scholarly journals Management of perioperative hemostasis in a severe hemophilia A patient with inhibitors on emicizumab using global hemostasis assays

2019 ◽  
Vol 10 ◽  
pp. 204062071986002 ◽  
Author(s):  
Hande Kizilocak ◽  
Clara Lana Yukhtman ◽  
Elizabeth Marquez-Casas ◽  
Jeanie Lee ◽  
Jennifer Donkin ◽  
...  
Keyword(s):  
Hemophilia A ◽  
High Titer ◽  
Standard Of Care ◽  
Major Surgery ◽  
The Novel ◽  
Severe Hemophilia ◽  
Thrombin Generation Assay ◽  
Perioperative Bleeding ◽  
Total Knee ◽  
Bypassing Agents

Background: Patients with severe hemophilia A and inhibitors are at risk of bleeding during invasive procedures. The standard of care for preventing perioperative bleeding has been replacement therapy with FVIII concentrates or for patients with high-titer inhibitors, bypassing agents. However, there is no consensus on the appropriate management of surgery in patients receiving the novel agent emicizumab. The aim of this study was to demonstrate a case of a patient on emicizumab undergoing major surgery with bypassing agents with preoperative use of the thrombin generation assay (TGA) and thromboelastography (TEG). Methods: We report a patient with hemophilia A with inhibitors who had undergone a total knee replacement while on emicizumab combined with a bypassing agent. We utilized TEG and TGA to determine which bypassing agent to choose as well as to inform about the ideal dose. Results: We elected to use recombinant FVIIa as a bypassing agent for the surgery based upon the TGA results. Conclusion: The TGA can be utilized to support decision-making in patients on emicizumab undergoing major surgery to both predict efficacy and potentially minimize the risk of thrombotic events.

Factor VIII Efficacy and Tissue Factor Levels in Hemophilia A Patients Undergoing Total Knee Replacement.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4029-4029
Author(s):  
Wolfgang Wegert ◽  
Manuela Krause ◽  
Inge Scharrer ◽  
Ulla Stumpf ◽  
Andreas Kurth ◽  
...  
Keyword(s):  
Total Knee Replacement ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Lag Time ◽  
Major Surgery ◽  
Plasma Samples ◽  
Time To Peak ◽  
Thrombin Generation Assay ◽  
Total Knee

Abstract The changes of tissue factor (TF) blood levels in patients undergoing major surgery has been reported presenting controversial data. Whether this TF is hemostatically active or if it interacts with other coagulation factors, e.g. FVIII, is still unclear, making thrombotic risk and complications assessment for even more difficult. We analyzed plasma samples from four male patients aged 27–55 with severe hemophilia A without inhibitory antibodies, undergoing total knee replacement, which all gave informed consent. Initial FVIII doses before intervention was 75–80 U/kg. Treatment following intervention was targeted at 100 % FVIII serum levels. None received heparin. No bleeding events occurred during the observation period. The samples were taken at these timepoints (TP): 1. before preoperative FVIII substitution, 2. at the time of first incision (intervention start), 3. at circulation arrest release + 90 s after prosthesis implantation, 4. final suture (intervention end), 5. 24 h and 6. 48 h after intervention to assay procedurally induced TF production. Coagulation analyses were carried out using a fluorometric thrombin generation assay (TGA) in platelet rich plasma (PRP), RoTEG (rotation thrombelastography) in whole blood and a TF ELISA for the plasma samples’ TF levels. Both clotting function tests were started using TF diluted 1:100.000 and calcium chloride 16,7 mM (final conc.). TGA parameters were ETP, PEAK (maximum thrombin generation velocity), TIME TO PEAK, LAG TIME. TGA parameters directly related to thrombin activity (ETP; PEAK) showed no change during the intervention, but a sharp decrease 24 h later with a partial recovery 48 h later. TGA time marks (TIME TO PEAK, LAG TIME) changed in an inverse way, except for the difference from LAG TIME and TIME TO PEAK, which shortened continously after circulation arrest removal. RoTEG was characterized using 4 parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF) and clot formation rate (CFR). After preoperative FVIII substitution, CT decreased by 10 % and CFT by 50 % in 48 h. MCF stayed unchanged during the intervention and the following 24 h, but increased by 20 % at 48 h. CFR increased by 10 % during intervention, and by 20 % from 24 to 48 h. TF ELISA showed preoperative TF plasma levels from 11 to 271 pg/ml. After release of circulation arrest (TP 3) TF concentration increased sharply (4 times the initial value), which was not detectable in the samples taken at TPs 2 and 4. TF levels further increased at TPs 5 and 6 to 170 % and 317 % resp. Altogether, TF plasma levels elevated after major surgery seem to correspond to a potential risk factor for postoperative thrombosis, especially when elevation is induced after intervention. However, functional coagulation assays do not change uniformly, as the thrombin generation assay reflects no marked changes under intervention, but in the period after(24–48 h). Changes in the RoTEG whole blood clotting assay are not dramatic but indicate a thrombophilic shift in coagulation balance also pronouned at 24–48h, too. These results demonstrate that increased coagulability after orthopedic surgery detected using functional clotting assays correlates with increased TF levels, but further studies must be performed to prove this relation in healthy individuals.

Thromboelastography (TEG) As a Global Assay to Elucidate Complex Nuances of Hemostasis in Pediatric Inhibitor Patients with High Titer Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2845-2845
Author(s):  
Natalie L Smith ◽  
Abimbola Onasoga ◽  
Linda Jacobson ◽  
Elizabeth Villalobos-Menuey ◽  
Katherine A. Ruegg ◽  
...  
Keyword(s):  
Young Children ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
High Titer ◽  
Healthy Adults ◽  
Healthy Children ◽  
Severe Hemophilia ◽  
Bypassing Agents ◽  
Inhibitor Titer ◽  
Over Time

Abstract Background: Pediatric severe hemophilia A patients with high titer inhibitors are often reported to have inadequate control of acute bleeding episodes because they do not respond to bypassing agents as predictably as with FVIII therapy for non-inhibitor patients. Thromboelastography (TEG) is a global assay of hemostasis that has promising benefits for use in clinical care for hemophilia patients. Aims: This study was performed to determine in pediatric inhibitor patients: 1) if baseline TEG, specifically R or reaction time that corresponds to time to thrombin generation and clot formation, is stable over time in individual inhibitor patients; 2) if there are any predictors of baseline TEG R time; 3) to determine response to recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisk, Copenhagen, Denmark); and 4) to determine predictors of TEG R time following rFVIIa. Methods: This analysis was conducted within a consented single institution prospective inceptional cohort study. Clinical data regarding healthy volunteers with no personal or family history of a bleeding or clotting disorder and pediatric hemophilia patients with and without inhibitors (assayed by Nijmegen modification of the Bethesda assay (BU)) were extracted from research records and electronic medical records. For this study, TEGs were performed in kaolin citrated samples with added TPA (final concentration 450 ng/mL). Descriptive data were presented as mean and SD. This report analyzed TEG R times, indicating time to clot formation and initial thrombin generation. Baseline TEGs were obtained at least five half-lives after the last infusion of each clotting factor or bypassing agent received. Post treatment TEGs were performed on patients 1 hour following a therapeutic treatment with rFVIIa. Results: R times on TEGs were obtained on 24 healthy adults, 23 healthy children, 15 children with severe hemophilia A without an inhibitor, and 12 children with severe hemophilia A and an inhibitor. 32 samples were obtained in the 12 children with inhibitors, with 1 to 11 samples from each child. Paired samples were obtained at baseline prior to and 1 hour following a dose (90-270 mg/kg) of rFVIIa. Mean TEG R times were 8.3 minutes (SD 1.4) for healthy adults, 7.7 minutes (SD 1.5) for healthy children, 20.2 minutes (SD 9.4) for children with severe hemophilia A and 102.1 minutes (SD 44.4) for children with severe hemophilia A and inhibitors. Healthy children did not differ from healthy adults (p=0.43), but children with hemophilia with inhibitors differed from healthy controls (p=0.046) and trended toward differences from children with hemophilia without inhibitors (p=0.08, however limited in sample number). Baseline R values in children with inhibitors did not correlate with age (r=-0.19) or inhibitor titer (r=0.23). Children studied on multiple occasions showed variability over time. TEG 1 hour following rFVIIa in a baseline state showed a mean R time of 25.1 minutes (SD 7.1). Post rFVIIa R time did not correlate with age (r=0.21) or inhibitor titer (r=-0.14), but showed considerable correlation with baseline TEG R time (Figure 1, r =0.65, p=0.013). Following infusion of rFVIIa, TEG R times of children with inhibitors never achieved the normal range. However, when rFVIIa was studied following multiple infusions without a washout, the mean TEG R was moderately, but non-significantly shorter at 20.6 minutes (SD 5.6). Conclusions: TEG R times in young children with severe hemophilia A with inhibitors are greatly prolonged compared to healthy children or adults, and moderately longer than that in children with severe hemophilia A without inhibitors. Baseline TEG R varies over time and cannot be predicted by age or inhibitor titer. Baseline TEG R time may be an important predictor of response to bypassing therapy and serial monitoring over time may be clinically useful to guide therapy. During the course of multiple infusions, moderately improved TEG R responses were determined compared with first infusions. This may, in part, explain our previously reported observation of longer duration of rFVIIa dosing in young children with inhibitors. Future studies employing TEG to help optimize response to bypassing agents are needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Maintaining Perioperative Hemostasis in Patients with Severe Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 635-635 ◽  
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Mark T. Reding ◽  
Jatin Rana ◽  
Michael U. Callaghan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Perioperative Management ◽  
Hemophilia A ◽  
Advisory Board ◽  
Severe Hemophilia ◽  
Invasive Procedures ◽  
Advisory Committees ◽  
Perioperative Bleeding ◽  
Bypassing Agents

Abstract Introduction: Patients with severe hemophilia A and anti-factor VIII (fVIII) antibodies (inhibitors) are at risk of significant bleeding during invasive procedures. Prior to the introduction of the bispecific humanized antibody, emicizumab, the standard of care for preventing perioperative bleeding in these patients consisted of repeated doses of bypassing agents such as recombinant activated factor VII (rfVIIa) and activated prothrombin complex concentrates (aPCCs) or high-doses of fVIII products. This practice often prolonged hospital admission and was associated with increased patient-care costs. Prophylaxis with emicizumab has significantly reduced bleeding symptoms in patients with hemophilia A and inhibitors. However, questions regarding the appropriate management of acute bleeding episodes and invasive procedures in patients receiving this novel therapy remain unanswered. Additionally, there are concerns about the hemostatic efficacy and safety of fVIII products and bypassing agents necessary for the management of perioperative bleeding and breakthrough bleeds in patients with inhibitors treated with emicizumab. In this case series, we report on the perioperative management and outcomes of patients receiving emicizumab prophylaxis who underwent invasive procedures. Methods: Patients between the ages of 1 - 60 years old with severe hemophilia A (fVIII activity <1%) with a history of low or high titer inhibitors on emicizumab prophylaxis treated at the Emory Pediatric Hemophilia Treatment Center, the Center for Bleeding and Clotting Disorders at the University of Minnesota Medical Center, the Michigan State University Center for Bleeding and Clotting Disorders, and the Children's Hospital of Michigan/Wayne State University were included in this analysis. All patients were continued on their emicizumab prophylaxis throughout the perioperative period. Due to the potential risk of thrombosis and thrombotic microangiopathy with aPCCs, these agents were avoided and rfVIIa was the preferred bypassing agent. Either recombinant (r) fVIII or plasma-derived (pd) fVIII were used in patients that had known response to high-dose fVIII. Perioperative treatment regimens, bleeding symptoms, and complications were monitored. Results: Seven patients underwent invasive procedures while on emicizumab prophylaxis and an additional two patients had minor procedures performed that required observation alone. These patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to starting emicizumab ranging from 2.0 - 4,792 BU/mL. Their inhibitor titers prior to the procedure ranged from 0 - 193.3 BU/mL. All patients initiated emicizumab prophylaxis at a median of 12 weeks prior to their procedures (range: 2 - 28 weeks). All 4 of the pediatric patients requiring invasive procedures underwent central venous access device (CVAD) - related procedures. The 3 adult patients requiring invasive procedures underwent removal of an infected penile prosthesis, a complex dental extraction consisting of 4 extractions and 1 alveoloplasty, and a right elbow synovectomy with radial head excision. Six patients were admitted to the inpatient hematology service for observation for a median of 48 hours (range: 24 - 168 hours) following their procedures. No patient required readmission after hospital discharge. All patients experienced minimal blood loss perioperatively, and none required transfusions of blood products. The patient undergoing CVAD removal developed a hematoma at the prior port site noted 1 week post-procedure that responded to rfVIIa 90 mcg/kg once daily for 2 days. A second patient had mild surgical site bleeding 1 week post-procedure, which responded to one dose of rfVIIa (90 mcg/kg). No other patient had bleeding complications, and no patient experienced thrombosis or thrombotic microangiopathy. The perioperative management plans are outlined in Table 1. Conclusions: This is the largest case series outside of the HAVEN series detailing the perioperative management of severe hemophilia A patients with a history of low or high titer inhibitors receiving emicizumab prophylaxis. During these invasive procedures, these patients required decreased dosing of fVIII products or bypassing agents and experienced minimal complications. Minor procedures were able to be completed with observation alone. Disclosures Zimowski: National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Batsuli:Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Reding:Genentech: Other: Advisory Board. Callaghan:Global Blood Therepeutics: Employment; Amgen: Employment; Octapharma: Honoraria; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Equity Ownership; Hema Pharmaceuticals: Honoraria; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria; Sancilio Pharmaceuticals Company: Employment; Pfizer: Employment, Honoraria, Research Funding. Meeks:HEMA Biologics: Other: Advisory Board; Genentech: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Uniqure: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Kedrion: Research Funding; Shire: Other: Advisory Board, Research Funding; Octapharma: Other: Advisory Board; Biomarin: Other: Advisory Board; Bioverativ: Other: Advisory Board, Research Funding; Grifols: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer &lt;0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR &gt;66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

Emicizumab for the treatment of acquired hemophilia A

Blood ◽  
2020 ◽  
Author(s):  
Paul Knoebl ◽  
Johannes Thaler ◽  
Petra Jilma ◽  
Peter Quehenberger ◽  
Karoline Veronika Gleixner ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Coagulation Factor ◽  
Standard Of Care ◽  
Early Discharge ◽  
Severe Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Breakthrough Bleeding ◽  
Hemostatic Efficacy ◽  
Bypassing Agents

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by inhibiting autoantibodies to coagulation factor VIII (FVIII). For hemostatic treatment, bypassing agents, human or porcine FVIII are currently standard of care. Emicizumab is a bispecific, FVIII-mimetic therapeutic antibody, that reduced the annualized bleeding rates in congenital hemophiliacs. Here we report on 12 patients with AHA, 6 male, 6 female, age 74 yrs (64/80) (all data medians and IQR), treated with emicizumab. Initial FVIII was &lt;1%, inhibitor 22.3BU/mL (range 3-2000). Eight patients had severe bleeding. Emicizumab was started with 3mg/kg sc. weekly for 2-3 doses, followed by 1.5mg/kg every 3 weeks to keep the lowest effective FVIII levels. For FVIII monitoring, chromogenic assays with human and bovine reagents were used. All patients received immunosuppression with steroids and/or rituximab. After the first dose of emicizumab, APTT normalized in 1-3 days, FVIII (human reagents) exceeded 10% after 11 (7.5/12) days. Hemostatic efficacy was obtained and bypassing therapy stopped after 1.5 (1/4) days. FVIII (bovine reagents) exceeded 50%, indicating complete remission, after 115 (67/185), and emicizumab was stopped after 31 days (15/79), in median 5 injections (range 3-9) were given. No patient died from bleeding or thromboembolism, and no breakthrough bleeding was observed after the first dose of emicizumab. In conclusion, emicizumab seems to be an effective hemostatic therapy for AHA, with the advantages of sc. therapy (every 1-3 weeks), good hemostatic efficacy, early discharge, reduction of immunosuppression and adverse events.

scholarly journals F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2922-2934 ◽  
Author(s):  
Samantha C. Gouw ◽  
H. Marijke van den Berg ◽  
Johannes Oldenburg ◽  
Jan Astermark ◽  
Philip G. de Groot ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gene Mutation ◽  
Hemophilia A ◽  
High Titer ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Secondary Outcome ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Inhibitor Development

Abstract This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Phase II Trial of Rituximab in the Treatment of Inhibitors in Congenital Hemophilia A: Results of the RICH Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 27-27 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Rebecca Kruse-Jarres ◽  
Suzanne Granger ◽  
Barbara A Konkle ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Null Hypothesis ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Minor Response ◽  
Inhibitor Titer

Abstract Abstract 27 Antibodies (inhibitors) to exogenously administered factor VIII (FVIII) develop in as many as 30 – 40% of patients with severe hemophilia A. Patients with persistent inhibitors are at increased risk of serious, poorly controlled bleeding which results in significant morbidity and in some cases early death. Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, suppresses circulating and tissue B cells and pre-B cells and has been used in the treatment of a variety of autoimmune and alloimmune disorders. The primary objective of this NHLBI Transfusion Medicine Hemostasis network-sponsored study was to evaluate the role of rituximab as an approach to inhibit the production of FVIII antibodies in patients with severe congenital hemophilia A and high titer inhibitors. Methods: This was a prospective, multi-institution, single-arm, open-label Phase II trial. Eligible subjects were males over 18 months of age with severe hemophilia A and a history of an inhibitor ≥5 Bethesda units (BU). Individuals who were HIV positive, undergoing immune tolerance, or receiving immune modulating therapies were excluded. Following a challenge dose of recombinant FVIII (rAHF-PFM) at 50 IU/kg, and evidence of an inhibitor titer ≥ 5 BU at 5 – 14 days after the challenge dose, subjects received rituximab 375 mg/m2 weekly for 4 weeks. Starting two weeks after the fourth rituximab treatment, inhibitor titers were drawn every 4 weeks. A major response was defined as a fall in the inhibitor titer to < 5 BU at any time up to and including week 22, with the titer remaining < 5 BU following re-challenge with FVIII. A minor response was defined as inhibitor falling to < 5 BU at any time up to and including week 22, with the anamnestic peak following re-challenge with FVIII between 5–10 BU and less than 50% of the original anamnestic peak. The null hypothesis was that no more than 5% of subjects treated with rituximab would be major responders. Results: A total of 23 subjects were enrolled; 21 received the initial FVIII challenge. Of these, 4 subjects did not meet the criteria to receive rituximab treatment, and 1 subject withdrew consent. A total of 16 subjects received at least one dose of rituximab and are included in this analysis. The median age was 14 y (range 4 – 38 y). Three subjects (18.8%) had a major response. If the null hypothesis were true, the probability of 3 or more major responses in 16 subjects would be 0.043, so the null hypothesis was rejected. One subject (6.2%) had a minor response to treatment. All 4 responders and 8 non-responders had a baseline inhibitor titer < 20 BU, resulting in a response rate of 33% in that group vs. 0% in the 4 subjects with a baseline inhibitor titer ≥ 20 BU. Discussion: Infusion of rituximab 375 mg/m2 once per week for four weeks was effective in reducing the anamnestic inhibitor response in 25% of severe hemophilia A subjects with inhibitors who were not receiving concurrent immune tolerance therapy. Those who responded tended to have lower baseline inhibitor levels compared to the group that did not meet the criteria for response. This Phase II study, designed as a proof of concept, demonstrated that rituximab may be useful in lowering inhibitor levels and anamnesis in some patients with inhibitors, but that the effect as a solo treatment strategy is modest, and possibly restricted to patients with inhibitor titers under 20 BU. Further studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies. Acknowledgments: The authors acknowledge the support of Genentech for the provision of rituximab and partial financial support for the study. The authors also acknowledge Baxter Healthcare Corporation for donating the recombinant FVIII used in the trial. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab, a drug approved for use in treating lymphoma, was studied for its efficacy in suppressing inhibitors against factor VIII in patients with hemophilia and high titer inhibitors. Kruse-Jarres:Baxter: Consultancy, Honoraria; Bayer:; Griforls: Consultancy, Honoraria; Inspiration: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria. Konkle:Baxter Corporation: Consultancy, Research Funding; Bayer Corp: Consultancy; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees. Neufeld:Genentech: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Bennett:Biogen IDEC: Honoraria. Valentino:Baxter Bioscience, Bayer Healthcare, GTC Biotherapeutics, NovoNordisk, Pfizer, CSL Behring, Inspiration Bioscience, and Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4693-4697 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
Günter Auerswald ◽  
Carmen Escuriola Ettinghausen ◽  
Ulf Tedgård ◽  
...  
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Von Willebrand ◽  
Relationship Of ◽  
Viii Product

Abstract It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

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