ALBERT

Description: Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 1011, 2.2 × 1011, or 4.4 × 1011 platelets/m2 per transfusion, given for morning counts of ≤ 10 000 platelets/μL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P 〈 .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Description: The use of subcutaneous (SC) low molecular weight heparin (LMWH), such as enoxaparin, in pediatric patients for treatment or prevention of thromboembolism is now considered standard practice; however, SC administration is often difficult in special populations such as premature neonates, children with minimal subcutaneous tissue, and critically ill children with severe edema. Impaired SC absorption may lead to difficulty achieving adequate anticoagulation, as measured by anti-Xa levels 4 to 6 hr after the second or third dose. Intravenous (IV) administration of enoxaparin has, therefore, been employed in our intensive care unit (ICU) in an attempt to achieve adequate anticoagulation. However, the published experience of IV dosing and its monitoring consists of one brief manuscript and one abstract describing one preterm infant each. Therefore, we retrospectively evaluated dosing, monitoring, and clinical outcomes of pediatric patients receiving IV enoxaparin in our ICU between April 1, 2005 and March 31, 2006. Seven patients, all with congenital heart defects, were identified using hospital pharmacy records. Five were switched to IV enoxaparin after having difficulty achieving therapeutic anti-Xa levels with SC administration, primarily due to marked edema. Two others were empirically started on IV enoxaparin. Five children were treated with enoxaparin for thrombosis and 2 were treated prophylactically. Median age at the initiation of IV enoxaparin was 4 mo (range, 18 d – 3 yr). Dosing of the enoxaparin was every 8 hr for the 5 children under 1 yr of age and every 12 hr for the 2 children over 1 yr of age. Of the total 64 anti-Xa levels obtained, 19 monitored the 12 hr dosing schedule and 45 the 8 hr schedule. In order to evaluate the anti-Xa levels drawn following different doses (mg/kg) and dosing regimens (q8h or q12h) we transformed the data by the following equation: anti-Xa level (IU/ml)/total daily dose of enoxaparin· kg−1. These transformed values were averaged and grouped by the time of the anti-Xa level after enoxaparin, as follows: Average anti-Xa levels, enoxaparin dose, and transformed levels grouped by time level obtained Time level drawn (hr) Anti-Xa level (U/ml) Dose (mg/kg/day) Anti-Xa/dose 0–1.9 0.68 4.67 0.19 2–3.9 0.46 3.67 0.15 4–5.9 0.77 5.93 0.16 6–8.0 0.13 5.98 0.03 The average enoxaparin dose necessary to achieve the therapeutic target (anti-Xa 0.5–1.0 IU/ml) at 1–2 hr for the 3 children 〈 1 yr of age was 2.4 mg/kg (± s.d. 0.58) q8h. The average dose to achieve the prophylactic target (anti-Xa 0.3–0.5 IU/ml) at 1–2 hr for the 2 children 1yr of age, the average dose to achieve the therapeutic target at 1–2 hr was 1.11 mg/kg (± s.d. 0.13) q12h. No serious bleeding complications occurred in any patient. In conclusion, IV enoxaparin dosing appears to exhibit different pharmacodynamics than SC dosing, with higher anti-Xa levels at 1 to 2 hr after administration rather than at 4 to 6 hr. More frequent administration may be indicated as the levels decrease substantially 6 to 8 hr following an IV dose. The average dose needed for therapeutic levels may be higher than with SC administration (especially in the younger child). Future prospective studies should be conducted to determine the pharmacodynamics of IV enoxaparin, its safety and its clinical indications.

Description: Abstract 3169 Background: Adapted from the adult definition, pediatric antiphospholipid syndrome [APS] has been defined as one or more arterial or venous thrombosis associated with persistent antiphospholipid antibodies, i.e. IgM or IgG anticardiolipin antibodies [ACL: cut-off 〉 99th age-dependent percentile] or the presence of lupus anticoagulants confirmed in at least one follow-up visit more than 8 to 12 weeks apart. Antiphospholipid antibodies play an important role in the development of pediatric thromboembolism [TE] with arterial TE or stroke being more often associated with primary APS compared to deep venous thrombosis [DVT], which is observed predominantly in children with secondary APS. However, results of single studies on the risk thromboembolism onset associated with APS have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of APS on risk of childhood arterial and venous TE via meta-analysis of published observational studies. Methods: A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2010 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, laboratory methodologies, country of origin, number of patients/controls, ethnicity, type and location of TE were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models. Results: Eight of 319 (DVT) and seven out of 185 (arterial TE) references found met inclusion criteria: In total 1403 patients and 1904 population-based controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. In addition, regression analysis did not reveal statistical significant differences between locations of TE, age at first disease onset, study country, or publication year. Thus, data from arterial and venous TE were analyzed together. A statistically significant association with a first TE onset was demonstrated with a cumulative summary ORs/CIs (fixed-effects model) of 5.9/3.6-9.7. Conclusions: The present meta-analysis indicates that APS serves as a clinical meaningful risk factor for a first symptomatic TE in children. However, the impact of APS upon outcome and recurrence risk needs to be further investigated. Disclosures: No relevant conflicts of interest to declare.

Description: Thromboembolic complications in children occur at an estimated rate of 5.3 per 10,000 hospitalized children per year. Over the last decade, investigators have determined that underlying medical conditions such as cancer and congenital heart disease (CHD) and the intensive therapies required to manage these conditions are strongly associated with the thromboembolic complications. Recently, we perceived an increase in the incidence of thrombosis in children with Down Syndrome (DS), a chromosomal abnormality which is associated with both CHD and cancer, but there is very little evidence in the medical literature to suggest that it is an independent risk factor for thrombosis. Although, there are case series describing an association of moyamoya disease and DS, only a few case reports describe venous and arterial thrombosis in children with DS, and there is no information about its rate and severity. Therefore, we conducted a retrospective analysis of patients treated at Children’s Medical Center Dallas between January 1, 2000 and November 30, 2005, hypothesizing that thrombosis would be more prevalent in patients with DS (with or without associated co-morbidities) than in children without DS. ICD-9 codes for CHD, DS, cancer, and thromboembolic complications and the CPT codes for the surgical procedures used to correct CHD were used to identify patients of interest. During the study period, the emergency center, ambulatory outpatient areas, and inpatient units saw 729,324 children. Among these, we identified 511 patients with DS (0.07%), 2168 (0.29%) with CHD, and 1182 (0.16%) with cancer. Sixty-one percent (n=311) of the patients with DS also had CHD, and 2.9% (n=15) had cancer. Thrombosis was identified in 398 (5.4 per 10,000 children). The majority (n=220, 55%) developed deep venous thrombosis (DVT), with catheter-related thrombosis (n= 156) being most common. There were 165 (41%) arterial ischemic strokes (AIS), 19 associated with moyamoya disease. Fifteen children with DS developed thrombosis (rate of 293 per 10, 000 children with DS). Among these 15, DVT occurred in 11 (73%) patients and AIS in 5 (33%), 2 with moyamoya. Among the subgroup of patients diagnosed with AIS, DS was not found to be a risk factor for moyamoya disease (OR 5.6, 95% CI 1.05, 30.5, p=0.1). Two patients with DS (13%) had both DVT and AIS. Children diagnosed with DS (OR 57.5, 95% CI 34.2, 96.5, p

Description: Introduction: Unpredictable, prolonged or heavy menstrual bleeding (HMB) is not unusual in many adolescents soon after menarche. Anovulation, owing to immaturity of the hypothalamic-pituitary-ovarian axis, is often the cause of HMB; however, it may coexist and mask an underlying bleeding disorder (BD). Retrospective data in adolescents with HMB suggest a prevalence of BDs from 10 to 62%. Prospective studies with uniform hemostatic evaluation and concurrent quality of life (QoL) assessments have not been performed. The incidence of BDs in adolescents, especially those with anovulatory bleeding, remains unknown. Methods: In this ongoing prospective cohort study (targeted n=200), 130 adolescents referred for HMB to multidisciplinary Young Women's Blood Disorders Clinics were enrolled. An assessment of menstrual loss using pictorial blood assessment chart (PBAC) and bleeding symptoms using ISTH-bleeding assessment tool (BAT) was undertaken. Participants underwent a comprehensive evaluation determined a priori, including assessment of hypermobility, standardized laboratory evaluation (prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin time, von Willebrand disease (VWD) panel, whole blood platelet aggregation with ATP secretion, factor assays (FIX and FXIII), global hemostasis and hyperfibrinolysis using ROTEM, and a pelvic ultrasound (US). Patient reported outcomes for health related QoL(HR-QoL) was completed. Results: The mean age of participants was 14 (range 11-18) and mean age at menarche was 11.7 yrs. (range: 9-16). The mean PBAC score, before contraceptive initiation, was 504 (range: 100- 1200) and the mean ISTH BAT score was 3.8 (range: 1-8) in all participants. 62% had anovulatory menstrual bleeding. An inherited BD and/or bleeding risk was diagnosed in 24.6% (n=32); 9% (n=12) were diagnosed with VWD, 5% (n=6) with qualitative platelet dysfunction and 2 subjects were found to be hemophilia A (HA) carriers. Low VWF levels (VWF:Rco 30-50%) were detected in 9% (n=12). 15% had evidence of mild systemic hyperfibrinolysis (lysis 3-8% on ROTEM) but none met the criteria for further investigation for an inherited disorder of hyperfibrinolysis . Of those without BD, 2 were diagnosed to have VWF exon 28 polymorphism, and 3 were referred and ultimately diagnosed with hypermobility syndrome by Genetics. One was found to have endometriosis by laparoscopy and 3 were diagnosed with PCOS. Of those with BDs (all with low VWF), 3 were diagnosed with hypermobility syndrome (total 6) and 4 with PCOS (total 7). US was normal in all subjects. The PBAC scores were higher in BDs (634 vs. 410; SD ± 275 p=0.002), irrespective of the pattern of bleeding. No differences were found in the ISTH BAT scores (after excluding HA carriers) (3.6 vs. 4.8; SD ± 1.19, p=0.06), initial hbg or ferritin levels between the two groups. Only 6% (n=8) with BDs required ED visit and/or hospitalization for HMB vs. 14% (n=18) without a BD, of which majority had anovulatory bleeding. On multivariate logistic regression, no predictors of BDs were found. Adolescents with BDs had a decreased HR-QoL compared to those without a BD (QoL score 58 vs.87; SD± 12.5, p=

Description: Central venous catheters (CVCs) are a common adjunct to hemophilia therapy, but the risk of CVC-related deep venous thrombosis (DVT) in hemophiliacs is not well defined. In a previous study, 13 patients with CVCs had no radiographic evidence of DVT. However, recent abstracts and case studies demonstrate that DVT does occur. Therefore, this study sought to determine the frequency of DVT in children with hemophilia and long-term CVCs and to correlate venographic findings with clinical features. All hemophilia patients with tunneled subclavian CVCs in place for 12 months or more were candidates for evaluation. Patients were examined for physical signs of DVT and questioned about catheter dysfunction. Contrast venograms were obtained to identify DVT. Fifteen boys with severe hemophilia were evaluated, including 9 from the initially studied group of 13. Eight patients had evidence of DVT, 5 of whom previously had normal venograms. Five of 15 patients had clinical problems related to the CVC, all of whom had DVT. Four of 15 patients had suggestive physical signs; 3 had DVT. The mean duration of catheter placement for all patients was 57.5 months (range, 12-102 months). For patients with DVT, the mean duration was 66.6 ± 7.5 months, compared to 49.5 ± 7.2 months for patients without DVT (P = .06). No patient whose CVC was in place fewer than 48 months had an abnormal venogram. Many hemophilia patients with CVCs develop DVT of the upper venous system, and the risk increases with duration of catheter placement.

Description: Background: Diagnosis of von Willebrand disease (VWD) is challenging in clinical practice due to variability in laboratory testing and clinical bleeding history. We investigated the prospective diagnosis of VWD in academic hematology clinics across the U.S. and Kingston, ON and report on the final cohort here. Methods: Subjects were enrolled as new consults to their hematologist for evaluation of a bleeding disorder from 11 centers. Laboratory results including VWF antigen (VWF:Ag) and VWF platelet binding activity were determined both locally (VWF ristocetin cofactor activity [VWF:RCo] or VWF:GPIbM) and centrally (VWF:GPIbM) to determine the comparative effectiveness in VWD diagnosis. Some centers defined type 1 VWD with levels

Description: Background: Sickle cell disease (SCD) and its complications are associated with frequent hospital visits and treatment often requires venous access for administration of fluids, medications and blood transfusions. Due to frequent use, peripheral venous access can become difficult over time because of venous scarring. Moreover, certain interventions such as chronic simple or exchange transfusions require reliable venous access for prolonged periods of time. Implantable central venous devices such as ports offer definitive access and mitigate the need for frequent peripheral access attempts. However, existing knowledge on the use of these devices in pediatric patients with SCD is limited. Due to possible increased risks of thrombosis and mechanical occlusion from hypercoagulable state, risk of infectious complications and need for surgical placement, ports are often not used routinely. We review the indications and complications associated with placement of ports in the pediatric cohort of patients with SCD - to better define the scope of port placement in this group. Methods: We performed an IRB-approved, retrospective chart review to assess the indications, complications and risk factors associated with port placement in children and adolescents with SCD at the University of Oklahoma Health Sciences Center (OUHSC). The study period analyzed was 17.5 years from January 1st, 2000 to July 30th, 2018 and included patients from birth to 21 years of age, diagnosed with SCD who had homozygous sickle cell disease (HbSS) or compound heterozygous SCD - either sickle cell-β0-thalassemia, sickle cell-β+-thalassemia or sickle cell-hemoglobin C (HbSC) disease, and had ports in place for more than 7 days. Patients were identified systematically by querying the OUHSC Clinical Data Warehouse using diagnostic codes followed by chart review. Results: Thirty-two patients with SCD and ports were identified during the study period, out of which 31 patients had HbSS and one patient had HbSC disease. The median age at first port insertion was 8 years (range 1-20 years). A total of 63 ports were placed for a total of 99,272 port days with a median port life span of 1340 days. The two main indications for port placement were - either chronic transfusions for which 48 ports were placed for a total of 80,238 port days, or poor venous access (PVA) for which 15 ports were placed for a total of 19,034 port days. Out of the 48 ports placed for chronic transfusions, 6 ports were for transfusions for primary stroke prophylaxis, 22 ports were for transfusions for secondary stroke prophylaxis, 17 ports were for transfusions for recurrent vaso-occlusive episodes (VOE) and 3 ports were for transfusions after multi-organ failure. A total of 54 port complications occurred (malfunction=29, infection=20, thrombosis=3, difficult port access=1, and intractable pain over port site=1). From the data available, more ports were placed in the left subclavian vein (LSV=20) than right subclavian vein (RSV=4) and right internal jugular (RIJ=2), however rate of overall complications were similar between LSV and RSV - 0.57 complications/1,000 catheter days in LSV and 0.58 complications/1,000 catheter days in RSV. The rate of port associated infection, defined as a positive blood culture drawn from the port, was 0.2 per 1,000 port days. A total of 20 infections identified mostly gram-positive organisms (n=15) predominantly Staphylococcus, compared to gram-negatives (n=3), fungus with Candida albicans (n=1) and a rare acid-fast bacilli infection with Mycobacterium mucogenicum (n=1). The rate of thrombosis, identified radiologically using vascular doppler ultrasound, was 0.03 per 1,000 port days. The rate of premature port removal arising from complications was 0.36 per 1,000 port days. Ports placed for chronic transfusions had a lower rate of removal (0.31 per 1,000 port days) compared to ports placed for poor venous access (0.58 per 1,000 port days) with a ratio of 0.54 which approached statistical significance (p=0.09; CI 0.26-1.21). Conclusion: Ports in pediatric patients with SCD are associated with low rates of thrombosis, infection and malfunction. Ports may be a reasonable alternative for vascular access in patients with SCD - especially in patients who require chronic simple or exchange transfusions and have difficult access. Larger prospective studies will be needed to further assess the scope of use of ports in this population. Disclosures No relevant conflicts of interest to declare.

Description: 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.

Description: Introduction: Inhibitor formation affects approximately 30% of individuals with severe hemophilia A. The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy, although typically requires daily high-dose factor VIII via a port for up to a year. Extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc, Eloctate¨) has a half-life extension 1.5-fold longer than standard recombinant FVIII (rFVIII), reducing treatment frequency, and also induces regulatory T cell response to FVIII in animal models. We hypothesized that rFVIIIFc would provide more effective ITI, specifically shortening ITI, than rFVIII. We describe ITI with rFVIIIFc in three patients with severe hemophilia A. Methods: Immune tolerance induction was initiated with rFVIIIFc (Eloctate) in three children with severe hemophilia A and an anti-FVIII inhibitor. Dosing was per MD discretion with family agreement, and performed by central venous access device or intravenous infusion via heplock. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to 6 hours was documented, incremental reduction to 50 IU/kg every other day or three times weekly, once there was evidence of maintenance of inhibitor neutralization and a 〉6 hour FVIII:C half-life. Results: Immune tolerance induction was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc via central venous access device every other day or three times weekly per MD discretion in three children with severe hemophilia A and in anti-FVIII inhibitor 〉 5 B.U. (Table 1). Two patients had F8 genetic testing. In two patients, Pt 1 and Pt 3, this was the initial ITI course, and in the third child (Pt 2) this was salvage ITI after failing to achieve tolerance due to noncompliance with daily rFVIII ITI taper regimen. In two rFVIIIFc ITI was begun when anti-FVIII was 〈 10 B.U. Historic peak titers were 16-422 B.U. The time to anti-FVIII tolerance was 4-12 weeks Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. There were no adverse effects. These data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in children with inhibitors. Whether ITI may be accomplished more rapidly with rFVIIIFc, and the optimal dose for ITI will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the H emophilia I nhibitor R esponse to E loctate (HIRE) Study, is underway. Table 1. Immune Tolerance Induction with rFVIIIFc in Hemophilia A Inhibitor Patients Patient (Pt) Hemophilia Severity F8 Gene Mutation Age at Anti-FVIII Detection Peak Anti-FVIII Titer Initial ITI Dose Time toAnti-FVIII = 0 Current Anti-FVIII 1