Pharmacokinetics of Continuous Infusion Therapy of Factor VIII Concentrates in Hemophilia A Patients with Inhibitors,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3320-3320
Author(s):  
Katsumi Nishiya ◽  
Ichiro Tanaka ◽  
Keiji Nogami ◽  
Kenichi Ogiwara ◽  
Koji Yada ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Infusion Rate ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
High Titer ◽  
Infusion Therapy ◽  
Target Level ◽  
Ci Therapy ◽  
The Difference

Abstract Abstract 3320 Continuous infusion (CI) of factor VIII (FVIII) concentrates is aimed at maintaining a steady hemostatic level of FVIII activity (FVIII:C) in hemophilia A patients during various surgeries. However, there are few reports that mentioned the difference of pharmacokinetics of CI therapy in hemophilia A patients with inhibitors. We investigated the relationship between the FVIII:C levels and the rate of CI, and the difference of clearance (CL) and volume of distribution (Vd) of FVIII in hemophilia A patients with/without inhibitors. 8 severe hemophilia A patients without inhibitors (arthroscopic synovectomy; 4 cases, total knee arthroplasty; 2 cases, total nephrectomy; 1 case, partial hepatectomy; 1 case), 3 patients with low-titer (2.0–2.9 BU) inhibitors and 3 patients with high-titer (6.0–9.0 BU) inhibitors (insertion or removal of a central venous access device), were enrolled in this study between 2005 and 2010. According to the Japanese guideline for hemophilia treatment, we should do CI therapy to keep target level 80–100% for 5–10 days for joint surgery and other major surgeries. An initial bolus infusion (BI) of FVIII concentrates was administered to achieve this level prior to CI. In addition, we have to neutralize the inhibitors by FVIII concentrates in case of the patients with inhibitors. FVIII:C was measured using one-stage clotting assays and FVIII inhibitor assays were performed using the Bethesda method. All therapy was conducted after obtaining fully informed consent. The median FVIII:C level after BI was 120.2% (range: 90–150) in the patients without inhibitors, 72.0% (range: 68–160) with low-titer inhibitors, and 20.0% (range: 9.4–30) with high-titer inhibitors, respectively. The target level of FVIII:C was adjusted to approximately 100%. The initial infusion rate was 3.7 U/kg/hr (range: 2.2–5.0), 8.3 U/kg/hr (range: 8.0–8.5) and 18.5 U/kg/hr (range: 15–22), respectively. After adjustment for the target level, the final infusion rate decreased to 2.6 U/kg/hr (range: 1.5–5.4), 4.7 U/kg/hr (range: 3.0–5.6) and 8.0 U/kg/hr (range: 7.0–9.0), respectively. CL was 2.3 ml/hr/kg (range: 1.5–3.9), 4.0 ml/hr/kg (range: 2.3–5.1) and 9.3 ml/hr/kg (range: 9.0–9.6), respectively. Vd was 0.04 L/kg (range: 0.031–0.047), 0.18 L/kg (range: 0.12–0.29) and 1.54 L/kg (range: 0.95–2.43), respectively. No unexpected safety concerns associated with CI, such as thrombosis, was identified during the study. On CI therapy, we could keep target level of the patients without inhibitors and with low-titer inhibitors easier than those with high-titer inhibitors. One of the reason is that CL and Vd in patients with inhibitors are higher than those in patients without inhibitors. CI with appropriate monitoring of FVIII:C level and concerning CL and Vd forms a safe method for perioperative care in hemophilia A patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.

Retrospective Audit of a Factor VIII Continuous Infusion Protocol to Examine Inhibitor Formation, Complications and Product Use.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4030-4030
Author(s):  
Meghan Walsh ◽  
Rebecca Mulcahy ◽  
Mary-Frances Scully
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Infusion Rate ◽  
Hemophilia A ◽  
Average Dose ◽  
Patients Âgés ◽  
Product Use ◽  
Retrospective Audit ◽  
The Mean ◽  
Infusion Protocol

Abstract Continuous infusion (CI) of factor concentrates has been suggested to decrease both the risk of bleeding and cost in the treatment of bleeding disorders. However, concerns have been raised with regards to the stability and sterility of products administered by CI and the risk of local thrombophlebitis. Most recently, there has been a concern about a potential association between the use of CI and the development of an inhibitor in mild hemophilia. A retrospective chart review was conducted to determine the effectiveness, safety, product use and risk of inhibitor formation of a continuous infusion protocol in the management of hemophilia A. Currently 248 patients are registered with the Provincial Hemophilia Program for Newfoundland and Labrador. These patients include 104 with mild hemophilia A, 3 with moderate hemophilia A and 5 with severe hemophilia A. The charts of twelve hemophilia A patients who received factor VIII (FVIII) by CI a total of 18 times between April 1998 and September 2003 were reviewed. All patients were affected by hemophilia A; 8 patients were diagnosed as mild, 1 as moderate and 3 as severe. The mean age of the cohort was 36.1 years and the patients’ ages ranged from 4 months to 75 years. Continuous infusion was used as treatment for severe bleeds in 12 cases and as prophylaxis for surgical procedures in 6 cases. All patients received recombinant FVIII. Recommended devices such as a syringe pump and mini-pump were unavailable therefore all infusions were carried out by diluting the reconstituted concentrate in saline and delivering via IV infusion. The CI protocol followed required a bolus of 50 U/kg of FVIII followed by CI at an initial rate of 4 U/kg/hr. Based on daily FVIII levels, this maintenance dose could be adjusted, with an initial targeted FVIII level of 1.0 U/L. The maximum initial infusion rate was 6.7 U/kg/hr and the minimum was 3.2 U/kg/hr (mean 4.3 U/kg/hr). The infusion rate was reduced in 8 cases to a minimum of 1.2 U/kg/hr. Adequate FVIII levels were maintained after the reduction of the infusion rate in all cases. The mean low and high FVIII levels were 0.79 U/L and 1.23 U/L, respectively (range 0.05 to 1.82 U/L). Excluding the patient who developed an inhibitor, the FVIII level remained above the minimum acceptable level of 0.3 U/L for the duration of CI in all but one case (low 0.29 U/L). Patients required an average dose of 53,163 units (range 2651–299,137 units) of factor concentrate delivered by continuous infusion over a mean period of 8.1 days (range 2–21 days). FVIII infusion was well tolerated in all cases; there were no documented cases of significant bleeding, adverse reactions, thrombophlebitis or infection. One patient was documented to have a minor bleed from an NG tube despite adequate FVIII levels throughout the period of infusion. One patient with mild hemophilia developed a low titer inhibitor (0.8 BU) approximately 2 years after receiving FVIII by continuous infusion for 8 days. Another mild hemophilia patient was discovered to have a low titer inhibitor (1.3 BU) on the eighth day after the third infusion had begun. It is possible that CI contributed to the development of an inhibitor in this patient. CI was not found to significantly reduce product use. More rapid downward adjustment of infusion rates in response to high FVIII levels might improve product utilization.

Anti-Factor VIII C1 Domain Antibodies Are Present in the Plasmas of Patients with Hemophilia and Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1482-1482
Author(s):  
Glaivy Batsuli ◽  
Courtney Cox ◽  
John F. Healey ◽  
Pete Lollar ◽  
Shannon L Meeks
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
High Titer ◽  
Plasma Samples ◽  
Severe Hemophilia ◽  
Competition Elisa ◽  
Antigenic Properties ◽  
C1 Domain ◽  
Inhibitor Titer

Abstract Hemophilia A is an X-linked disorder characterized by a deficiency or absence of blood coagulation protein factor VIII (fVIII). Treatment involves replacement of fVIII through infusions for acute bleeding episodes or prevention of bleeding events. Approximately 30% of individuals with severe hemophilia A will develop antibodies to fVIII. Many studies have characterized the antigenic properties of the C2 and A2 domains as these domains are considered the predominant immunogenic domains of the fVIII protein. However, there is increasing evidence that the C1 domain contributes to fVIII function and immune response to fVIII. Our laboratory has produced and purified a murine IgG2ak anti-human C1 domain monoclonal antibody (MAb), designated 2A9. In this study, we characterized the functional properties of MAb 2A9 using standard coagulation testing including its anti-fVIII inhibitor titer by Bethesda assay and its ability to inhibit fVIII binding to von Willebrand factor (VWF) by competition ELISA. In the Bethesda assay, 2A9 has an inhibitor titer of 97 BU/mg and is a type II inhibitor. In addition, MAb 2A9 inhibits fVIII binding to VWF in an ELISA assay with a 50% inhibitory concentration (IC50) of 1 µg/ml. This is in comparison to the potent high-titer inhibitory anti-C2 MAb I89 (IC50 0.02 µg/ml) and a control non-inhibitory anti-A2 MAb ID4 (IC50 > 10 µg/ml). We tested 11 plasma samples from patients with congenital hemophilia with inhibitors in the Emory IRB-approved inhibitor bank. The plasma samples have inhibitory titers ranging from 1 - 188 BU/ml with a median inhibitory titer of 54 BU/ml and mean inhibitory titer 59 BU/ml. The plasmas were tested for the presence of antibodies that compete with anti-C1 domain MAb 2A9 using competition ELISA with fVIII as the antigen. Biotinylated MAb 2A9 was serially diluted and the concentration of antibody required to produce an absorbance at 405 nm of 0.3 was compared between control severe hemophilia A plasma and inhibitor plasma samples. Inhibitor plasma samples that reduced the ELISA titer of MAb 2A9 were considered a competitive inhibitor. Of the 11 inhibitor plasma samples, 4 were found to compete with MAb 2A9. Our study demonstrates that anti-C1 domain antibodies are present in the plasma of patients with hemophilia A and inhibitors. Given the increasing evidence that the C1 domain is important in fVIII function it is likely that these anti-C1 antibodies are clinically relevant. Therefore, domains other than A2 and C2 need to be included in future studies of fVIII B cell epitopes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acquired hemophilia A and plasma cell neoplasms: a case report and review of the literature

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Katarzyna A. Jalowiec ◽  
Martin Andres ◽  
Behrouz Mansouri Taleghani ◽  
Albulena Musa ◽  
Martina Dickenmann ◽  
...  
Keyword(s):  
Factor Viii ◽  
Plasma Cell ◽  
Hemophilia A ◽  
High Titer ◽  
Coagulation Factor ◽  
Laboratory Diagnostics ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Plasma Cell Neoplasm ◽  
Cell Neoplasm

Abstract Background Acquired hemophilia A is a rare autoimmune disease with clinically often significant bleeding diathesis resulting from circulating autoantibodies inhibiting coagulation factor VIII. Half of acquired hemophilia A cases are associated with an underlying disorder, such as autoimmune diseases, cancer, or use of certain drugs, or occur during pregnancy and in the postpartum period. In the other half, no underlying cause is identified. An association of acquired hemophilia A with plasma cell neoplasm seems to be extremely rare. Case presentation We describe a case of a 77-year-old Swiss Caucasian man who was diagnosed with acquired hemophilia A and smoldering multiple myeloma as an underlying cause. Acquired hemophilia A was treated with prednisolone, cyclophosphamide, and immunoadsorption. Extensive workup revealed a plasma cell neoplasm as the only disorder associated with or underlying the acquired hemophilia A. For long-term control of acquired hemophilia A, we considered treatment of the plasma cell neoplasm necessary, and a VRD (bortezomib, lenalidomide, and dexamethasone) regimen was initiated. Due to multiple complications, VRD was reduced to VRD-lite after two cycles. After nine cycles of induction therapy and five cycles of consolidation therapy, the patient is in complete remission of his acquired hemophilia A and very good partial remission of the plasma cell neoplasm. We conducted a literature review to identify additional cases of this rare association and identified 15 other cases. Case descriptions, including the sequence of occurrence of acquired hemophilia A and plasma cell neoplasm , treatment, evolution, and outcome are presented. Discussion and conclusions Our case, together with 15 other cases described in the literature, underscore the possibility of plasma cell neoplasm as an underlying cause of acquired hemophilia A. Physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with acquired hemophilia A. The occurrence of excessive and unexplained bleeding in patients diagnosed with plasma cell neoplasm should raise suspicion of secondary acquired hemophilia A and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Additionally, early intervention with immunoadsorption can be lifesaving in cases with high-titer factor VIII inhibitors, especially when surgical interventions are necessary.

Study On The Effect Of Ddavp On Factor VIII- Related Properties In Hemophilia And VWD

1981 ◽  
Author(s):  
N Ciavarella ◽  
S Solinas ◽  
D Pilolli ◽  
P Ranieri ◽  
D Corrao ◽  
...  
Keyword(s):  
Factor Viii ◽  
Electrophoretic Mobility ◽  
Hemophilia A ◽  
The Other ◽  
Strong Response ◽  
The Difference ◽  
Classic Form ◽  
O 19

Twenty-one patients affected by mild and moderate Hemophilia A as well as 9 patients with the classic form of vonWillebrand’s disease (vWD) were given a total of 58 infusions of DDAVP. Concerning Hemophilia a three fold mean raise ( x = 3.0, sem O. 19; range of ratios post/preinfusion 1.35 - 5.55) of factor VIII : C levels was observed after the infusion of 0.3 μg/Kg b.w. A mean raise of 3.44 ( sem 0.48, range 2.20 - 6.7) after the infusion of 0.4/ug/Kg was found. The difference between the two regimens is not statistically significant (p < 0.5). As to the vWD 18 infusions were given. In 6 patients the changes of factor VI1I: C, VIIIR: Ag and VIII: vWF were roughly consensual ( ratios post/preinfusion ranging from 2.2 to 4.0 for VIII: C; from 1.8 to 3.5 for VIHR:Ag and from 3.1 to 6.2 for VIII: vWF). In the remaining 3 patients a very strong response of VIII : C ( ratios post/preinfusion 12.0, 15.1 and 6.5) was observed. Also the other properties related to factor VIII underwent to relevant increase. In one of these patients a modified electrophoretic mobility of factor VIII was found; the other two (father and doughter) had a normal factor VIII mobility after stimulation with DDAVP.

Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

2002 ◽  
Vol 87 (02) ◽  
pp. 273-276 ◽  
Author(s):  
Miao-Liang Liu ◽  
Shelley Nakaya ◽  
Arthur Thompson
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
High Titer ◽  
Direct Sequencing ◽  
Normal Variant ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Intron Splice ◽  
Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

Differential Immunodominance of Human and Porcine Factor VIII in Hemophilia A Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 40-40 ◽  
Author(s):  
John F. Healey ◽  
Ernest T. Parker ◽  
Rachel T. Barrow ◽  
Pete Lollar
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
Domain Specificity ◽  
Chi Square ◽  
C2 Domains ◽  
Intravenous Injections ◽  
Domain Specific ◽  
Human Factor Viii ◽  
Chi Square Test

Abstract Hemophilia A inhibitor patients and patients with acquired hemophilia A recognize immunodominant epitopes in the A2 and C2 domains of human factor VIII (fVIII). Hemophilia A mice also recognize A2 and C2 domain epitopes when immunized with human fVIII using a dosing schedule that mimics clinical use. We compared the immune responses of hemophilia A mice to human and porcine fVIII using a domain specific ELISA. In this assay, monoclonal antibodies are tested against a panel of six single human fVIII domain hybrid human/porcine fVIII molecules that contain the human A1, A2, ap, A3, C1 or C2 domains. With anti-human antibodies, a positive signal with one of the single human domain proteins identifies domain specificity, whereas loss of signal indicates domain specificity of anti-porcine fVIII antibodies. Exon16 (E16) - disrupted hemophilia A mice (n = 3) received six weekly μ10 g/kg intravenous injections of recombinant B-domain deleted human fVIII and a final 25 μg/kg boost. To obtain comparable inhibitor titers, E16 mice (n = 3) received six weekly injections of μ40 g/kg of recombinant B-domain deleted porcine fVIII. Spleens from high titer mice were fused with NS1 mouse myeloma cells and 485 of the resulting hybridomas were analyzed for fVIII domain specificity (Table). Only two hybridomas secreted antibodies specific for the ap domain. Human fVIII elicited a significantly greater number of antibodies to the A2 domain, whereas porcine fVIII elicited a significantly greater number of antibodies to the A1 and A3 domains (p < 0.01, chi square test). The greater number of anti-C2 antibodies to human fVIII was not significant at the 95% confidence level (p = 0.08). The differential immunodominance of human and porcine fVIII epitopes suggests that it may be possible to design a recombinant hybrid human/porcine fVIII molecule that is less immunogenic than human fVIII in the treatment of patients with hemophilia A. Domain Specificity of Anti-FVIII MAbs Mouse ID: Immunogen No. of MAbs A1 A2 A3 C1 C2 CR & MD CR: Cross Reactive MD: Multidomain 1- Human fVIII 95 2 16 2 7 21 23 & 24 2- Human fVIII 126 13 23 1 2 27 39 & 21 3- Human fVIII 54 1 15 2 1 10 9 & 15 4- Porcine fVIII 123 39 7 19 8 16 33 & 0 5- Porcine fVIII 27 13 5 0 0 4 2 & 3 6- Porcine fVIII 60 9 6 12 1 9 13 & 10

Successful Treatment of Inhibitor Formation in Adult Congenital Hemophilia A with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4074-4074 ◽  
Author(s):  
Chirag J. Amin ◽  
Alice D. Ma
Keyword(s):  
Factor Viii ◽  
Knee Replacement ◽  
Immune Tolerance ◽  
Bolus Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
Recombinant Factor Viii ◽  
Promising Alternative ◽  
Immune Tolerance Induction

Abstract Inhibitor development in congenital hemophiliacs can be clinically catastrophic. Immune tolerance induction therapy has previously been the standard of care in eradicating inhibitors; however due to a multitude of factors, this may not be applicable in certain patients. The role of Rituximab is receiving more attention in this subset of patients. In this abstract, we report that treatment with Rituximab led to successful eradication of high-titer inhibitors in 3 patients with mild to moderate hemophilia A who developed inhibitors after receiving intensive treatment with recombinant Factor VIII (FVIII). Patient Characteristics: Three patients, aged 50–70, with baseline FVIII levels of 2–9%, developed inhibitors after recombinant Factor VIII infusion. Patient A was treated with continuous infusion FVIII for a post-surgical hemarthrosis for approximately 7 days. Patient B received bolus dose FVIII for a GI bleed for at least 10 days, and Patient C received bolus dose FVIII for knee replacement for 10 days. Factor VIII inhibitors were detected in these patients after one month. None of these patients had been treated with immune tolerance previously or had known inhibitors. Each patient received Rituximab 375mg/m2 every week for 4 weeks total. During and after treatment, FVIII levels and Bethesda inhibitor titers (BU) were monitored. Results: All three patients had eradication of their inhibitors (Figure 1) and return of their FVIII levels to baseline by six months post-treatment. Notably, patient C’s inhibitor peak was 117 BUs, 7 months prior to Rituximab treatment. Patient C’s initial response to Rituximab has been previously reported at ASH in abstract form. We now report that 4 years later, this patient has had a recurrence of his inhibitor after monoclonal FVIII for a contralateral knee replacement but with a peak titer of only 2 (Table 1). Inhibitor Trends after Rituximab Treatment Inhibitor Trends after Rituximab Treatment Bethesda Inhibitor Titer (BU) per Month (*) after Receiving Rituximab 0* 1 3 6 36 48 51 NA=Not applicable as data has not matured yet Patient A (BU) 5 0.7 0 0 NA NA NA Patient B (BU) 17 7 2 0 NA NA NA Patient C (BU) 40 4 0 0 0 2 0.5 Conclusion: Inhibitors in patients with mild-moderate hemophilia differ from those with severe FVIII deficiency, behaving more like the autoantibodies seen in patients with spontaneous FVIII inhibitors. In support of this idea, we successfully treated high titer inhibitors which developed in 3 patients with baseline FVIII levels of 2–9%. All three patients had prompt resolution of their inhibitor titers during the course of therapy, with return of their baseline FVIII levels. Historically, patients with mild-moderate hemophilia treated at the Harold R. Roberts Comprehensive Hemophilia Center at the University of North Carolina were treated either with immune tolerance induction or by bypass agents alone, with inhibitor eradication taking months to years (data not shown). While performance of larger prospective trials would be ideal, the small number of patients with this condition limits the ability to perform these trials. Our findings, in combination with other case series from other institutions, reveal a promising alternative for prompt and reliable treatment in mild-moderate hemophiliacs with inhibitors.

Increased Prevalence of Inhibitors in Mexican-Hispanic Patients with Severe Hemophilia A Enrolled in the Universal Data Collection Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3488-3488 ◽  
Author(s):  
Shannon Carpenter ◽  
J. Michael Soucie ◽  
Sophia Sterner ◽  
Rodney J Presley
Keyword(s):  
African Americans ◽  
Data Collection ◽  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Treatment Center ◽  
Hispanic Population ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Insurance Type

Abstract Abstract 3488 Poster Board III-425 Neutralizing inhibitor formation occurs in up to 20-30% of patients with severe factor VIII deficiency, leading to significantly increased morbidity in affected individuals. It has been well-established that patients of African descent have a higher prevalence of inhibitor development. [Oldenburg, J et al. Semin Hematol, 2004] The Hispanic population also has been assumed to have an increase in inhibitor development when compared with Caucasians. The study presented here is the first to definitively demonstrate an increased prevalence of inhibitors in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 6198 males with severe hemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables including age, insurance type (as a proxy for access to care and socio-economic status), age at first bleed, age at diagnosis and use of prophylaxis. The included table shows those variables that were determined to be independently predictive of inhibitors. We assigned Mexican derivation to participants who labeled themselves as Hispanic and who were born either in Mexico, in states bordering Mexico or in states with large Mexican populations as established by Census data. The prevalence of high titer inhibitors in the Mexican-Hispanic population was 26.3% compared to 16.4% for Caucasian patients [OR 1.5, 95% CI 1.1, 1.9], and 26.8% for African-Americans. The underlying cause of increased inhibitor prevalence in these populations is still unknown, though a recent study in African-Americans demonstrated wild-type factors unique from commercially available product. [Viel KR, et al. Inhibitor of Factor VIII in Black Patients with Hemophilia. N Engl J Med, 2009] Further investigation of this phenomenon in the Mexican-Hispanic population, as well as the potential impact of differing immune responses, is warranted. Multivariate analysis of ethnicity and other variables found to be independently predictive of a prevalent inhibitor Characteristic Odds Ratio 95% CI Race/Ethnicity African-American 1.5 1.2 - 1.9 Mexican Hispanic 1.5 1.1 - 1.9 Hispanic 1.2 0.9 - 1.7 Other 1.2 0.9 - 1.6 White Ref Age* (years) <2 4.2 3.0 - 5.9 2-5 6.4 5.1 - 8.0 6-10 2.8 2.2 - 3.5 11-18 1.7 1.4 – 2.1 >18 Ref Insurance type Medicare 1.8 1.4 - 2.3 Medicaid 1.3 1.1 - 1.5 State program 1.1 0.6 - 1.9 TRICARE 1.0 0.4 - 2.1 Other 0.8 0.6 - 1.2 Uninsured 1.6 1.0 - 2.4 Commercial Ref Prophylaxis Yes 0.6 0.5 - 0.7 No Ref * Age with inhibitor or last UDC visit if no inhibitor The authors wish to acknowledge the contributions of the Hemophilia Treatment Center Network Investigators in the completion of this study. Disclosures: No relevant conflicts of interest to declare.

A Subset of High Titer Acquired Hemophilia Patients May Benefit from Treatment with High Dose Factor VIII.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3476-3476
Author(s):  
Shannon Meeks ◽  
John F Healey ◽  
Ernest T Parker ◽  
Pete Lollar
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Type I ◽  
C2 Domain ◽  
Type Ii ◽  
Acquired Hemophilia ◽  
Proteolytic Activation

Abstract Abstract 3476 Poster Board III-413 Approximately 30% of patients with severe hemophilia A will develop inhibitory antibodies (Abs) to factor VIII (fVIII inhibitors). The immune response to fVIII currently is the most significant complication in the management of patients with hemophilia A. In addition, autoimmune Abs to fVIII can develop in non-hemophiliacs, producing acquired hemophilia A, which frequently produces life- or limb-threatening bleeding. Patients with autoimmune hemophilia often have Abs with type II kinetics in which there is incomplete inactivation of fVIII at saturating concentrations of inhibitor. We have characterized the antibody response to the C2 domain of human fVIII in a murine hemophilia model and described 5 structural groups of Abs. Groups A, AB, and B are classical anti-C2 Abs that block fVIII and fVIIIa binding to phospholipid. Groups BC and C consist of non-classical anti-C2 Abs that inhibit the proteolytic activation of fVIII but do not block the binding of fVIII to phospholipid. Subsequently, we identified classical and non-classical anti-C2 Abs in human fVIII inhibitor plasmas. Most murine non-classical Abs have inhibitor titers greater than 10,000 Bethesda units/mg IgG. In a murine in vivo bleeding model, both type I classical C2 Abs, type II non-classical C2 Abs, and a type I anti-A2 Ab produced similar amounts of blood loss that were significantly greater than control mice injected with 180 U/kg of fVIII alone. Increasing the dose of fVIII to 360 U/kg overcame the bleeding diathesis produced by the type II MAbs, but not the type I Abs. These results were consistent with the in vitro Bethesda assay in which a type I anti-A2 Ab, 4A4, completely inhibited both 1 U/mL and 3 U/mL fVIII, while there was 40% residual activity at saturating concentrations of a type II anti-C2 Ab, 2-77, at either concentration of fVIII. To determine if similar in vitro characteristics exist in patients with acquired hemophilia, plasmas from 3 patients with high titer type II inhibitors were studied. All 3 plasmas primarily had C2 domain epitope specificity that included non-classical Abs. Plasma A7 additionally had detectable anti-A2 activity. Recovery of fVIII activity after a 2 h incubation at 37 °C at nominal added concentrations of 1 mL and 3 U/mL fVIII was compared (Table 1). At 3 U/mL added fVIII, recovery of activity in plasmas A4 and A5 was 1.1 U/mL and 0.51 U/mL, respectively, despite the presence of inhibitor titers of 18 and 11 Bethesda units (BU) per mL. The presence of anti-A2 Abs, which typically have type I kinetics, may have contributed to the overall lower recovery of activity in plasma A7. These results suggest that treatment with high-dose fVIII rather than bypassing agents may be warranted in patients with an inhibitor response dominated by non-classical anti-C2 Abs. Table 1 Patient Plasma Inhibitor Titer (BU/mL) Recovered Activity at 1U/mL FVIII (U/mL) Recovered Activity at 3 U/mL FVIII (U/mL) A4 18 0.31 1.1 A5 11 0.18 0.51 A7 62 0.07 0.12 Disclosures: No relevant conflicts of interest to declare.

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