed relevant for the development of TEEs in temporal association with APCC treatment.Results: More than 7 billion units of APCC (more than 2million infusions) were distributed during the review period. Overall 108 TEE have been reported in patients with different indications (congenital haemophilia, acquired haemophilia, anticoagulation reversal, etc.). Of these, 85 reports including one or more thromboembolic events were received for PWH (thereof 60 spontaneous reports), aged 0-73 years (mean 32, median 22). Of the 85 TEEs, 13 were reported as deep vein thrombosis and/or pulmonary embolism (median age: 11 years, min-max 3-22), 32 as myocardial infarction or stroke (median age: 41 years; min-max 8-73), 18 as disseminated intravascular coagulation (median age: 49; min-max: 0-71) and 22 as other events (median age: 30 years; min-max: 3-57). Of the 85 TEEs, 31 TEEs were reported with rFVIIa as a concomitant medication (7 DVT/PE, 9 MI/stroke, 9 DIC, 6 others).Conclusion: The reporting rate of TEEs associated with APCC remains comparable with data published earlier and confirms its long-time overall safety profile. Moreover, the majority of the TEEs occurred in the presence of additional/confounding risk factors such as underlying disease and concomitant medications. The review of clinical details of all TEEs reported in temporal association with the use of APCC is a valuable resource for the understanding and perhaps the prevention. DisclosuresCrea:Shire: Employment, Equity Ownership. Novack:Shire: Employment, Equity Ownership. Reininger:Shire: Employment, Equity Ownership. Kennedy:Shire: Employment, Equity Ownership. Raff:Shire: Employment, Equity Ownership. Gringeri:Shire: Employment, Equity Ownership. Bajwa:Shire: Employment, Equity Ownership.

Tissue Factor Pathway Inhibitor Causes Unresponsiveness to Activated Prothrombin Complex Concentrates for Hemophilia A Patients with Inhibitors.

AbstractAbstract 3663Bypassing agents such as activated prothrombin complex concentrates (APCC, FEIBA®) and recombinant activated factor VII (rFVIIa, NovoSeven®) are effective for most hemophiliac patients with inhibitors. While, some patients exhibit unresponsiveness to the treatment with APCC and/or rFVIIa, but their mechanisms remain unknown. We had a severe hemophilia A patient with inhibitor whose bleeding worsened despite of consecutive infusion of APCC. Switching from APCC to rFVIIa was very effective for his bleeding symptoms, and one-week cessation of bypassing agents had restored good response for APCC. Comprehensive coagulation assay such as thromboelastometry and thrombin generation test (TGT) provided us clear evidence of unresponsiveness to APCC. In particular, tissue factor (TF)-triggered TGT showed two significant features, the prolonged lag time and reduced peak thrombin level even after APCC infusion. Although FII, FVII(a), FIX, FX(a) and protein C contained in APCC were elevated in his plasmas after APCC infusion, increased amounts of these factors did not affect the parameters of TGT described above in vitro. We focused on a natural anticoagulant, tissue factor pathway inhibitor (TFPI), since the prolonged lag time in TF-triggered TGT might result from the impairment of FVII/TF-induced initial reaction of blood coagulation. In vitro experiment on the addition of TFPI to FVIII-deficient plasma with APCC showed similar inhibitory pattern in TGT. TFPI antigen levels (total and free forms) in his plasma actually increased above normal range after APCC infusion, whilst these levels unchanged after rFVIIa infusion and returned to the normal range after one-week cessation, speculating that TFPI might contributes to unresponsiveness to APCC. To confirm this, plasmas from several hemophiliac patients with APCC and/or rFVIIa infusion, including 4 patients with poor response pattern in TGT, were prepared. Among 12 pairs of plasmas (a pair; pre and post bypassing agents), each of 4 pairs were for APCC-poor response (APCC-PR), APCC-good response (APCC-GR), and rFVIIa-good response (FVIIa-GR). Free form TFPI antigen levels (normal; 15–35 ng/ml) increased after infusion in APCC-PR (pre/post; 38±4/51±3 ng/ml, p<0.05) and APCC-GR (28±4/37±4 ng/ml, p<0.05), but not increased in FVIIa-GR (23±3/21±3 ng/ml, p>0.05). Post-infusion levels in APCC-PR were significantly higher than those in APCC-GR (p<0.05). By adding anti-TFPI antibody, plasmas in APCC-PR showed marked increase of peak thrombin levels than those in APCC-GR in TGT, supporting that APCC-PR possessed more TFPI activity. Unexpectedly, ELISAs revealed that total TFPI were contained in APCC at 24±4 ng/unit (corresponded to 25≂f50% of physiological concentration), and 34% of them were free form, speculating that APCC infusion with ≂f90 units/kg appeared to increase free TFPI by ≂f15 ng/ml in plasma. Taken together, our results supported that TFPI contained in APCC attenuated the potentials of thrombin generation in hemophilia A patients with inhibitors, and some patients exhibited APCC-resistance due to TFPI accumulated by the consecutive use of APCC. Disclosures:Ogiwara:Baxter Hemophilia Scientific Research and Education Fund in Japan 2009: Research Funding. Nogami:Bayer Hemophilia Award Program 2009: Research Funding.

Effects of Agents, Used to Treat Bleeding Disorders, on Bleeding Time Prolonged by a Very High Dose of a Direct Thrombin Inhibitor in Anesthesized Rats and Rabbits

Melagatran is the active form of the oral, direct thrombin inhibitor, H 376/95, that is under evaluation in clinical trials for the prevention and treatment of thromboembolism. In this study, a single dose, calculated on body weight basis, of antifibrinolytic treatment, factor VIIa, factor VIII with and without von Willebrand factor (vWF), factor IX, activated (APCC) or nonactivated (PCC) prothrombin complex concentrates was given intravenously to rats and rabbits, in an attempt to reverse the prolonged bleeding time during intensive anticoagulation with melagatran (2 μmol/kg/h). The doses used were at or above human therapeutic doses. The cutaneous tail bleeding time in the rat, as well as the ear incision bleeding time and cuticle bleeding time, and the blood loss in the rabbit were used for evaluation of the hemostatic effects of these agents. In vivo Feiba (APCC) and Prothromplex-T (PCC) shortened the prolonged cutaneous bleeding times in rats ( P<.05); Feiba and Autoplex (APCC) shortened the cutaneous bleeding times in rabbits ( P<.05). In contrast, Prothromplex-T prolonged bleeding times and blood loss in the rabbits ( P<.05). Ex vivo Feiba, Autoplex and NovoSeven (rF VIIa) significantly ( P<.05) shortened the prolonged whole blood clotting time (WBCT). Prothromplex-T significantly prolonged WBCT, activated clotting time (ACT) and activated partial thromboplastin time (APTT). Feiba, Autoplex, and Prothromplex-T increased thrombin generation measured as increased thrombin–antithrombin complex (TAT) formation. In conclusion, APCCs were found to be the most effective agents for reversing bleeding time induced by a very high plasma concentration of melagatran. APCC and recombinant activated factor FVII (rF VIIa) effectively shortened the prolonged WBCT. Thus, stimulating thrombin generation with the use of APCC may counteract the anticoagulant effect observed with a very high dose of a thrombin inhibitor.