Doses Of aPCC Research Articles

Follow-up and Evaluation of the Efficacy of the Hemostatic Treatment in Congenital FVII Deficiency during Development of Inhibitor

Introduction The development of inhibitors is an extremely rare complication in patients with factor (F)VII deficiency treated with replacement therapies such as recombinant activated FVII (rFVIIa), and represents a major therapeutic challenge in the treatment of this disorder. When inhibitors result in loss of response to high doses of rFVIIa, activated prothrombin complex concentrate (aPCC) is often used as an alternative treatment for these patients. The use of high-dose rFVIIa or aPCC might be accompanied by an increased risk of thromboembolic events, so it is important monitoring properly the effect of the hemostatic treatment Here we describe the therapeutic management and follow-up of a patient with elevated inhibitor titres, resistant to rFVIIa treatment who switched to prophylaxis with aPCC, using several global coagulation tests. Methods The coagulation status of the patient and the reponse to in vitro spiking of different doses of rFVIIa or aPCC were assessed with several global tests: Prothrombine time (PT) was tested using HemosIL®RecombiPlasTin 2G. Clot formation was evaluated with Rotational Thromboelastometry (ROTEM®) using blood with CTI (to inhibit contact activation) and activated with a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using plasma collected with CTI and activated with 1 pM TF plus phospholipids (PPP-Low®, Stago). Thrombus formation under flow conditions was assessed with the Total Thrombus-formation Analysis System (T-TAS®) in AR-chips coated with collagen and thromboplastin. The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Results Three year-old girl affected by severe congenital FVII deficiency (FVII 9.1%) with significant severe bleeding history (spontaneous intracranial hemorrhage at 1st month of life). Since then she is in prophylaxis treatment with rFVIIa. At 6 months of life she developed an inhibitor (9.8 BU). Despite prophylaxis she presents frequent spontaneous mucocutaneous bleedings. When she was 2 years old she needed to be admitted at hospital because of port-A-Cath infection. Due to the administration of intensive treatment with rFVIIa during admission she developed thrombosis of peripheral venous access, so prophylaxis treatment was temporary suspended. After 5 days without prophylaxis treatment, and increasing inhibitor titres, she developed a new intracranial haemorrhage, which needed intensive treatment with continuous rFVIIa infusion (90 µg/Kg/12h), immunoglobulines and rituximab for lowering inhibitor titre. Hemostatic parameters improved during the administration of these treatments and inhibitor level was reduced. After restarting prophylaxis treatment with rFVIIa (50 µg/Kg/48h), inhibitors and a hypocoagulable state were observed with all global coagulation test showing extended PT, clotting time (CT), TG Lag-time (LT) and anomalous thrombus formation (AUC) but presented very good response to low dosis (2.5 IU/Kg) of aPCC in vitro (Table-1). At the age of three years she required admission at hospital because of port-A-Cath infection again, needing its replacement by a new one after administration of high doses of rFVIIa without bleeding complications. After this, inhibitor titre raised again (> 50 BU), presenting frequent bleeding episodes (spontaneous muscle bleedings and tonsillar bleeding), and due to the clinical worsening, treatment was modified to prophylaxis with aPCC (30 UI/Kg/48h). Despite the treatment change she continued presenting bleeding episodes, global tests continued showing an hypocoagulable state, and required 10 times higher doses in vitro of aPCC (25 IU/Kg) to restore all the monitored hemostatic parameters (Table-1), probably related to the important increase in inhibitor titre. This situation led to employing higher doses of aPCC prophylaxis (60 UI/Kg/48 h) to try to avoid bleeding episodes without increasing the risk of suffering thrombotic events. Conclusions Global coagulation tests used in this study were sufficiently sensitive methods to show an abnormal hemostatic profile in FVII-deficient patients with clinical hemorrhagic symptoms with inhibitor development, supporting their use to manage the risk of bleeding or thrombosis in this life-threatening condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of thrombotic complications related to weight-based dosing of activated prothrombin complex concentrate (aPCC) for reversal of apixaban and rivaroxaban in obese patients.

Factor eight inhibitor bypassing activity (aPCC) is recommended as a non-specific reversal agent for direct oral anticoagulants (DOACs) according to the 2017 American College of Cardiology (ACC) guidelines for reversal of anticoagulation. Factor eight inhibitor bypassing activity carries a black box warning for thrombotic events such as stroke, pulmonary embolism, deep vein thrombosis, and myocardial infarction, particularly at high doses. This was a retrospective, single-center, cohort investigation that included patients who received a weight-based dose of aPCC for reversal of apixaban and rivaroxaban between January 1, 2015, and December 31, 2020. Patients were grouped by BMI as obese (BMI ≥ 30kg/m2) or non-obese (BMI < 30kg/m2) for analysis. The primary outcome of this investigation was the occurrence of thrombotic complications [venous thromboembolism (VTE), myocardial infarction, stroke] documented in the medical record at any point during hospitalization after administration of aPCC. Secondary outcomes included bleeding complications, in-hospital mortality, ICU and hospital length of stay. Patients in the obese group were younger [76.4 years (SD +/- 11.3 years) vs. 69.6 years (SD +/- 12.4 years); p < 0.0001] and a higher proportion had a diagnosis of diabetes mellitus prior to admission [37 (19.2%) vs. 35 (36.8%); p = 0.0011]. There was no difference in the primary outcome of thrombotic events between non-obese and obese patients [12 (6.2%) vs. 5 (5.3%); p = 0.75], or for any of the secondary outcomes of bleeding, in-hospital mortality or length of stay. This investigation did not reveal a difference in rates of thrombosis or bleeding events between obese and non-obese patients who received aPCC for reversal of apixaban and rivaroxaban.

Effects of Bypassing Hemostatic Agents in the Co-Presence of NXT007, Emicizumab-Based Engineered Bispecific Antibody to Fixa/Fx, Using in Vitro Global Assays: Rough Indicators for Their Concomitant Use

Background:NXT007, emicizumab (Emi)-based engineered therapeutic bispecific antibody which increases tissue factor (TF)-triggered thrombin generation (TG) potential of factor(F) VIII-deficient plasma to non-hemophiliac ranges at around 5-30 μg/mL (Yamaguchi, ASH 2020), is currently in a phase 1/2 clinical study. In the clinical settings under NXT007-prophylaxis, bypassing hemostatic agents (BPAs), such as activated prothrombin complex concentrates (aPCC) and recombinant(r) FVIIa, may be concomitantly administered. Under Emi-prophylaxis, repeated doses of aPCC impose a thrombotic risk. Against the risk, NHF's Medical and Scientific Advisory Council (MASAC) recommends ≤50 U/kg and ≤100 U/kg of aPCC as initial dose and one day dosage, respectively. In case of NXT007-prophylaxis, concomitant-use with BPAs should be also carefully managed and thus basic non-clinical combination data are needed.Objectives:To examine in vitro effects of BPAs in the co-presence of NXT007 for providing rough indicators for determining their safe doses.Methods:First, TF-triggered TG assay was performed using commercial FVIII-deficient plasma. rFVIII, rFVIIa or aPCC was spiked in the co-presence of NXT007 or Emi (0.1-50 μg/mL). Second, the TG assay and whole blood clot viscosity test (ROTEM) using Ca 2+-trigger was performed using healthy volunteer's blood incubated with anti-FVIII antibodies (HA model), where aPCC or rFVIIa was spiked in the co-presence of NXT007. Third, ROTEM was performed as above using whole blood from persons with hemophilia A (PwHA) under Emi- or FVIII-prophylaxis.Results:Peak height of TF-triggered TG assay using FVIII-deficient plasma was increased by spiking each of the agents (rFVIII, rFVIIa or aPCC) in the co-presence of NXT007 (0.1-50 μg/mL). Peak height increase by rFVIII under NXT007 was roughly additive. Peak height increase by each BPA under NXT007 was synergistic. Synergistic effect by aPCC was more intensive than that by rFVIIa. The combination effect of 0.1 U/mL aPCC and 0.1-50 μg/mL NXT007 on peak height did not exceed that of 0.5 U/mL aPCC and 50 μg/mL Emi. Peak height at 2 μg/mL NXT007 alone was comparable to that at 50 μg/mL Emi alone. When adding BPAs to these two settings, similar synergistic effects were observed. It suggested that NXT007's combination actions with BPAs were qualitatively similar to Emi's.In the TG assay using the HA model plasma (n=2), the combined effect of aPCC and NXT007 was similarly confirmed. In ROTEM using the same HA model whole blood (n=2), clotting time (ROTEM-CT, 7380±605 sec) was shortened by spiking 5 μg/mL NXT007 (791±148 sec) to yield normal levels (1521±110 sec). Spiked aPCC (0.13, 0.65 U/mL in whole blood, equivalent to ~10, ~50 U/kg infusion) shortened ROTEM-CT (1228±549, 435±54 sec) and further shortened it in the co-presence of 5 or 15 μg/mL NXT007 (171±11, 113±1* or 143±4, 90±5* sec [* significantly ( p<0.05) shorter than that of the Emi-treated PwHA blood spiking 0.65 U/mL aPCC, 162±21 sec)].In PwHA without Emi-prophylaxis (n=2), ROTEM-CT (5148±1290 sec) was shortened by spiking 5 or 15 μg/mL NXT007 (1598±482 or 1116±14 sec) to non-hemophiliac levels (20 IU/dL rFVIII, 1569±222 sec). Spiked aPCC (0.13, 0.65 U/mL) shortened ROTEM-CT (1383±322, 680±84 sec) and further shortened it in the co-presence of 5 or 15 μg/mL NXT007 (230±35, 144±4 or 193±11, 121±0* sec). Spiked rFVIIa also shortened ROTEM-CT in the co-presence of NXT007, but the intensity was less than spiked aPCC.ROTEM using blood from PwHA under Emi-prophylaxis (n=3) were also performed and demonstrated that the effects by co-spiking BPAs and NXT007 were roughly consistent with those using PwHA blood without Emi-prophylaxis. These ROTEM data indicated that the combined effect of 0.13 U/mL aPCC and 5-15 μg/mL NXT007 was less intensive than that of 0.65 U/mL aPCC spiked to the Emi-treated PwHA blood, while that of 0.65 U/mL aPCC and 5-15 μg/mL NXT007 had more intensive effect (Table).Conclusion:In considering concomitant use of BPA under NXT007-prophylaxis, dose of aPCC should be more carefully determined than that of rFVIIa. In this non-clinical study, the combined effect of ~0.13 U/mL aPCC (equivalent to ~10 U/kg infusion) and ~15 μg/mL NXT007 did not exceed that of 0.65 U/mL aPCC (50 U/kg infusion) under Emi-prophylaxis situation corresponding to the upper limit of initial concomitant dose recommended by MASAC, which might be rough indicators in future clinical settings. [Display omitted] DisclosuresOgiwara: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Sasai: Chugai Pharmaceutical Co., Ltd.: Research Funding. Inaba: Chugai Pharmaceutical Co., Ltd.: Current Employment. Kitazawa: Chugai Pharmaceutical Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding.

Emicizumab Prophylaxis in Adolescent/Adult Patients with Hemophilia A Previously Receiving Episodic or Prophylactic Bypassing Agent Treatment: Updated Analyses from the HAVEN 1 Study

Emicizumab Prophylaxis in Adolescent/Adult Patients with Hemophilia A Previously Receiving Episodic or Prophylactic Bypassing Agent Treatment: Updated 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

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

The Influence of Personalized 2-Year Physiotherapy on Musculoskeletal Health and Quality of Life in Severe Hemophilia Patients with Inhibitor - Interim Analysis after 1 Year of the Program

Development of factor VIII (FVIII) inhibitor is a serious complication of factor replacement therapy observed in about 15-30% of severe hemophilia A (HA) patients. Inhibitors interfere with the treatment by neutralizing intravenously injected FVIII. Although bleeding rate is not increased in severe HA patients who developed the inhibitor, the inhibitors reduce the efficacy of factor replacement therapy during bleeding episodes and in consequence accelerate the progression of hemophilic arthropathy. In Poland, prophylaxis in hemophilia with inhibitors has been introduced in 2016, and therefore many HA patients with inhibitor still suffer from particularly severe arthropathy, and have a reduced quality of life. The aim of the study was to evaluate the musculoskeletal health and quality of life in patients with severe hemophilia A with inhibitor before initiation of personalized physiotherapy and after 2 years of the personalized physiotherapeutic program. The study was performed in 24 persons with severe HA with inhibitor (mean age 42.1 years, median age 42 years) receiving prophylaxis regimen with aPCC 85 ± 15 IU/kg 3 times a week. At the beginning of the project, the patients were examined by hematologist and physiotherapist. Joint condition was evaluated using the Hemophilia Joint Health Score (HJHS) and magnetic resonance imaging of the most affected joint. Quality of life was evaluated using EQ-5D scale (EuroQoL). aPCC dosing schedule in context of rehabilitation program was adjusted by the hematologist. Each patient was enrolled to a personalized exercise program developed based on age, general condition, stage of arthropathy, date of the last bleeding episode, and a history of physiotherapy. The program consisted of weekly 60 to 90 minutes rehabilitation sessions at home, and participated in four 5-day rehabilitation camps with 5 hours of rehabilitation sessions a day organized in Poznan after 6, 12, 18 and 24 months of the program. All patients were examined by hematologist, and the rehabilitation was provided only to the patients on regular prophylaxis with aPCC provided that a dose of aPCC was always administered 1 hour before the initiation of rehabilitation session. HJHS varied among the participants, with mean value at baseline 34.2 (median 36.5). Baseline mean EQ-5D score was 54.2 (median 60). Evaluation at month 12 was performed in 18 participants (2 patients withdrawn from the program, and 4 patients could not participate in the evaluation due to COVID-19 pandemics). The results obtained at month 12 show a significant improving the quality of life and musculoskeletal health of patients with HA after combined prophylaxis and personalized rehabilitation. Mean HJHS decreased from 34.2 to 30.4 points (median from 36.5 to 31 points). An average 3.8 point decrease confirms positive effects of long-term aPCC prophylaxis with personalized, regular rehabilitation. Increase in mean EQ-5D score from 54.2 to 70.1 (median from 60 to 72) show enhancing patients' mood resulted from the improved health status and regained capability to conduct more normal lifestyle. After the first year of the project we can conclude that regular prophylaxis with aPCC and personalized, once-a-week rehabilitation program positively influence joint status and quality of life of adult HA patients with inhibitor complicated with significant arthropathy. Regular rehabilitation may slow down the progression of arthropathy due to the choice of the exercise program appropriate for each patient. These positive effects justify the continuation of the project in patients with hemophilia A with inhibitor. Figure Disclosures No relevant conflicts of interest to declare.

Impact of Obesity on Warfarin Reversal With Fixed-Dose Factor VIII Inhibitor Bypassing Activity (aPCC).

Data are limited addressing anticoagulant reversal in obese patients using activated prothrombin complex concentrate (aPCC). Assess the impact of obesity on INR reversal with fixed aPCC dosing. Institutional review board-approved, retrospective cohort conducted in a large academic medical center. Patients 18 years or older who received fixed-dose aPCC for warfarin-associated hemorrhage were included. Patients who received aPCC for any other indications or who had no follow-up INR after aPCC administration were excluded. Patients with an INR of 5 or greater received 1000 units aPCC, whereas those with INR less than 5 received 500 units aPCC, per institutional protocol. Patients were stratified into obese and nonobese based on body mass index. Primary end point was INR reversal, defined as repeat INR of 1.4 or less within 4 hours following aPCC treatment, without a repeated dose. Secondary end points included percentage change in INR, proportion of patients requiring an additional dose of aPCC, bleeding complications, thrombotic complications, hospital length of stay, and in-hospital mortality. 259 patients were included, of whom 83 were obese (32%). A significantly higher proportion of nonobese patients achieved an INR of 1.4 or less within 4 hours of treatment (169 [96.02%] vs 69 [83.13%]; P = 0.0004). There were no differences in any secondary end points. When fixed-dose aPCC is used for warfarin reversal, obesity is associated with a significantly lower rate of INR reversal, without increased bleeding. This study adds to the limited amount of literature on aPCC dosing in obesity.

91-Year-Old Man With Upper Extremity Ecchymoses

91-Year-Old Man With Upper Extremity Ecchymoses

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.

Efficacy of Anti-TFPI Antibody PF-06741086 Alone and in Combination with Activated Prothrombin Complex Concentrates in Mouse Hemophilia a Bleeding Model

BACKGROUND: Tissue Factor Pathway inhibitor (TFPI) is a plasma serine protease inhibitor that modulates the initiation of coagulation by directly binding and inhibiting the Tissue Factor (TF)/Factor VIIa/Factor Xa complex. TFPI is a multi-Kunitz domain protein that directly binds to and inhibits both activated Factor Xa (FXa) and FVIIa. Blocking TFPI can act as a bypass therapy by facilitating hemostasis initiated by tissue factor/FVIIa, thereby, compensating for loss of Factor VIII or Factor IX (in hemophilia A or B). PF-06741086, a fully human antibody engineered to inhibit TFPI, exhibits broad cross reactivity to TFPI from numerous species, including mouse. PF-06741086 is being developed as a potential treatment for bleeding disorders including hemophilia A and hemophilia B with and without inhibitors. aPCC (activated Prothrombin complex concentrates or FEIBA, Factor Eight Inhibitor Bypass Agent) is a bypass agent for to control bleed in Hemophilia patients with inhibitors. Since it is a plasma-derived concentrate containing various prothrombin complex coagulation factors in their enzymatic or zymogen form, it is possible that FEIBA could potentially impact the activity of PF-06741086.AIMS: Here, we directly compare the hemostatic effect of PF-06741086 alone, and in combination with aPCC in Hemophilia A mouse model using severe tail vein transection.METHODS: Male hemophilia A mice were dosed with a single intravenous dose of PF-06741086 (0.5, 1, 2 or 6 mg/kg) 30 minutes prior to a 3mm tail clip, or aPCC (50, 100 or 200 U/kg) was administered 5 minutes before the tail clip. Mice were also treated with a combined dose of 0.5 mg/kg anti-TFPI PF-06741086 and aPCC at 50, 100 or 200 U/kg. Blood was collected for 10 minutes and quantified against a standard curve of hemoglobin as volume blood loss.RESULTS: PF-06741086 demonstrated a dose dependent response in improving hemostasis in Hemophilia A mice after tail clip. PF-06741086 was able to restore hemostasis at 1 mg/kg (49%), and higher doses further improved hemostasis at 2 mg/kg (63%), and 6 mg/kg (78%). aPCC also demonstrated a dose dependent reduction in blood loss and improved hemostasis with all tested doses of 50 U/kg (25%), 100 U/kg (23%) and 200 U/kg (66%). At a dose of 0.5 mg/kg, PF-06741086 did not show any improvement in hemostasis over vehicle control. We used this dose for all combination studies with aPCC. Combined use of low dose PF-06741086 (0.5 mg/kg) and 100 U/kg aPCC shows a trend towards improvement in hemostasis compared to either drug alone. A higher dose of aPCC (200 U/kg) combined with low dose PF-06741086 (0.5 mg/kg) significantly reduces blood loss (86%) in Hemophilia A mice in tail clip model compared to saline, TFPI or aPCC alone used at the same dose of 0.5 mg/kg or 200 U/kg respectively.CONCLUSIONS: Prophylactic administration of PF-06741086 exhibits a dose response and improves hemostasis in an injury model in Hemophilia A mice. The addition of aPCC alone restores hemostasis at 200 U/kg and this effect was enhanced in combination with PF-06741086 in this mouse model. DisclosuresBarakat:Pfizer: Employment. Jasuja:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.

A decade-long clinical experience on the prophylactic use of activated prothrombin complex concentrate in acquired haemophilia A

: 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.

The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII in apixaban‐treated patients in vitro

Unlabelled Box BackgroundThe number of patients under treatment with FXa inhibitors is increasing, but there is no concensus on how to reverse their anticoagulant effect in case of a life‐threatening bleeding. A specific antidote is not yet commercially available. Prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are suggested available reversal agents. ObjectivesTo find the most effective reversal agent to apixaban and to determine the optimal dose. Patients/MethodsPCC, aPCC, and rFVIIa at concentrations imitating 80%, 100%, and 125% of suggested therapeutic doses were added to blood drawn from apixaban‐treated patients (n=30). aPCC was also tested in a 50% dose. Samples from healthy subjects (n=40) were used as controls. Thromboelastometry in whole blood (WB) and thrombin generation in platelet‐poor plasma (PPP) were measured to assess the reversal effect. ResultsaPCC shortened clotting time (CT) in WB, and increased the peak thrombin concentration and velocity index in PPP to a greater extent than PCC and rFVIIa. No significant differences were seen between rFVIIa and aPCC on thrombin generation lag time, or between PCC and aPCC on endogenous thrombin potential (ETP). The 50% dose of aPCC had a slightly inferior effect, but was comparable to the other reversal agents. ConclusionsIn this in vitro study the 80% dose of aPCC (40 IU/kg) reversed the anticoagulant effect of apixaban more effectively than the corresponding dose of rFVIIa and PCC both in WB (CT) and PPP (peak, ETP).

Alternating Activated Prothrombin Complex Concentrate and Recombinant Activated Factor VII in the Successful Treatment of Patients with Acquired Hemophilia Α

Introduction: Acquired hemophilia A (AHA) is a rare (1.5 per million/year) autoimmune disorder due to formation of spontaneous antibodies against factor VIII (FVIII) with an estimated mortality of 8-22%. First-line hemostatic agents to control a bleed include activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rVIIa) whereas immunosuppressive therapy to eradicate the inhibitor include prednisone, cyclophosphamide, and rituximab. We present data on 12 AHA patients from our institution.Methods: We conducted a retrospective review of patients with AHA from January 1, 2010 to July 1, 2016.Results: Eight women and 4 men with a median age of 68 years (range 29-88 years) were included in the study. AHA was idiopathic in 7 patients, others being associated with HIV/Hepatitis C (1), Hepatitis C only (1), lymphoma (1) pregnancy (1), and pregnancy/systemic lupus erythematosus (SLE) (1).Of the 12 patients, 11 were admitted at least once with a bleeding episode. In total, there were 38 bleeding episodes, with 15 being characterized as severe (39%). The most common site of bleeding was deep muscle (50%), and 71% of bleeding episodes were considered spontaneous. The median FVIII activity at admission was <1% (range <1%-5%) with a median FVIII inhibitor titer of 102.4 BU/ml (range 7.4 - 5734.4 BU/ml).Table 1 summarizes the number of bleeding episodes and immunosuppression for each patient. Patient 7 experienced 24 bleeding episodes with 23 requiring both aPCC (median 75 u/kg, range 50-80 u/kg) and rVIIa (median 50 mcg/kg, range 50-90 mcg/kg) alternating every 6 hours. This patient had breakthrough bleeds on either aPCC or rFVIIa but responded to the alternating regimen. Patient 11 developed severe bleeding in his upper extremities, necessitating bilateral upper extremity amputation. He was initially treated with only aPCC (100u/kg every 12 hours for 11 doses total); however, concern for disseminated intravascular coagulation prompted aPCC discontinuation. He received a total 121 doses of rVIIa (90mcg/kg every 2-4 hours) during his hospital stay. Patient 2 required two doses of rVIIa (90 mcg/kg every 12 hours) after having continued bleeding despite treatment with 11 doses of aPCC (50u/kg every 12 hours). Ten bleeding episodes were treated with only aPCC with a median 8 doses (range 2-16 doses), while 1 bleeding episode was controlled with only rVIIa. One bleeding episode did not require treatment. The median dosage of aPCC (with or without rVIIa) was 75u/kg (range 50-100 u/kg) given every 12 hours (range 8-24 hours) for 8 doses (range 1 -16 doses). The median dosage of rVIIa when used in conjunction with aPCC was 50mcg/kg (range 50-100 mcg/kg) given every 12 hours (range 4-24 hours) for 6 doses (range 1-13 doses). No patient experienced a thromboembolic event.Follow-up data was available for 9 patients (Table 1). Six patients achieved complete remission (CR) at a median 126 days (range 68-1103 days). Patient 12 was initially treated with 1mg/kg prednisone; however, upon tapering, her FVIII activity shortened from 114% to 36%. Cyclophosphamide (2mg/kg) was added with eventual inhibitor eradication. Patients 3 and 7 failed to attain CR and were treated with prednisone, cyclophosphamide, and rituximab. They continued to have a FVIII activity <1% at 71 days and 12 years follow-up respectively. Patient 11 had pregnancy and SLE associated AHA. She was treated with 1mg/kg prednisone, 1 dose of rituximab, and hydroxychloroquine for her concurrent SLE. Her inhibitor titer was undetectable at 89 days, but her FVIII activity remained at 36% (blood type O) after 184 days.Conclusion: CR was achieved in 6 of 9 patients with follow-up data. There were no deaths related to AHA. A combination of aPCC and rVIIa, alternating every 6 hours, can safely be used to treat severe bleeding, reducing drug and administrative costs. [Display omitted] DisclosuresSarode:CSL Behring: Consultancy, Honoraria.

Activated prothrombin complex concentrate (FEIBA®) for the treatment and prevention of bleeding in patients with acquired haemophilia: A sequential study

Despite anti-haemorrhagic therapy with proper doses of activated prothrombin complex concentrate (aPCC, Feiba®), patients with acquired haemophilia A (AHA) have a considerable risk of recurrent bleeding complications. Evidence in support of the benefit-to-risk ratio of prevention strategies with the use of lower doses of aPCC following the end of the initial treatment period is scarce and inconclusive.We report our experience in the management of 18 consecutive patients with AHA admitted to two Haemophilia centres in Italy. We managed the first 11 according to current guidelines (e.g., with conventional aPCC doses until bleeding resolution). Then, we decided to prolong the treatment beyond bleeding resolution with lower doses of the same concentrate (short-term prophylaxis) in the 7 additional patients. In these patients, the treatment was continued for as long as the titre of FVIII inhibitor was found to decrease by at least 50% when compared to the baseline one.We observed six relapses of bleeding in patients in whom aPCC was confined to the treatment of the qualifying bleeding episode, and none in patients to whom lower doses were administered until the pre-specified decrease in the titre of FVIII inhibitor was achieved. No patients experienced thrombotic complications during the study period.Prolonging the treatment with lower doses of aPCC beyond the initial phase in patients with AHA in whom the titre of FVIII inhibitor is still high is likely to safely prevent further bleeding complications.

Multimodal assessment of non‐specific hemostatic agents for apixaban reversal

Non-specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off-label, to reverse the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban. Healthy volunteer whole blood was spiked with therapeutic or supra-therapeutic apixaban concentrations and two doses of aPCC, PCC or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time. aPCC generated a dense clot constituting thin and branched fibers similar to those of a control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters. aPCC was more effective than PCC or rFVIIa in reversing in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only a partial effect.

Attempts to treat patients with hemophilia, the "royal disease"

Our poor family seems persecuted by this awful the worst I know. Queen Victoria (1819-1901) of the United Kingdom of Great Britain and Ireland wrote in her diary. She is well known as the most famous carrier of hemophilia, the disease, and had passed on the disease to several royal families in Europe through her daughters. Since first described in a hemophilia patient by Lawrence and Johnson in 1941 [1], inhibitor development has been the most serious complication of hemophilia A treatment. Inhibitor development occurs in up to 36% of patients with severe hemophilia A [2, 3]. The inhibitor is an alloantibody against VIII (FVIII), which if developed during hemophilia treatment, impairs FVIII activity and thus neutralizes the effect of the factor therapy, leading to increased complications and therapeutic cost [4]. Some genetic and environmental risk factors for inhibitor development are well known; however, it is still unclear why some, but not other patients, develop inhibitors. The inhibitors in hemophiliacs may be temporary or can be eradicated with immune tolerance induction (ITI) therapy. The recent study (International Immune Tolerance Study) of 115 good-risk subjects with severe hemophilia A and high-titer inhibitors showed that there was no difference between the low-dose (50 IU/kg 3 times/week) and high-dose (200 IU/kg/day) regimens in achieving tolerance, with the former taking longer [5]. These data might be important for nations with limited resources. Although the eradication of inhibitors and recommencement of FVIII replacement therapy is a long-term goal in treating inhibitor patients, ITI therapy has limited indications and a success rate of 63-80% [6]. Patients with high-titer inhibitors and intractable bleeding episodes should be given recombinant activated VII (r-FVIIa) or activated prothrombin complex concentrate (aPCC), called the hemostatic bypassing agent (to circumvent FVIII in the coagulation pathway), as the first choice therapy. The FEIBA NovoSeven Comparative (FENOC) Study evaluated the hemostatic efficacy of both products on 96 joint bleeds of 48 inhibitor patients and showed nearly equivalent efficacy, with both agents being effective and safe, although a substantial number of patients reported different efficacies for both agents [7]. Nevertheless, 10-20% of bleeding events in hemophiliacs with high-titer inhibitors cannot be controlled by either r-FVIIa or aPCC alone and thus may need sequential combined bypassing therapy (SCBT). The rationale for the use of a combination of r-FVIIa and aPCC is based on data from experiments using a rabbit stasis model, where an early thrombotic effect was shown, indicating the synergistic effect of both agents on thrombus formation during stasis [8]. Clinically, SCBT is predicated upon the fact that neither bypassing agent controls bleeding completely and the response of each individual patient to either agent differs [9]. These aspects were also observed in the FENOC study [7], where up to 43.8% of subjects considered one product more effective than the other. A recent study employing a comprehensive literature search revealed that a significant number of patients treated with SCBT experienced complications such as thrombosis: 5 of 9 patients with acquired hemophilia and 5 of 40 with congenital hemophilia, among which 4 cases were fatal [8]. Moreover, no randomized controlled study has been carried out to investigate SCBT. Hence, the sequential use of both bypassing agents should have strict indications as mentioned earlier and should be accompanied by a thorough follow up to assess for thrombosis, including disseminated intravascular coagulation. In the current issue of Blood Research, Han and Park report their retrospective experience with the use of SCBT to treat 5 bleeds in 4 hemophilia A patients with high-titer inhibitors and refractoriness to both bypassing agents used individually [10]. The bleeds were associated with various clinical conditions: peripherally inserted central catheter (PICC) insertion, small bowel surgery, hemothorax, and 2 total knee replacements. Patients were treated by infusing aPCC every 8 or 12 hours with administration of 1 or 2 doses of r-FVIIa between the doses of aPCC (50-100 IU/kg aPCC and 90 µg/kg r-FVIIa). The dosage and intervals were similar to those used in previous studies [7]. Twelve- to 24-hour bleeding episodes were controlled satisfactorily with no thrombotic events associated with SCBT. Because there is a paucity of data on the treatment of high-titer inhibitor patients, this report contributes valuable information for the management of bleeding episodes in such patients in Korea. It is hoped that a prospective, randomized, and controlled study of SCBT will be carried out in Korea in the near future to overcome the limits of this retrospective study.

Dramatic Efficacy of Sequential Bypassing Agent Treatment for a Life-Threatening Bleeding in An Infant with Severe Hemophilia and Inhibitor

In hemophiliacs the treatment of bleeding in infancy is more difficult than in adults and children due to insufficient knowledge in pharmacokinetics. Moreover the clinical response to coagulation concentrates is known to have not only inter-patients but also inter-bleeding episodes variability and only scarce experience is available. We report an experience in a one-month old infant managed with a successful sequential therapy.Severe hemophilia A was diagnosed at day 4 of life because of a cephalhematoma without intra cerebral hemorrhage (ICH) and severe anemia (Hb: 4 g/dl). Packed red blood cells (RBC) were given, FVIII concentrate was infused daily during 12 days and the hematoma resolved. At day 50 recurrent seizures led to the diagnosis of subdural haemorrhage, in the absence of any trauma. Anti FVIII inhibitor was detected (while negative 10 days before). Treatment with recombinant FVIIa (rFVIIa) was started at 1.2 mg (200μg/kg) every 2 hours and then progressively decreased. Outcome was good. To avoid ICH recurrence because FVIII inhibitor titer>30 BU, rFVIIa prophylactic treatment was decided and a central venous access device (CVAD) was inserted into the left internal jugular vein. No abnormal blood loss was observed during this procedure and a compressive bandage on CVAD was immediately performed. Collapse and respiratory distress developed within 24 hours. Chest X-ray showed a complete left hemothorax. Hemoglobin(Hb) level dropped to 5.2 g/dl. RBC infusion was required and rFVIIa dose was increased to 2.4 mg then alternately 1.2 mg and 2.4 mg every 2 hours until hemodynamic stabilization. Pleural aspiration yielded only 25 ml bloody fluid. Twelve hours later the Hb level fell again to 7 g/dl and RBC were again infused. Recombinant FVIIa treatment was stopped and activated prothrombin complex concentrate (aPCC) was started at a dose of 500 units (83u/kg) every 6 hours. After 2 doses of aPCC the Hb level fell again requiring new RBC infusion. A sequential therapy was decided with alternate rFVIIa 1.2 mg and aPCC 500 units every 4 hours. and, the hemodynamic parameters and Hb level stabilized. Pleural aspiration yielded 190 ml. The infant's clinical status improved dramatically with the disappearance of the hemothorax. This alternative treatment was maintained for 20 hours with good tolerance according to frequent monitoring of platelet count, D-dimers and fibrinogen. A more usual treatment (aPCC 500 units tid) was prescribed but after the first 2 infusions fibrinogen level fell to 0.9 g/l, with positive D-dimers and platelet count dropped to 36 109/l. The therapy was decreased to 500 units bid and the biological parameters quickly improved. The baby's clinical status was excellent and one day after, therapy was switched to rFVIIa 1.2 mg every 6 hours. The outcome was excellent.Conclusion: This report evidences differential response to the same treatment according to the type of bleeding in the same patient with inhibitor. After inhibitor development, for ICH, where r FVIIa treatment is well known to be efficient, the patient's response was very good at usual doses for this age. For the second episode (hemothorax) where life was threatened at several instances the escalating and sequential treatment schedule shows that sometimes very aggressive therapy is required despite high risks of thrombosis and disseminated intravascular coagulation.

Prophylactic treatment with activated prothrombin complex concentrate (FEIBA®) reduces the frequency of bleeding episodes in paediatric patients with haemophilia A and inhibitors

Orthopaedic complications are among the most disabling sequelae occurring in patients with haemophilia and inhibitors. Recurrent or refractory joint bleeds can lead to joint damage, limiting mobility and causing permanent disability. Activated prothrombin complex concentrates (aPCCs) are effective in controlling acute, intraoperative and postoperative bleeding in patients with haemophilia and inhibitors. The relatively long, dosing interval and safety profile distinguish aPCCs as a well-suited option for prophylaxis. Therefore, it is postulated that long-term routine aPCC administration will decrease the frequency of recurrent bleeds, prevent damage to normal joints, and slow the progression of existing joint disease in patients with inhibitors. To test this hypothesis, a retrospective chart audit was performed. In four treatment centres, five patients were identified who received aPCC [Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex (FEIBA); Baxter AG, Vienna, Austria] prophylactically for > or = 6 months to prevent or reduce further joint deterioration, reduce bleeding and prevent postsurgical bleeding. Median treatment duration was 15 months and included administration of >1300 doses of aPCC. Dosages ranged from 50 to 75 U kg(-1) three times per week in four patients; one patient received 100 U kg(-1) daily. Orthopaedic status was maintained in four patients and improved in one; the frequency of bleeding episodes was reduced in all patients. No adverse events or thrombotic complications were reported. This case series demonstrates that routine aPCC administration may be used safely and effectively to reduce the occurrence of bleeding episodes and to maintain or improve clinical joint status in some patients.