The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Pharmacokinetics and the transition to extended half-life factor concentrates: communication from the SSC of the ISTH.

Extended half-life proteins (EHL) are increasingly used in clinical practice, but there is no standardized approach to sampling, interpretation and implementation of pharmacokinetics (PK) data to maximize treatment benefit. The goal of EHL treatment is to attain a trough level sufficient to protect against spontaneous bleeds and reduce infusion frequency and limitations on individual activity and lifestyle. Performing classical PK assessments requires multiple blood samples, which is burdensome for patients and providers. Herein we review a population pharmacokinetic (popPK) approach to estimate individual PK parameters to transition patients from standard half-life (SHL) to EHL concentrates. We propose that a minimum of two to four post-infusion samples is sufficient to estimate individual PK profiles, with sufficient certainty to maintain factor levels above 1% and achieve bleed-free lifestyles. We also survey current PK use in patients transitioning to EHL, review key PK parameters and popPK models, and recommend an approach to using PK in patients initiating or switching to EHL.

Bleeding and liver transplantation outcomes in haemophilia.

BACKGROUND: Hepatitis C is the major cause of end-stage liver disease and the major indication for orthotopic liver transplantation (OLTx) in individuals with haemophilia. AIM: To assess the epidemiology and outcomes of OLTx in U.S. haemophilia patients. METHODS: We investigated haemophilia liver transplant recipients between 1993 and 2012, using the Nationwide Inpatient Sample, identified by ICD9 code 50.59. RESULTS: Of the 11 267 (weighted n = 54 691) patients undergoing OLTx, 44 (0.4%; weighted n = 213) had haemophilia. Those with haemophilia were more likely than non-haemophilic OLTx recipients to have bleeding complications (45.3% vs. 31.5%, P = 0.009) and hypovolemic shock (7.0% vs. 1.1%, P < 0.0001). They also had a significantly higher incidence of HIV (24.8% vs. 0.5%, P < 0.005), hepatitis B (16.2% vs. 7.9%, P = 0.04) and vitamin K deficiency (2.1% vs. 0.02%, P < 0.001). In spite of these differences, there was no difference in in-hospital mortality between haemophilic and non-haemophilic recipients (6.8% vs. 6.2%, P = 0.9). In multivariate logistic regression, bleeding complications in haemophilia increased the risk of in-hospital mortality by more than 3-fold (P < 0.0001), and disseminated intravascular coagulation increased the risk of bleeding complications in haemophilic recipients by over 10-fold (P < 0.0001). CONCLUSIONS: Bleeding complications are common in haemophilia OLTx recipients. Thus, aggressive correction of coagulation defects in this group may be a medically sound approach to reduce complications and mortality associated with OLTx.

Von Willebrand factor for menorrhagia: a survey and literature review.

BACKGROUND: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. METHODS: We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. RESULTS: Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. CONCLUSIONS: This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Liver Retransplantation in Patients With HIV-1 Infection: An International Multicenter Cohort Study.

Liver retransplantation is performed in HIV-infected patients, although its outcome is not well known. In an international cohort study (eight countries), 37 (6%; 32 coinfected with hepatitis C virus [HCV] and five with hepatitis B virus [HBV]) of 600 HIV-infected patients who had undergone liver transplant were retransplanted. The main indications for retransplantation were vascular complications (35%), primary graft nonfunction (22%), rejection (19%), and HCV recurrence (13%). Overall, 19 patients (51%) died after retransplantation. Survival at 1, 3, and 5 years was 56%, 51%, and 51%, respectively. Among patients with HCV coinfection, HCV RNA replication status at retransplantation was the only significant prognostic factor. Patients with undetectable versus detectable HCV RNA had a survival probability of 80% versus 39% at 1 year and 80% versus 30% at 3 and 5 years (p = 0.025). Recurrence of hepatitis C was the main cause of death in the latter. Patients with HBV coinfection had survival of 80% at 1, 3, and 5 years after retransplantation. HIV infection was adequately controlled with antiretroviral therapy. In conclusion, liver retransplantation is an acceptable option for HIV-infected patients with HBV or HCV coinfection but undetectable HCV RNA. Retransplantation in patients with HCV replication should be reassessed prospectively in the era of new direct antiviral agents.

Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction.

BACKGROUND: Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg-1 day-1 ) and low-dose (LD) (50 IU kg-1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. METHODS: We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. RESULTS: There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non-neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]. CONCLUSION: In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority.

Von Willebrand disease in the emergency department.

BACKGROUND: The emergency department (ED) is often the first medical contact point for von Willebrand disease (VWD) patients experiencing acute conditions, notably bleeding. However, knowledge of VWD disease types and management options by ED providers is uncertain. AIM: To determine the scope of VWD bleeding and treatment in the ED. METHODS: We evaluated medical record data in an IRB-approved study from 922 notes accounting for 385 ER visits by 183 VWD patients from a single large institution's emergency department. RESULTS: Over half the ED visits were for an active or suspected bleed, the majority of which were associated with trauma, surgery, epistaxis, gastrointestinal bleeding or gynaecologic bleeding. By treatment, only 25% of all bleeds, including 77.8% of those with menorrhagia and 50.0% of those with epistaxis, received DDAVP or von Willebrand factor concentrate (VWF). The likelihood of receiving treatment was related to referral source, with the highest rates of treatment in patients referred by a haematologist. CONCLUSIONS: These data suggest more patient and physician education are needed in managing patients with VWD, preferably at the time of diagnosis, including confirmation of the diagnosis, response to DDAVP testing, indication for DDAVP testing and formulation of a plan for suspected or actual bleeding.

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

BACKGROUND: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood. OBJECTIVES: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI. METHODS: In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. RESULTS: A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3). CONCLUSIONS: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.

Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register.

INTRODUCTION: von Willebrand factor (VWF) plays a critical role in platelet adhesion and aggregation after vascular injury and at sites of high shear rate. Elevated VWF levels are associated with an increased risk of ischemic cardiovascular events; however, it is unclear whether VWF deficiency is protective against atherosclerosis. We aimed to compare the prevalence of cardiovascular disease (CVD) among patients with and without von Willebrand disease (VWD). METHODS: A cross-sectional analysis was performed on discharge data for adults from the Nationwide Inpatient Sample (NIS) between the years 2009 and 2011. CVD was defined as ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, or peripheral vascular disease. For prevalence calculations and statistical analyses, we used discharge-level weights provided by the NIS to reflect national estimates. CVD was compared across groups by use of the Rao-Scott chi-square test. Multivariable logistic regression was used to estimate the likelihood of CVD in VWD patients after adjustment for age, gender, and CVD-related risk factors. RESULTS: The prevalence of CVD in VWD patients was less than the prevalence of CVD in non-VWD patients (15.0% versus 26.0%). VWD was associated with a decreased likelihood of CVD after adjustment for age, gender, and CVD-related risk factors (odds ratio 0.85; 95% confidence interval 0.79-0.92). DISCUSSION: These findings indicate that the risk of CVD is decreased among VWD patients, and that VWF deficiency may be protective against CVD.

Hepatitis B vaccination is effective by subcutaneous route in children with bleeding disorders: a universal data collection database analysis.

Subcutaneous (SQ) vs. intramuscular (IM) vaccination may cause fewer injection site complications in children with bleeding disorders, but little is known about comparative immunogenicity. To compare immunogenicity of hepatitis B virus (HBV) vaccination administered SQ or IM to individuals <2 years old with bleeding disorders, we performed a retrospective analysis of HBV surface antibody titres among patients enrolled in the universal data collection database who had received three doses of HBV vaccine solely by one route (SQ or IM). Data reviewed were from an initial visit before 24 months of age, until time of hepatitis antibody titre testing. The SQ and IM study groups did not differ in demographics, haemophilia type or severity or bleeding history. The mean age at the time of HBV surface antibody (anti-HBs) testing was 56.9 ± 20.3 months. Eighty-five of 92 subjects (92.4%) who received vaccine SQ developed a positive antibody titre (>12 IU/L), compared to 101/114 (88.6%) who received IM (P = 0.30). There was no statistically significant difference in distribution of titre values. The average age of the subjects at time of testing was 53 ± 20 months in the SQ group vs. 60 ± 20 months in the IM group (P = 0.02). The average time between the last dose of vaccine and anti-HBs testing was 47.6 ± 18.5 months among SQ vaccinated subjects vs. 51.6 ± 20.5 months in the IM group (P = 0.2). Immunogenicity to hepatitis B vaccination by the SQ and IM routes is similar.

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis.

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0-21 days (median 6). VWF levels peaked at 250% of baseline--4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.

Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels.

BACKGROUND: Routine prophylaxis with replacement factor VIII (FVIII) - the standard of care for severe hemophilia A - often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A. OBJECTIVE: In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens. METHODS: We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed. RESULTS: As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL(-1) (1%) with rFVIIIFc than with equivalent rFVIII regimens. CONCLUSION: These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL(-1) than with rFVIII products requiring more frequent dosing regimens.

Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.

Liver transplant outcomes in HIV+ haemophilic men.

Hepatitis C virus infection is the major cause of end-stage liver disease and the major indication for transplantation (OLTX), including among HIV-HCV co-infected individuals. The age of HCV acquisition differs between haemophilic and non-haemophilic candidates, which may affect liver disease outcomes. The purpose of the study was to compare rates of pre- and post-OLTX mortality between co-infected haemophilic and non-haemophilic subjects without hepatocellular cancer participating in the Solid Organ Transplantation in HIV Study (HIV-TR). Clinical variables included age, gender, race, liver disease aetiology, BMI, antiretroviral therapy, MELD score, CD4 + cell count, HIV RNA PCR and HCV RNA PCR. Time to transplant, rejection and death were determined. Of 104 HIV-HCV positive subjects enrolled, 34 (32.7%) underwent liver transplantation, including 7 of 15 (46.7%) haemophilic and 27 of 89 (30.3%) non-haemophilic candidates. Although haemophilic subjects were younger, median 41 vs. 47 years, P = 0.01, they were more likely than non-haemophilic subjects to die pre-OLTX, 5 (33.3%) vs. 13 (14.6%), P = 0.03, and reached MELD = 25 marginally faster, 0.01 vs. 0.7 years, P = 0.06. The groups did not differ in baseline BMI, CD4, detectable HIV RNA, detectable HCV RNA, time to post-OLTX death (P = 0.64), graft loss (P = 0.80), or treated rejection (P = 0.77). The rate of rejection was 14% vs. 36% at 1-year and 36% vs. 43% at 3-year, haemophilic vs. non-haemophilic subjects, respectively, and post-OLTX survival, 71% vs. 66% at 1-year and 38% vs. 53% at 3-year. Despite similar transplant outcomes, pretransplant mortality is higher among co-infected haemophilic than non-haemophilic candidates.