A cross-sectional study of non-attendance among patients at a US hemophilia treatment center 2010-2014.

INTRODUCTION: Among patients with chronic disease, non-attendance at scheduled healthcare visits is associated with poor outcomes. The impact of non-attendance among patients with bleeding disorders is unknown. METHODS: Scheduling and medical record data over a 5-year period for all individuals with at least one scheduled appointment during 2010-2014 at a US Hemophilia Treatment Center (HTC) were analysed. Non-attendance rates were calculated as the number of non-attended visits divided by the number of years as a patient during the time period. Consistent non-attenders were patients who did not attend more than one scheduled appointment per person-year on average. Logistic regression determined characteristics associated with consistent non-attendance and Poisson regression estimated adjusted incidence rate ratios (aIRRs) describing associations between non-attendance and emergency department (ED) visits and hospitalizations. RESULTS: There were 8028 appointments scheduled for 950 individuals; 12% were not attended. Consistent non-attenders (n = 62; 7% of the HTC patient population) accounted for over one-third of non-attended appointments and over one-quarter of hospitalizations. Characteristics associated with consistent non-attendance included public health insurance and black race. Higher non-attendance rates were associated with more ED visits (aIRR 1.78; 95% CI: 1.37-2.30) and hospitalizations (aIRR 2.73; 95% CI: 2.18-3.42). Consistent non-attenders had more ED visits (aIRR 2.49; 95% CI: 1.56-3.96) and hospitalizations (aIRR 4.73; 95% CI: 2.96-7.57) compared with patients who never missed appointments. CONCLUSIONS: Frequent non-attendance identified a small but at-risk population. Interventions to improve disease management that target them may have an impact on health outcomes and healthcare utilization.

Impact of pain and functional impairment in US adults with haemophilia: Patient-reported outcomes and musculoskeletal evaluation in the pain, functional impairment and quality of life (P-FiQ) study.

INTRODUCTION: Standardized and disease-specific patient-reported outcome (PRO) instruments assessing pain, functional impairment and health-related quality of life (HRQoL) in people with haemophilia (PWH) have been used in studies, but infrequently in comprehensive care settings for individual assessment or treatment planning. AIM: To assess the impact of pain and functional impairment on HRQoL in PWH. METHODS: P-FiQ enrolled 381 adult PWH with a history of joint pain/bleeding and included 5 PROs and a clinical joint evaluation (Hemophilia Joint Health Score v2.1 [HJHS]). RESULTS: Median age was 34 years; 49.9% reported a history of joint procedure or surgery. On EQ-5D-5L, most reported problems with mobility (61.4%), usual activities (53.2%) and pain/discomfort (76.1%). On Brief Pain Inventory v2 Short Form, median worst pain (range 0-10) was 6, least pain 1, average pain 3 and current pain 2. Ankles were most frequently reported as the most painful joints (37.4%), followed by knees (23.7%) and elbows (18.9%). On International Physical Activity Questionnaire, 51% reported no activity in the prior week. On SF-36v2 health survey, median subscores were worse for 4 physical health domains vs 4 mental health domains. Among Hemophilia Activities List domains (range 0 [worst]-100 [best]), functions of the legs (median, 66.7) and lying/sitting/kneeling/standing (median, 67.5) were most impacted and self-care least impacted (median, 100.0). On HJHS, ankle scores (median, 6.0; range, 0-40) were worse than elbow/knee scores (median, 4.0/4.0). Results were consistent across PROs/HJHS. CONCLUSION: Data demonstrate challenges of predominantly ankle/knee pain and lower extremity functional impairment in US adult PWH, affecting HRQoL across PROs/HJHS.

Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

INTRODUCTION: Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. AIM: The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. METHODS: Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. RESULTS: IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. CONCLUSIONS: IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients.

Physician trust and depression influence adherence to factor replacement: a single-centre cross-sectional study.

INTRODUCTION: Poor adherence to factor replacement therapy among patients with haemophilia can lead to joint bleeding and eventual disability. AIM: The aim of this study was to determine patient-related characteristics associated with adherence to factor replacement in adults with haemophilia. METHODS: Adults with haemophilia were recruited to participate in this cross-sectional study. Adherence was measured using either the Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS)-Pro or the VERITAS-PRN questionnaire. Simple and multiple regression analyses that controlled for confounding were performed to determine the association between patient-related characteristics and adherence to factor replacement therapy. RESULTS: Of the 99 subjects enrolled, all were men; 91% had haemophilia A and 78% had severe disease. Age ranged from 18 to 62 years. Most (95%) had functional health literacy; but only 23% were numerate. Mean adherence scores were 45.6 (SD 18) and 51.0 (SD 15) for those on a prophylactic and those on an episodic regimen, respectively, with a lower score indicating better adherence. On multivariable analysis, being on any chronic medication, longer duration followed at our haemophilia treatment centre, higher physician trust and better quality of life were associated with higher adherence. A history of depression was associated with lower adherence. CONCLUSION: Two potentially modifiable characteristics, physician trust and depression, were identified as motivator and barrier to adherence to factor replacement therapy. Promoting a high level of trust between the patient and the healthcare team as well as identifying and treating depression may impact adherence to factor replacement therapy and accordingly reduce joint destruction.

Self-reported prevalence, description and management of pain in adults with haemophilia: methods, demographics and results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

INTRODUCTION: Haemophilia is characterized by frequent haemarthrosis, leading to acute/chronic joint pain. AIM: To assess self-reported prevalence, description and management of pain in adult males with mild-to-severe haemophilia and history of joint pain/bleeding. METHODS: Participants completed a pain survey and five patient-reported outcome instruments assessing pain, functional impairment and health-related quality of life (HRQoL). RESULTS: Of 381 participants enrolled, median age was 34 years; 77% had haemophilia A, 71% had severe disease and 65% were overweight/obese. Many (56%) were not receiving routine infusions; 30% never received routine infusions. During the prior 6 months, 20% experienced acute pain, 34% chronic pain and 32% both acute/chronic pain. Subjects with both acute/chronic pain (vs. none, acute or chronic) were more likely to be depressed (30% vs. 0-15%), obese (35% vs. 20-29%) and have lower HRQoL (mean EQ-5D visual analog scale, 69 vs. 83-86) and function (median overall Hemophilia Activities List, 60 vs. 88-99). Most common analgesics used for acute/chronic pain during the prior 6 months were acetaminophen (62%/55%) and non-steroidal anti-inflammatory drugs (34%/49%); most common non-pharmacologic strategies were ice (65%/33%) and rest (51%/33%). Hydrocodone-acetaminophen was the most common opioid for both acute/chronic pain (30%); other long-acting opioids were infrequently used specifically for chronic but not acute pain (morphine, 7%; methadone, 6%; fentanyl patch, 2%). CONCLUSION: Patients with chronic pain, particularly those with both acute/chronic pain, frequently experience psychological issues, functional disability and reduced HRQoL. Treatment strategies for acute pain (e.g. routine infusions to prevent bleeding) and for chronic pain (e.g. long-acting opioids) may be underused.

Bone health in persons with haemophilia.

INTRODUCTION: As the population of patients with haemophilia (PWH) ages, healthcare providers are required to direct greater attention to age-related co-morbidities. Low bone mineral density (BMD) is one such co-morbidity where the incidence not only increases with age, but also occurs with greater frequency in PWH. AIM: To review risk factors for low BMD, and strategies to promote bone health and identify patients who would benefit from screening for osteoporosis and subsequent treatment. METHODS: A narrative review of the literature was performed in MEDLINE with keywords haemophilia, bone density, osteoporosis and fracture. Reference lists of retrieved articles were also reviewed. RESULTS: Low BMD occurs more commonly in PWH than the general population and is most likely the result of a combination of risk factors.  Steps to promote bone health include preventing haemarthrosis, encouraging regular exercise, adequate vitamin D and calcium intake, and avoiding tobacco and excessive alcohol intake. Adults 50 years of age and older with haemophilia and those younger than 50 years with a fragility fracture or increased fracture risk based on FRAX (The Fracture Risk Assessment Tool), regardless of haemophilia severity, should be screened for low BMD using dual x-ray absorptiometry (DXA). Once osteoporosis is diagnosed based on DXA, fracture risk should guide treatment. Currently, treatment is similar to those without haemophilia and most commonly includes bisphosphonates. CONCLUSION: Haemophilia care providers should promote adequate bone formation during childhood and reduce bone loss during adulthood as well as identify patients with low BMD that would benefit from therapy.

US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors.

INTRODUCTION: The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs. AIM: Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors. METHODS: Results from the International ITI study and other available evidence were used to develop guidelines for ITI. RESULTS: Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI. CONCLUSION: Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies.

Distress in patients with bleeding disorders: a single institutional cross-sectional study.

INTRODUCTION: Distress may affect a patient's ability to cope with and manage disease. AIM: To report distress prevalence in adult patients with bleeding disorders and determine whether specific clinical and health characteristics, including disease severity and employment status, are associated with distress. METHODS: Patients who visited a Haemophilia Treatment Centre (HTC) between January 1st, 2012 through February 28th, 2014 and who completed a distress screen, pain screen and questionnaire were evaluated cross sectionally. Distress was measured by the National Comprehensive Cancer Network Distress Management Tool, which allowed patients to rate recent distress on a 0-10 point scale. A rating of five or more was categorized as high distress. Pain was measured by the Brief Pain Inventory Short Form, which asked patients to rate pain types on 0-10 point scales. Patients reported employment and other demographic and behavioural information on the questionnaire. Primary diagnosis, age, HIV and HCV status were abstracted from medical records. Adjusted logistic regression was used to identify distress associations. RESULTS: High distress prevalence among 152 patients with bleeding disorders was 31.6%. Unemployment, disability, greater depressive symptoms and higher pain were associated with high distress in multivariable models. Bleeding disorder diagnosis, race/ethnicity, HIV/HCV status and on-demand treatment regimen were not associated with high distress. CONCLUSION: Distress among patients with congenital bleeding disorders followed at a comprehensive HTC was high and similar to that reported among patients with cancer. Future research should determine whether distress impacts clinical outcomes in patients with bleeding disorders as demonstrated in other chronic disorders.

The role of disease severity in influencing body mass index in people with haemophilia: a single-institutional cross-sectional study.

The aim of this study was to evaluate the effect of haemophilia disease severity and potential intermediaries on body mass index (BMI) in patients with haemophilia. A secondary analysis of a cross-sectional study of 88 adults with haemophilia was undertaken. On bivariate analysis, persons with severe haemophilia had 9.8% lower BMI (95% CI -17.1, -3.0) than persons with non-severe haemophilia. The effect of haemophilia severity on BMI varied significantly by human immunodeficiency virus (HIV) status. Among HIV-positive subjects, haemophilia severity was not associated with BMI (+5.0%, 95% CI -22.4, 41.9). Among HIV-negative subjects, severe haemophilia was associated with 15.1% lower BMI (95% CI, -23.6, -5.7). Older (>41 years) HIV-negative subjects with severe haemophilia had a BMI that was 24.8% lower (95% CI -39.1, -7.0) than those with non-severe haemophilia. No statistically significant association was detected between BMI and severe vs. non-severe haemophilia for younger HIV-negative subjects. Although joint disease, as measured by the World Federation of Hemophilia (WFH) joint score, did not influence the association between haemophilia disease severity and BMI, adjustment for the atrophy component of the WFH score reduced the association between haemophilia severity and BMI by 39.1-69.9%. This suggested that muscle atrophy mediated at least part of the relationship between haemophilia severity and BMI. Haemophilia disease severity is associated with BMI and appears to be mediated by muscle atrophy of surrounding joints. This association appears to be modified by HIV status and possibly age.

Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database.

Several risk factors for inhibitors have recently been described for haemophilia A. It has been assumed that similar risk factors are also relevant for haemophilia B, but there is limited data to confirm this notion. The aim of this study was to determine the prevalence of and risk factors associated with inhibitors in haemophilia B. The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998-2011 was queried to determine the prevalence of inhibitors in haemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Of the 3785 male subjects with haemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age <11 years (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Inhibitors in haemophilia B are much less prevalent than haemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in haemophilia A also seem to be present for haemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required.

Bone density in haemophilia: a single institutional cross-sectional study.

Haemophilia has been associated with low bone mineral density (BMD). However, prior clinical studies of this population have neither clearly elucidated risk factors for development of low BMD nor identified who may warrant screening for osteoporosis. The aim of the study was to evaluate the relationship between BMD and haemophilic arthropathy and other demographic and clinical variables. We undertook a cross-sectional study of BMD in adult men with haemophilia. Measures of predictor variables were collected by radiographic studies, physical examination, patient questionnaires and review of medical records. Among 88 enrolled subjects, the median age was 41 years (IQR: 20); median femoral neck BMD (n = 87) was 0.90 g cm(-2) (IQR: 0.24); and median radiographic joint score was 7.5 (IQR: 18). Among subjects <50 years (n = 62), after controlling for BMI, alcohol, HIV and White race, BMD decreased as radiographic joint score increased (est. ß = -0.006 mg cm(-2) ; 95% CI -0.009, -0.003; partial R(2) = 0.23). Among subjects ≥50 years (n = 26), 38% had osteoporosis (T score less than or equal to -2.5) and there was no association between BMD and arthropathy. Risk factors for low BMD in men with haemophilia <50 years include haemophilic arthropathy, low or normal BMI and HIV. Men with haemophilia over age 50 years should have routine screening for detection of osteoporosis.

A study of prospective surveillance for inhibitors among persons with haemophilia in the United States.

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113,205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Late immune tolerance induction in haemophilia A patients.

The incidence of inhibitor development in patients with severe haemophilia A is approximately 30%. Immune tolerance induction (ITI) is commonly utilized to eradicate these antibodies and is successful in 63-100% of cases. Potential predictors of a poor outcome in ITI include a high preinduction titre, high historical peak titre, older age at start of ITI and prolonged interval from diagnosis to start of ITI. The goal of this study was to characterize the outcomes of patients from our centre who have undergone late ITI, many of whom had poor prognostic features. Medical records of patients in our centre with severe/moderately severe haemophilia A (<2% FVIII activity) and history of inhibitor were reviewed. Data were abstracted from all patients who attempted late ITI. Nine patients underwent late ITI between January 1999 and December 2011. Within this cohort, 7 (78%) patients were black, 6 (67%) were <21 years old and 4 (44%) had a family history of inhibitor. Three patients had previously received ITI unsuccessfully. To date, 4 (44%) patients are tolerized (persistently negative inhibitor titre, FVIII recovery >66% and successfully treated with FVIII products ± FVIII t(½) of >6 h). Three patients are partially tolerized (have low responding inhibitor, variable FVIII recovery and successfully treated with FVIII products). Two patients are not tolerized. Some patients with haemophilia A and long-standing inhibitors may benefit from ITI.

Physical activity and functional abilities in adult males with haemophilia: a cross-sectional survey from a single US haemophilia treatment centre.

Physical activity and functional ability are important determinants of quality of life and these metrics are affected by both haemophilia and ageing. Outside haemophilic arthropathy, risk factors leading to reduced physical activity and function in people with haemophilia (PWH) are under-explored. The purpose of this analysis was to determine risk factors for reduced physical activity and functional limitations in PWH. A secondary analysis was conducted on data indexing physical activity and functioning of 88 PWH using data originally collected as part of a cross-sectional study at a single large haemophilia treatment centre. The Framingham Physical Activities Index (PAI), the Hemophilia Activities List (HAL) and the Timed Up-and-Go Test (TUG) were the outcome measures. The World Federation of Haemophilia (WFH) orthopaedic joint score was used as a measure of arthropathy. Multiple linear regression analysis was used to assess the relationship between the outcome measures and covariates. Worsening WFH joint score was independently associated with all three outcome measures (P < 0.05). Increasing age was associated with reduced PAI and increased TUG time (P < 0.05). The HAL summary score was decreased in patients with chronic liver disease (P = 0.006). The adjusted R(2) for each model was ≤ 0.35. This study provides evidence for the relationship between arthropathy and reduced physical functioning/activity, but also highlights that much of the variation in physical functioning/activity is not explained by haemophilia-related characteristics.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged ≥ 12 years weighing ≥ 40 kg, with severe or moderately severe haemophilia B (FIX activity ≤ 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg(-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC(0-t) and AUC(0-∞) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.

Inhibitors in previously treated patients: a review of the literature.

Previously treated patients are the first patients to receive novel factor VIII products during clinical investigations under the rationale that a product with increased antigenicity is more likely to be detected in this population because of a low baseline risk of inhibitor formation compared with previously untreated patients. As clinical investigations of factor products are not typically randomized comparisons, the rate of new inhibitor formation in a clinical trial is compared with the expected rates based on prior reports. The published experience of inhibitors in previously treated patients (PTPs) informs the number of new inhibitors per cohort that are acceptable in a clinical trial. However, a single acceptable limit of new inhibitors fails to recognize the heterogeneity of inhibitors and their variable impact on clinical care. This review will discuss the published literature on epidemiology and clinical characteristics of inhibitors and possible risk factors for formation in PTPs.