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Introduction We previously showed that pharmacokinetic-guided prophylaxis ( PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII ( FVIII) levels and area under the curve ( AUC) with breakthrough bleeding have not been investigated. Aim The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Methods Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. Results During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL−1, with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding ( P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL−1 was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. Conclusion When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL−1 provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life ( HRQoL). Aim To examine the impact of prophylaxis on HRQoL from prospective clinical trials. Methods We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. Results Thirteen trials (haemophilia A [ n = 8]; haemophilia B [ n = 2]; inhibitors [ n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO- KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ- VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. Conclusion Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults. [ABSTRACT FROM AUTHOR]

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers ( HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% ( n = 64/159). Thirty-eight percent of respondents ( n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor ( n = 25; 39%) followed by the concern for bleeding ( n = 22; 34%) and issues related to vascular access in the neonate ( n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent ( n = 14) of respondents did not use more than one dose of factor replacement but 32% ( n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. [ABSTRACT FROM AUTHOR]

The phenotypic variability in haemophilia is well documented; however, the biological basis beyond factor VIII and IX activities to explain the differing clinical pictures of the disease remains unclear. It has therefore been of interest to explore other modulators of the disease's variability. Furthermore, a scoring system that reflects the multiple facets of haemophilia symptoms would be useful to compare patients via a comprehensive assessment tool. To this end, Schulman et al., created a measure known as the Haemophilia Severity Score ( HSS) as one way to compare phenotypic severity. The aim of this study was to document the differing symptomatology of haemophilia patients using the HSS. Clinical data for 178 haemophilia patients without inhibitors were reviewed and annual incidence of haemarthrosis, orthopaedic joint scores and annual factor usage calculated. Each parameter was then entered into the formula to create the HSS for haemophilia A and B patients with mild, moderate and severe factor deficiencies. Variability in the HSS for patients with the same baseline level of factor was observed for all three deficiency levels and both haemophilia types. In addition, we found that moderate and severe haemophilic B patients tended to have more morbidity based on the above calculations than the haemophilic A counterparts. The HSS is a comprehensive tool that allows for easy numerical comparison of haemophilic patients and elucidates the variable clinical presentation of the disease. The HSS could be used to stratify patients via other possible modulators of haemophilia and discover other aetiologies of the disease. [ABSTRACT FROM AUTHOR]

In haemophilia patients with well-established high-titer inhibitors, even seemingly minor acute bleeding episodes or surgical procedures may become refractory to treatment and transform into limb- or life-threatening situations. In the absence of evidence-based treatment guidelines, this article presents 10 cases of difficult to control acute and surgical bleeding and offers consensus opinions regarding their management from a panel of experienced haemophilia treaters. [ABSTRACT FROM AUTHOR]

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 AUC0-t and AUC0-∞ (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. [ABSTRACT FROM AUTHOR]

. Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low. [ABSTRACT FROM AUTHOR]

. Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease. [ABSTRACT FROM AUTHOR]

Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01-1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. [ABSTRACT FROM AUTHOR]

Prophylaxis with concentrates of factor VIII has become the standard of care for patients with severe haemophilia A because of its ability to prevent joint and other bleeding events. Recent evidence suggests that the prophylactic use of bypassing therapy – activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) – provides similar benefits to haemophilia patients with inhibitors. To assess the efficacy and safety of prophylaxis with the aPCC FEIBA, a meta-analysis was conducted of six studies and a total of 34 inhibitor patients. The mean prophylactic dose was 78.5 U kg−1, typically infused three to four times weekly. A total of 31 of 33 patients (94%) for whom bleeding data were available prior to prophylaxis experienced a decrease in the rate of haemorrhage, albeit minor in some patients, and, regardless of the type of haemorrhage measured, had on average a 63.9% reduction in bleeding episodes during FEIBA prophylaxis. In the three studies that specifically assessed all joint bleeding, the 18 patients evaluated experienced an average reduction in annual joint bleeding of 74% while on prophylactic regimens. Among the four patients in this group who received concurrent immune tolerance induction and the 14 patients treated with prophylaxis only, annual joint bleeding decreased by an average of 79% and 78%, respectively. Anamnesis following FEIBA exposure was observed in some patients but had no impact on prophylactic efficacy. No thrombotic or other complications were reported. These results suggest that the prophylactic administration of FEIBA can be an effective and safe method for reducing bleeding events in patients with haemophilia A and inhibitors. [ABSTRACT FROM AUTHOR]

The article presents several case studies to prevent bleeding and joint damage with the help of prophylaxis treatment of severe hemophilia patients. A 19 year old boy started prophylaxis at the age of seven which has reduced his joint bleeding episodes or trauma. A 21year old man diagnosed with hemophilia followed prophylaxis treatment regularly and resulted in effective state. But, the use of FVIII prophylaxis treatment by a 61 year old man with severe hemophilia was ineffective.

The emergence of a population of relatively healthy adults with severe haemophilia A presents a unique challenge for haemophilia care in the 21st century. Understanding how best to continue, restart, initiate or modify prophylaxis in younger and older adult patients is essential to optimizing their care. To elucidate practice and outcome data, a survey was sent to 23 US hemophilia treatment centers (HTCs); 10 centers responded, providing data concerning up to 145 adults (mean age of 34 years). Forty-eight patients (33%) were on regular prophylaxis when first seen at the HTC; the prophylactic regimen was modified for 22/48 (46%), often because of breakthrough bleeding. Five of 21 patients (24%) for whom data were available discontinued prophylaxis. Three of those five patients (60%) experienced increased bleeding episodes and the other two (40%) subsequently resumed regular prophylactic infusions because of the increased bleeding. Of the 77 patients not initially receiving prophylaxis for whom data were available, prophylaxis was started or resumed in all. The prophylactic regimen was modified in 57/77 patients (74%) at some point during treatment, often because of breakthrough bleeding. Of the 55 patients whose prophylactic regimens were modified for whom data were available, 22 (40%) discontinued prophylaxis. Thirteen of 20 patients (65%) for whom data were available experienced an increase in bleeding episodes and 7/18 patients (39%) who had discontinued prophylaxis and for whom data were available subsequently resumed regular prophylactic infusions because of bleeding. These findings suggest that prophylaxis prevents bleeding in adults with severe haemophilia A and that discontinuation of the prophylactic regimen is associated with increased bleeding events. [ABSTRACT FROM AUTHOR]

The article presents a meeting report on the application of factor eight inhibitor in patients with haemophilia A. The panel of clinicians are indicated to accomplish goals such as knowledge examination on the bypassing activity of factor eight inhibitor as FEIBA VH for prophylaxis and the formulation of investigational and clinical recommendations. An overview of FEIBA and its effectivity in haemophilia patients with inhibitors are also being discussed.

Recurrent haemarthrosis results in chronic synovitis and destructive arthropathy. The long-term effect of a single haemorrhage is not known. To investigate the histopathological changes following a single, but major joint haemorrhage, an animal model of massive haemarthrosis without mechanical trauma was developed and is described in this manuscript. The knee joint capsule of mice deficient in coagulation factor VIII or IX and non-haemophilic wild type mice was punctured to induce a one time, but massive haemorrhage. The single joint puncture resulted in acute haemarthrosis in both types of haemophilic mice but not in wild type mice. Subsequent to injury, the changes in the knee joints were analysed using gross, histological and radiographic assessments and compared with the uninjured knee. In addition, a novel imaging modality, micro-computed tomography, was used to document the structural damage to the joint. Our results indicate that the long-term changes classically observed in patients with advanced haemophilic arthropathy are evident following a single massive haemarthrosis. This model will allow a thorough investigation of the pathobiology of blood-induced joint disease and will be useful to test the efficacy of innovative therapeutic strategies to prevent haemophilic synovitis and arthropathy. [ABSTRACT FROM AUTHOR]

The article reports on optimizing outcomes for patients with severe hemophilia A in the U.S. It states that prophylaxis is the most effective strategy for optimizing outcomes in patients with severe hemophilia A. Primary prophylaxis can prevent the development of arthropathy, protect against other serious bleeding events, and allow patients to live full, active lives.

Orthopaedic complications are among the most disabling sequelae occurring in patients with haemophilia and inhibitors. Recurrent or refractory joint bleeds can lead to joint damage, limiting mobility and causing permanent disability. Activated prothrombin complex concentrates (aPCCs) are effective in controlling acute, intraoperative and postoperative bleeding in patients with haemophilia and inhibitors. The relatively long, dosing interval and safety profile distinguish aPCCs as a well-suited option for prophylaxis. Therefore, it is postulated that long-term routine aPCC administration will decrease the frequency of recurrent bleeds, prevent damage to normal joints, and slow the progression of existing joint disease in patients with inhibitors. To test this hypothesis, a retrospective chart audit was performed. In four treatment centres, five patients were identified who received aPCC [Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex (FEIBA®); Baxter AG, Vienna, Austria] prophylactically for ≥6 months to prevent or reduce further joint deterioration, reduce bleeding and prevent postsurgical bleeding. Median treatment duration was 15 months and included administration of >1300 doses of aPCC. Dosages ranged from 50 to 75 U kg−1 three times per week in four patients; one patient received 100 U kg−1 daily. Orthopaedic status was maintained in four patients and improved in one; the frequency of bleeding episodes was reduced in all patients. No adverse events or thrombotic complications were reported. This case series demonstrates that routine aPCC administration may be used safely and effectively to reduce the occurrence of bleeding episodes and to maintain or improve clinical joint status in some patients. [ABSTRACT FROM AUTHOR]

The development of pseudotumors represents one of the most challenging complications facing physicians who care for patients with hemophilia. The successful removal of the giant pseudotumor described in this case report was acheived by a multidisciplinary team and demonstrates that this approach, albeit associated with significant risk, may be curative. [ABSTRACT FROM AUTHOR]