Congenital Thrombotic Thrombocytopenia Purpura - Safer Treatment with Plasma-Derived Viral-Attenuated Clotting Factor

Abstract Congenital Thrombotic Thrombocytopenia Purpura (cTTP) has been considered a very rare disorder. Several international registries have estimated 250 patients worldwide. While the total number of patients in the U.S. is unknown, an ongoing U.S. Registry has recorded only 89 patients. (Singleton et al NORD 2014) Therapy for this disease, for prophylaxis and treatment, has been replacement of the absent ADAMTS13 with fresh frozen plasma (FFP). The major complication has been allergic reactions including anaphylaxis making this treatment unviable for some patients. Virally- inactivated FFP is not readily available in the U.S. A recombinant ADAMTS13 is in initial PK studies. There have been anecdotal reports that a plasma-derived FVIII/vWF biologic (Koate-DVI), double virally inactivated, FVIII replacement product, has been successfully used prophylactically in cTTP patients in lieu of FFP therapy to prevent episodes of TTP (Naik et al J Pediatr Hematol Oncol 2013). No other therapeutic biologic has been able to provide this benefit. Pursuant to that observation, two independent laboratories in the U.S. and Italy conducted analyses of the content of ADAMTS13 in several FVIII concentrates. The ADAMTS13 content in reconstituted concentrate of Koate-DVI was up to 9.08 + 0.70 units/ml, and was substantially higher than other FVIII products and pooled plasma. Table 1 and Table 2 We report here a cohort of 10 cTTP patients currently being managed with Koate-DVI prophylaxis. The average age of the patients is 15 years (range 7-22 years). The patients are being treated with a dose range of 25 to 40 IU/kg, at an average of once per week. This dose of Koate-DVI (containing 100 IU FVIII/ml after reconstitution) will provide approximately 2 to 4 IU/kg of ADAMTS13. Patients have been treated for variable lengths of time ranging from less than a year to over 10 years. The patients have responded very well to the Koate-DVI treatment; no severe adverse events or allergic reactions have been reported. We are prospectively comparing the frequency of new TTP episodes in this cohort with the frequency observed prior to initiation of this therapy. We report a unique experience of 10 cTTP patients being successfully managed prophylactically at home with self-infusion of Koate-DVI (Factor VIII concentrate with a long history of viral safety in the treatment of hemophilia A). These patients are receiving a convenient virally-inactivated alternative to FFP without manifesting life-threatening allergic reactions that require immunosuppression and/or hospitalization. A prospective clinical study of the safety and efficacy of Koate-DVI is planned. Table 1. Concentrate ADAMTS13 activity U/mL ADAMTS13 antigen U/mL Koate-DVI (5 lots) 9.08 ± 0.70 8.42 ± 0.12 Product A 0.12 0.13 Product B 0.22 0.61 Product C 2.30 3.87 (Peyvandi et al Am J Hematol 2013) Table 2. Concentrate ADAMTS13 Units/ml Koate-DVI 5.77 Product A 0.18 Product B 0.23 Product C 1.40 (Konkle Personal Communication 2013) Disclosures Aledort: Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation. Off Label Use: Koate-DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. This presentation discusses the use of factor VIII concentrate for ADAMTS13 deficiency.. Boggio:CSL Behring: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Selexys: Research Funding; Bayer: Consultancy, Research Funding; OctaPharma: Consultancy, Research Funding; OPKO: Research Funding; Novo Nordisk: Consultancy, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Rajasekhar:American Society of Hematology: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shapiro:Baxalta: Research Funding; Shire: Speakers Bureau; BioCryst: Research Funding. Ulsh:Kedrion Biopharma: Employment.

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Treatment Of Serious Bleeds With a B-Domain Deleted Recombinant Porcine Sequence Factor VIII (OBI-1) In Patients With Acquired Hemophilia A: A Prospective Clinical Trial

Blood ◽

10.1182/blood.v122.21.206.206 ◽

2013 ◽

Vol 122 (21) ◽

pp. 206-206 ◽

Cited By ~ 1

Author(s):

Rebecca Kruse-Jarres ◽

Jean St. Louis ◽

Anne Greist ◽

Amy D. Shapiro ◽

Hedy Smith ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Positive Response ◽

Acquired Hemophilia A ◽

Advisory Committees ◽

Baxter Healthcare ◽

Bayer Healthcare ◽

Travel Grant

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder, resulting from auto-antibodies to human factor VIII (hFVIII). The challenges created by the management of AHA and the co-morbidities present in this typically elderly population, can be managed by a recombinant, highly pure, B-domain deleted, porcine sequence FVIII (OBI-1) that is not generally susceptible to the inhibitory activity of anti-human FVIII antibodies. Treatment with OBI-1 allows for monitoring of FVIII levels which provides a reproducible and objective surrogate predictor of hemostasis. Eradication of hFVIII inhibitors with immunosuppressive therapy is critical for disease management. During immunosuppression, the patient transitions from a bleeding state at initial presentation to a relative hypercoagulable state which can be an issue in patients who are susceptible to thromboembolic events due to their comorbidities. This transition period is of most concern especially when using traditionally utilized bypassing agents that cannot be monitored. OBI-1 enables measurement of FVIII levels, guiding dosing and enhancing treatment safety during this critical period. Methods This global, prospective, multi-center phase 2/3 open label clinical trial investigates the efficacy and safety of OBI-1 in the treatment of serious bleeds in adults with AHA conducted under ICH guidelines and local IRB/Ethics Committee oversight. Primary efficacy endpoint was assessed at 24 hours (eg. effective, partially effective). All subjects (N= 18) presented with a serious bleed and were treated with an initial dose of OBI-1 (200 U/kg), followed by additional doses based on the subject's target factor VIII levels, anti-OBI-1 titer, and clinical factors. Results In all 18 subjects, a positive response (14 effective/4 partially effective) to treatment was observed at 24 hours. This positive response to OBI-1 treatment was seen by 8 hours in 14/18 of the subjects and at 16 hours in 16/18 of the subjects. Median total exposure to OBI-1 per subject was 1782.5 U/kg. The median total first dose was 14,000 U. For subjects who received additional doses of OBI-1, the median dose was reduced from the initial dose, but did not differ considerably over subsequent doses (9180 to 13561 U; median 11000 U). The majority of subjects (17/18) received concomitant immunosuppressive therapies. No related serious adverse reactions occurred. Non-serious adverse events related to treatment were noted in 5/18 (27.8%) subjects. One subject had mild tachycardia, hypotension and constipation. One subject had 2 instances of mild PICC line occlusion. One subject had a mild hypofibrogenemia. All of these adverse effects completely resolved. Three subjects developed anti-porcine inhibitors after infusion of study drug (range 8-108 BU) and two were discontinued from treatment. Anti-porcine inhibitors were detected prior to infusion in 6/18 patients (range 0.8-29 BU). All of these subjects had a favorable clinical response at 24 hours post-OB-1 infusions. Conclusions Data from this prospective study demonstrate OBI-1 as a safe and effective treatment of bleeding episodes in patients with AHA, with the added advantage over other bypass therapies of allowing FVIII monitoring throughout treatment and healing phase. Disclosures: Kruse-Jarres: Baxter Healthcare: Consultancy; Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy. St. Louis:CSL Behring: Research Funding; Octapharma: Consultancy, Research Funding; Baxter: Consultancy; Novo Nordisk: Honoraria. Shapiro:Kedrion Biopharma: Consultancy; Chugai Pharma USA: Consultancy; Biogen IDEC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Baxter Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Chowdary:Baxter Healthcare: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel grant Other; Novo Nordisk: Honoraria, Research Funding, Travel grant, Travel grant Other; Bayer HealthCare: Honoraria, Travel grant, Travel grant Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Biogen IDEC: Honoraria, Travel, Travel Other. Drebes:Octapharma: Travel grant Other; CSL Behring: Travel grant, Travel grant Other; Leo-pharma: Travel grant, Travel grant Other; Bayer Healthcare: Consultancy, Honoraria. Gomperts:Baxter Healthcare: Consultancy; Asklepios Biopharmaceutoicals Inc: Consultancy; Cangene Inc: Consultancy. Chapman:Baxter Healthcare: Employment. Mo:Baxter Healthcare: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽

10.1182/blood-2018-99-117413 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 382-382 ◽

Cited By ~ 3

Author(s):

Beth Boulden Warren ◽

Dianne Thornhill ◽

Jill Stein ◽

Michael Fadell ◽

Sharon Funk ◽

...

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

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Surveillance of Hemophilia in Indiana: A Preliminary Report

Blood ◽

10.1182/blood-2018-99-118849 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3516-3516

Author(s):

Amanda Okolo ◽

John M Soucie ◽

Scott D. Grosse ◽

Chris Roberson ◽

Isaac Janson ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Claims Data ◽

Factor Ix ◽

Clotting Factor ◽

Advisory Committees ◽

Mortality And Morbidity ◽

Factor Ix Deficiency

Abstract Background and objectives: Hemophilia is a rare heritable bleeding disorder resulting from missing or deficient levels of factor VIII or factor IX. Hemophilia related complications result in high utilization of health care resources and include severe, debilitating chronic joint disease. In 1998, Soucie et al. published the results of a six-year surveillance study investigating the incidence and prevalence of hemophilia in six U.S. states. The study also described the relationship between mortality and morbidity and each patient's primary source of hematologic care (i.e. whether each patient had visited a federally designated hemophilia treatment center (HTC)). The Indiana Hemophilia Surveillance Project (IHSP) aims to identify all persons with hemophilia who resided in Indiana in 2011-2013, to calculate the prevalence and incidence of hemophilia in Indiana, and to determine the percentage of patients cared for at a federally recognized HTC. The IHSP further aims to compare morbidity and mortality data to the results of the Soucie et al. study. Methods: A hemophilia case in this study is defined as a male with physician-diagnosed hemophilia A or B and a measured baseline factor VIII or IX activity level less than 50%. A retrospective review of medical charts and other records was conducted to identify hemophilia cases during the surveillance years from 2011-2013. Case finding methods involved obtaining medical information from a variety of medical care resources including: HTCs in Indiana and surrounding states, hospitals, vital records, Indiana's birth defects registry, hospital and administrative claims data from the Regenstrief Institute, Medicaid claims data, clinical laboratories, specialty pharmacies, hematology/oncology clinics, and primary care physicians. Demographic and clinical data were collected on all identified cases. Data collected included: demographic information, clinical characteristics, joint health assessments, insurance status, clotting factor product utilization and cost, source of hemophilia care, hospitalizations and emergency room visits, and mortality information. Associations between clinical characteristics were assessed for statistical significance using chi-square and fisher's exact tests. Incidence was calculated by using the number of births from prevalent cases during the three surveillance years as the numerator and the number of live male births in Indiana for each year as the denominator. Results: 704 hemophilia cases were identified in Indiana in 2011-2013. Of those cases, 456 (64.8%) had factor VIII deficiency and 248 (35.2%) had factor IX deficiency. The median age of the population was 25 years. 453 cases (64.3%) were adult patients and 251 cases (35.7%) were pediatric patients under 18 years. Among those with known severity levels (n=685), 233 (33.1%) were severe, 185 (26.3%) were moderate, and 267 (37.9%) were mild. Overall, 81.7% of the hemophilia patients identified visited an HTC at least once during the three year study period, which was the minimum requirement for being considered a patient of an HTC. Age-adjusted prevalence was 21.8 cases per 100,000 males; 14.3 per 100,000 for factor VIII and 7.5 per 100,000 for factor IX. Mean incidence of hemophilia over the three year study period was 1:4059 live male births in Indiana. 24 cases (3.4%) died within the study period; 4.2% of the deaths occurred in HIV positive patients. Of those with a known cost of clotting factor (n=184), the average and median cost of factor over the three year period was $375,532 and $71,525 respectively. Conclusions: There was a significantly higher percentage of patients seen at an HTC (81.7%) as compared to the results of the Soucie et al. study (67%; p =<0.001). Indiana has a 62% higher prevalence and 24% higher incidence of hemophilia than in the Soucie et al. study. A high frequency of factor IX deficiency associated with a founder mutation in the Amish community contributes to the higher incidence of factor IX deficiency in Indiana, with a 64% higher percentage of factor IX deficiency among hemophilia cases. The higher prevalence likely reflects improved survival and increased utilization of HTCs in the past two decades. This report is the first follow-up study of the original Soucie et al. report using the same systematic approach. Further analysis on mortality and morbidity complications in this population will be completed and reported in future reports. Disclosures Shapiro: Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Bio Products Laboratory: Consultancy; Prometic Life Sciences: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; BioMarin: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; OPKO: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Octapharma: Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Large Cohort of Symptomatic Female Carriers of Hemophilia in an Extended Native American Family

Blood ◽

10.1182/blood.v126.23.4700.4700 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4700-4700

Author(s):

Becki Berkowitz ◽

Amber Federizo ◽

Garrett E. Bergman ◽

Paula J. Ulsh

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Gene Mutation ◽

Hemophilia A ◽

Clotting Factor ◽

Factor Level ◽

Advisory Committees ◽

Low Levels ◽

Female Carriers

Abstract Hemophilia A is an X-linked recessive genetic bleeding disorder resulting in a lack of clotting factor VIII. Although this disorder primarily affects males, a female who inherits one affected X chromosome from a parent becomes a carrier of hemophilia. While it is widely believed that carriers are asymptomatic, some of these women have mild hemophilia, defined by ISTH as a circulating factor VIII level > 0.5 to 0.40 IU/ml or 5 - 40 % of normal. (White et al Thromb Haemost 2001) Data demonstrates hemophilia A carriers have the same risk for bleeding as a male with mild hemophilia A at the corresponding factor level. Carriers report significantly more bleeding events than non-carriers from small wounds and after invasive procedures, and their bleeding tendency is inversely correlated to their factor level. (Plug et al Blood 2006) Carriers have been shown to demonstrate decreased joint range of motion, soft tissue and osteochondral changes on MRI, consistent with subclinical joint bleeds leading to structural abnormalities in their joints. (Gilbert et al Haemophilia 2014). Additionally, carriers have been shown to report higher scores on pictorial blood assessment charts, a semi-quantitative measure of menstrual blood loss. (Kadir et al Haemophilia 1999) We report here a unique patient population from our Owyhee Indian Health Hemophilia Treatment Center Outreach Clinic on the Duck Valley Indian Reservation in Owyhee, NV. On this reservation, a German Immigrant with hemophilia A married 2 women of the Shoshone Indian Tribe, and they had 14 children (8 females and 6 males). The family tree reveals after four generations there are currently 162 descendants with the same hemophilia A gene mutation, which has been identified. Factor VIII levels in the female family members range from 7% to 50%. The male hemophilia A patients are treated on demand with plasma-derived factor VIII products, currently Koate-DVI, for traumatic events, and prophylactically for medical or dental procedures, or surgery. Approximately 20-25% of the female carriers in this population have been treated with plasma-derived FVIII concentrates, currently Koate-DVI, for childbirth and surgeries. Additionally, all female carriers from teenage years to age 30 are treated with desmopressin acetate nasal spray (Stimate) for menorrhagia and are treated with oral aminocaproic acid (Amicar) for nose bleeds and soft tissue bleeds. Carriers of hemophilia A with factor VIII levels in the range observed in this family, particularly when symptomatic, should receive the diagnosis of "mild hemophilia". Their propensity for developing subclinical as well as clinical bleeding needs to be recognized to assure the receive treatment appropriate to their symptomatology. The low levels of FVIII observed in this family are likely due to extreme lyonization associated with their particular gene mutation. Familial low levels of FVIII can also be seen in some forms of type 2 von Willebrand Disease secondary to poor FVIII binding and a shortened half-life. However, since VWD is inherited in an autosomal recessive pattern, males would not selectively have the severity observed here. Optimal diagnostic and therapeutic strategies as well as many other aspects concerning mild hemophilia remain to be clarified. Additional studies to define these findings are underway. Disclosures Berkowitz: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Speakers Bureau; Baxter: Speakers Bureau. Federizo:Emergent: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Bergman:Kedrion Biopharma: Employment. Ulsh:Kedrion Biopharma: Employment.

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Breakthrough Bleeding in Hemophilia a Patients on Prophylaxis

Blood ◽

10.1182/blood.v128.22.2581.2581 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2581-2581 ◽

Cited By ~ 2

Author(s):

Beth Boulden Warren ◽

Taylor Blades ◽

Natalie L Smith ◽

Michael Wang ◽

Marilyn J. Manco-Johnson

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Advisory Committees ◽

Breakthrough Bleeding ◽

University Of Colorado ◽

The University

Abstract Background: Patients with severe hemophilia A (factor VIII (FVIII)<1%), as well as many patients with moderate hemophilia A (FVIII 1-5%), are treated intravenously with FVIII prophylaxis to prevent bleeding. However, breakthrough bleeding occurs in many patients. Methods: To better understand breakthrough bleeding, we evaluated the effect of hemophilia severity, prophylaxis adherence, and replacement FVIII utilization on bleeding rates in patients with hemophilia A on prophylaxis. Data on hemophilia severity and bleeding rates were collected from subjects with hemophilia A, ages 2-30 years, treated at the University of Colorado for hemophilia A, using the University of Colorado Clinical Research Bleeding Disorders Database (UCBDD). Adherence and FVIII utilization data were collected from a subset of subjects with hemophilia A on prophylaxis without active inhibitors who participated in the Centers for Disease Control/American Thrombosis and Hemostasis Network Community Counts (CDCCC) registry between December 2013 and June 2016, which surveyed participants about their estimated percentage of missed prophylaxis doses. The CDCCC registry was also used to corroborate bleeding rates. The effect of hemophilia severity and missed prophylaxis doses (percentage of prescribed doses) on bleeding rates were analyzed using logistic regression, with bleeding rates dichotomized as high or low relative to study population median bleeding rates. The relationship between weekly factor utilization and annualized bleeding rates was evaluated using Pearson's correlation. Results: Of 89 patients with severe hemophilia A in the UCBDD, 86.5% of patients were on continuous prophylaxis, with an additional 7.9% on immune tolerance induction. The 5.6% of patients with severe hemophilia on episodic treatment had been encouraged to use prophylaxis but had declined. Of 37 patients with moderate hemophilia A, 48.7% were on continuous prophylaxis. Sixty-nine subjects on prophylaxis had data in the UCBDD and the CDCCC registry collected during the defined time period. Bleeding rates are shown in Table 1. Prophylaxis doses in this population had an interquartile range of 74.3 to 120 units/kg/week (mean 96.9 units/kg/week), dosed 2-7 times per week depending on activities and historic bleeding patterns. Eighty-two percent of patients rated their percentage of missed prophylaxis doses at <10%, 11.6% rated their missed doses at 10-20%, 2.9% rated their missed doses at 21-50%, and 2.9% rated missed doses at >50%. There was not a statistically significant relationship between any bleeding rate and percentage of missed doses, hemophilia severity, or factor utilization, as shown graphically in figures 1 and 2. Conclusion: Although prophylaxis usage and adherence were excellent, breakthrough bleeding was common, with breakthrough joint bleeding occurring in 36% of subjects, and was not related to FVIII dose per week. Prospective studies are needed to better determine individually tailored prophylaxis regimen using dose, product class, and timing with activities, in order to achieve more effective prophylaxis. Table 1 Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Table 1. Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Figure 1 Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 1. Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 2 No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Figure 2. No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Disclosures Warren: HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria.

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Combined Effect of By-Pass Agents and a Sequence Identical Analogue of Emicizumab on Fibrin Clot Turbidity and Structure in Factor VIII Deficient Plasma

Blood ◽

10.1182/blood-2018-99-116112 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2473-2473

Author(s):

Iva Pruner ◽

Yanan Zong ◽

Nida Mahmoud Hourani Soutari ◽

Roza Chaireti ◽

Aleksandra Antovic ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Single Agent ◽

Fibrin Clot ◽

Fiber Formation ◽

Factor X ◽

Advisory Committees ◽

Normal Plasma

Abstract Development of inhibitors to Factor VIII is a serious and not uncommon (occurs in about 30% of treated patients) complication of the treatment with factor concentrate in hemophilia A. Treatment of patients with inhibitors is complicated, expensive and not always successful. By-pass agents (rFVIIa and aPCC) have been considered as a treatment of choice for those patients. Very recently bispecific factor IXa- and factor X-directed antibody - Emicizumab has been approved for the treatment of hemophilia A patients with inhibitors. However, there are data from the clinical studies which raise concerns about potential prothrombotic effect of Emicizumab in combination with by-pass agents particularly aPCC. To elucidate a potential mechanism of hypercoagulability we have investigated fibrin clot quality in hemophilic plasma after addition of a sequence identical analogue (SIA) of Emicizumab in combination with by-pass agents. Parameters of fibrin clot turbidity (lag time, Max Abs, Slope, Slope time) were measured in recalcified FVIII-deficient plasma samples, after addition of low thrombin concentration (0.04 NIH/mL) and different concentrations of SIA (200 and 600 nM), rFVIIa (1.75 and 5.25 µg/mL) and aPCC (50 and 500 mU/mL). Pooled normal plasma (PNP) was used as control. After fixation, fibrin clots were analyzed by scanning electron microscopy (SEM) (Carl Zeiss, Oberkochen, Germany) and the thickness of individual fibers was measured using SIS iTEM software (FEI Company, Eindhoven, Netherlands). As previously determined, 50 randomly selected fibers in each sample were measured to obtain stable mean. All parameters of fibrin turbidity and structure were analyzed in triplicate and the results are presented as mean values. Fibrin clot in FVIII deficient plasma was difficult to analyze due to the lack of polymerization of fibrin monomers and absence of fiber formation. This structure is loose and prone to fibrinolysis. Interestingly the similar structure was observed after addition of both concentrations of rFVIIa while after addition of SIA fibrin structure improves. The best effect using single agent was noticed after addition of aPCC in concentration of 500 mU/mL. In combination with SIA (both concentrations of 200 nM and 600 nM) aPCC in concentrations of 500 mU/mL generated clots with highest density formed from very thin fibers and small intrinsic pores. These clots are even tighter than those formed from PNP samples. Parameters of fibrin turbidity obtained with higher concentrations of agents as well as representative SEM scans are presented on the Figure 1. Addition of SIA to by-pass agents additionally improved fibrin quality in FVIII deficient plasma. Combination of therapeutic concentrations of aPCC and SIA may produce clots even less porous than those in normal plasma. Figure 1. Figure 1. Disclosures Chaireti: Shire: Research Funding. Antovic:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Werfen: Honoraria; Stago: Honoraria; Siemens: Honoraria; Roche: Honoraria; Sysmex: Honoraria.

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Lack of Inhibitor Development in the American Thrombosis and Hemostasis Network (ATHN)-2 Factor Switching Study: Preliminary Report of Primary Outcome

Blood ◽

10.1182/blood-2019-128612 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1114-1114

Author(s):

Robert F. Sidonio ◽

Dunlei Cheng ◽

Christine Guelcher ◽

Janna M. Journeycake ◽

Susan U Lattimore ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Primary Outcome ◽

Hemophilia A ◽

Advisory Board ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development

Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

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Acquired Haemophilia: Clinical and Demographic Data.Results of European Acquired Haemophilia Registry (EACH2).

Blood ◽

10.1182/blood.v116.21.1398.1398 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1398-1398 ◽

Cited By ~ 7

Author(s):

Pascual Marco ◽

Peter W Collins ◽

Paul Knoebl ◽

Herve Levesque ◽

Francesco Baudo ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Board Of Directors ◽

Research Funding ◽

Demographic Data ◽

Advisory Committees ◽

Delay In Diagnosis ◽

Acquired Haemophilia ◽

Baxter Healthcare ◽

Number Of Patients ◽

European Registry

Abstract Abstract 1398 Acquired Haemophilia (AH) is an autoimmune disorder, characterized by autoantibodies against the coagulant activity of Factor VIII: C. Is a rare (estimated frequency 1.5 cases per million/year), but severe hemorrhagic condition. EACH2 is a multinational European registry from 90 centres in 11 countries that recruited between 2003–2009, This abstract describes the demographic, clinical and aetiological data recorded in a web database from EACH2 from the largest cohort described in the literature to date. Outcomes of haemostatic therapy, immunosuppression and during pregnancy are described elsewhere. Data were recorded on consecutive patients from each centre. Informed consent was taken as appropriate to each country. Parametric and non-parametric test, were used to analyse the study. There were 501 AH patients included in the registry. The basic demographic data are shown in Table 1. In 93 % of the patients the diagnosis was triggered by bleeding in a variety o locations, these were and mainly spontaneous (details will presented in another abstract).). There was no correlation between FVIII level or titre inhibitor and type or severity of bleeding. Aetiology of AH Table 2 The delay in diagnosis, stratified in etiologic groups, after detecting abnormal APTT is shown in Table 3 Survival analysis (Kaplan-Meyer curves), after 5 years of follow-up was: 71.5% in patients who had eradicated the inhibitor, 47.7% in patients dependent immunosuppressive therapy, and 37.6% in those who had not eradicated the inhibitor In conclusion this prospective multinational European registry (EACH2) includes a large number of patients affected of AH. Idiopathic remains the more frequent aetiological association. Bleeding is the principal clinical manifestation but in a proportion of patients there is a considerable delay in diagnosis. The finding of an abnormal APTT in a bleeding patient with no history of hemorrhagic condition should raise suspicion of AH. Survival in this patient cohort is clearly related to response to immunosuppressive therapy. Disclosures: Marco: Novo Nordisk: Consultancy. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk:. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Nemes:Novo Nordisk: Consultancy. Tengborn:Novo Nordisk: Consultancy. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk.

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Acquired Haemophilia A and Pregnancy/Postpartum – a Report From a European Registry

Blood ◽

10.1182/blood.v116.21.717.717 ◽

2010 ◽

Vol 116 (21) ◽

pp. 717-717 ◽

Cited By ~ 4

Author(s):

Laszlo Nemes ◽

Lilian Tengborn ◽

Peter W Collins ◽

Francesco Baudo ◽

Angela Huth-Kuehne ◽

...

Keyword(s):

Complete Remission ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Factor Vii ◽

Haemophilia A ◽

Red Cell ◽

Advisory Committees ◽

Acquired Haemophilia ◽

Baxter Healthcare

Abstract Abstract 717 Between 2003 and 2009 42 pregnant females were diagnosed with acquired haemophilia A (AHA) and included in the European Acquired Haemophilia A (EACH2) Registry. They constituted 8 % of the total number of admitted patients to the registry (n=501). In one female the diagnosis was made 36 days before delivery and the rest were diagnosed postpartum. One female had an autoimmune disorder, the others were without any associated disease. In 31 cases AHA occurred associated with the 1st pregnancy, in 7 the 2nd, in 2 the 3rd and in 2 the 4th pregnancy. Data are given as median and inter quartile ranges: Reference Age at pregnancy of interest 34 (30–37) Days after delivery until diagnosis 89 (25–180) Days between first abnormal APTT to diagnosis 1 (0–8) Factor VIII at diagnosis 2.5 (1–8) 50–200 IU/dL Anti Factor VIII antibody titre 7.8 (2.4–31.3) <0.4 BU/mL Hb 9.4 (7.5–12.9) 11.7–17.0 g/dL All the diagnoses were triggered by bleeds. Cause of bleed: spontaneous 24, trauma 1, surgery 4, peri postpartum 15. Site of bleed: deep (musculoskeletal, retroperitoneal) 14, haemarthroses 2, mucosa 18, skin 19, CNS none. In 11 females the bleeds started on day of diagnosis. In 22 females the bleeds started between 0 and 7 days before diagnosis and in 20 females the bleeds were reported to have started more than 7 days before the diagnosis suggesting a significant delay in diagnosis. In 25 the bleed was considered as severe (a drop of Hb >2 g/dL or received red cell transfusions) – in 7 of these no haemostatic treatment was given. 21/41 of first bleed required haemostatic treatment, 12 with rFVIIa (recombinant activated factor VII), 5 aPCC (activated prothrombin complex concentrate), 2 FVIII concentrate, 2 desmopressin. In addition, 6 received antifibrinolytics. Ten needed red cell transfusions. The bleeds were controlled in all cases and there was no fatality. First line immunosuppressive (IS) treatment: Regimen CR* n (%) NR** n (%) Treatment changed n (%) Days from start of IS Relapse n (%) Inhib <0.4 FVIII >70 IS stopped Steroids only n=31 22 (71) 8 (26) 1 (3) 47 (29–112) 40 (25–160) 105 (63–236) 2/20 (10) Steroids and Cytotoxics n=6 5 (83) 1 0 9, 35, 175, 261 12, 60, 175, 261 57, 60, 265, 363 0/5 Steroids and rituximab n=2 2 (100) 0 0 11, 76 11, 138 43, 53 0/2 * CR = complete remission i.e. FVIII >70 IU/dL and no antibodies ** NR = no complete remission Summing up, AHA is a rare but severe bleeding condition in pregnancy/postpartum and is often overlooked. The diagnosis should be considered when screening tests show an abnormal APTT which indicates an immediate specific coagulation analysis. Acute bleeds are effectively treated with rFVIIa or aPCC. Immunosuppression with steroids to eliminate the anti FVIII inhibitor activity should be instituted as soon as possible after confirmation of AHA and this treatment seems to give a better response compared to older patients with AHA. Disclosures: Nemes: Novo Nordisk: Tengborn: Novo Nordisk: Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Knoebl:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marco:Novo Nordisk:Levesque:NovoNordisk:

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