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Introduction Cardiovascular events in patients with inherited bleeding disorders are challenging to manage. The risk of bleeding secondary to antithrombotic treatment must be balanced against the risk of thrombosis secondary to haemostatic therapy. Methods Patients with inherited bleeding disorders with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or atrial fibrillation (AF) from a single centre (2010-2018) are included. Results A total of 11 patients undergoing CABG (n = 3), PCI (n = 5) or with AF (n = 3) and a diagnosis of haemophilia A (n = 8), haemophilia B (n = 1), factor XI deficiency (n = 1) and von Willebrand disease (n = 1) managed by a multidisciplinary team are reported. In patients undergoing CABG, factor levels were normalized for 7-10 days with trough levels of 70-80% with severe patients continuing high-dose factor prophylaxis (trough 20-30%) three weeks post-operatively with daily aspirin. In a patient with mild haemophilia A and an inhibitor, recombinant factor VIIa dosing was monitored with thromboelastometry. For PCI, a 3rd-generation drug-eluting stent with one month of dual antiplatelet therapy in addition to high-dose prophylaxis as needed was preferred. Patients with AF and severe haemophilia did not receive antithrombotic treatment, and a thrombin generation assay was used to guide heparin dosing in mild haemophilia. Conclusion Our experience demonstrates the importance of interdisciplinary communication to identify strategies that decrease the risk of bleeding and thrombosis. The use of extended, increased intensity prophylaxis facilitated antiplatelet therapy. Global assays may help balance the intensity of haemostatic and antithrombotic treatment.

Summary Inhibitor formation in non-severe haemophilia A is a life-long risk and associated with morbidity and mortality. There is a paucity of data to understand real-world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non-severe haemophilia A in seven London haemophilia centres. In the 2-year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy-nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had ‘high-risk’ F8 genotypes. In patients with ‘standard-risk’ F8 genotypes treated on-demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after ‘high-risk’ treatment episodes. In patients with ‘standard-risk’ F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of ‘high-risk’ F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non-severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism.

WOS: 000455039400008, PubMed ID: 30362288, Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg(-1), VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery., Baxalta (Shire, Lexington, MA, USA), Research was funded by the Sponsor, Baxalta (part of Shire, Lexington, MA, USA). The authors would like to thank the patients for their participation in the study, C. von Auer (Ill. Med. Klinik der Johannes Gutenberg-Universitat, Universitatsmedizin Mainz, Mainz, Germany) for her contributions as a principal investigator for the study, A. Grigorian (Shire, Westlake Village, CA, USA) for writing the clinical study report (CSR), B. Ploder (Shire, Vienna, Austria) for statistical analysis of the data and ensuring its accuracy within the CSR and manuscript, as well as E. Biguzzi and S. Siboni (Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) for their contributions to the conduct of the study. Under the direction of the authors, writing/editorial support for this manuscript was provided by C. Wing, PhD, employee of Excel Medical Affairs (Southport, CT, USA), and was funded by Baxalta (part of Shire, Lexington, MA, USA). Initial support for this manuscript was provided by C4 MedSolutions (Yardley, PA, USA), a CHC Group Company, funded by Baxalta (part of Shire, Lexington, MA, USA). All authors read the scientific content of this manuscript and critically revised it. Although employees of the sponsor were involved in the design, collection, analysis, interpretation, fact-checking of information, and coordination and collation of comments, the development of content of this manuscript, the interpretation of the data, and the decision to submit the manuscript for publication in JTH was made by the authors independently. All authors had access to the clinical study data.

Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty-eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study.

Introduction and Objectives: Neutralizing antibodies (inhibitors) directed against the FVIII protein may increase the bleeding frequency and compromise the management of bleeding episodes in nonsevere haemophilia A patients. The median annual bleeding frequency in patients without inhibitors is described to be 0 (IQR 0-3) for mild haemophilia and 1 (IQR 0-13) for moderate haemophilia. The aim of this study was to evaluate the burden of bleeding and to describe the treatment strategies that are used for bleeding episodes in a large group of unselected inhibitor patients with nonsevere haemophilia A. Materials and Methods: We included all inhibitor patients from the INSIGHT study, an international multicentre cohort study including all 2709 nonsevere HA patients (FVIII:C 2-4 IU/dL) that received at least 1 exposure to FVIII concentrate between 1980-2011. Data of the 1st inhibitor period were analyzed. Results: We included 107 nonsevere HA inhibitor patients (median baseline FVIII:C 9 IU/dL (IQR 6-16); median age of 38 years (IQR 15-61)). A high titre inhibitor (> 5 BU/mL) was present in 57 (53%) patients. In 30 (28%) patients the FVIII:C level was decreased ≤1 IU/dL. Eighty-nine patients (83%) received treatment for bleeding episodes. Most patients had spontaneous bleeds (n = 49, 46%); a higher proportion of high titre patients had spontaneous bleeds compared to low titre patients (83% vs. 53%, relative risk (RR) 2.7, 95% confidence interval (CI) 1.3-5.8). The median number of bleeding episodes per inhibitor year was 2 (IQR 1-5); this did not differ between patients with FVIII:C ≤ 1 IU/dL and those with measurable FVIII levels (p = 0.5), patients with low titre and high titre inhibitors (p = 0.5) and patients receiving eradication treatment or not (p = 0.7). In order to treat bleedings, FVIII concentrate was used in 59 patients (55%), FVIII bypassing agents in 50 (47%) and desmopressin in 18 patients (17%). Desmopressin was used more often in patients with remaining circulating FVIII:C levels compared to patients with a FVIII:C ≤ 1 IU/dL and in patients without eradication treatment compared to patients with eradication treatment (25% vs. 3%; RR 7.4, CI 1.0-53.5 and 25% vs. 0%; RR 14.0, CI 0.9 - 224.6, respectively). Conclusion: Inhibitor development in nonsevere HA patients aggravates the burden of bleeding with the majority (83%) of the patients needing treatment for bleeding episodes, at a median of 2 bleeding episodes per year.

Factor VIII Inhibitor Bypassing Activity (FEIBA) can effectively achieve haemostasis in haemophilia patients with inhibitors. Further evaluation of FEIBA in surgical settings is of significant interest considering the relatively limited prospective data published to date. The aim of the study is to evaluate the perioperative efficacy and safety of FEIBA in haemophilia patients with inhibitors. Haemophilia patients with inhibitors who underwent surgical procedures and received FEIBA for perioperative haemostatic control were prospectively enrolled in an open-label, noninterventional, postauthorization study [SURgical interventions with FEIBA (SURF)]. Outcome measures included haemostatic efficacy, safety, FEIBA exposure and blood loss associated with the perioperative use of FEIBA. Thirty-five surgical procedures were performed at 19 centres worldwide in patients with congenital haemophilia A, congenital haemophilia B, or acquired haemophilia A. Haemorrhagic risk was severe in 37.1% (13 of 35) of the procedures, moderate in 25.7% (9 of 35) and mild in 37.1% (13 of 35). One moderate risk surgery was excluded from the efficacy analyses because it did not meet all protocol requirements. Haemostasis was judged to be 'good' or 'excellent' in 91.2% (31 of 34) of surgical procedures and 'fair' in 8.8% (3 of 34). Among the 12 adverse events, three were serious adverse events (SAEs), two of which were unrelated to FEIBA therapy; one SAE, a clot in an arteriovenous fistula, was deemed to be possibly related to therapy. This prospective investigation confirms that FEIBA can be safely and effectively used when performing surgical procedures in haemophilia patients with inhibitors.

A growing number of publications have described the efficacy and safety of FEIBA as a first-line haemostatic agent for surgical procedures in haemophilia A patients with high-responding FVIII inhibitors. The aim of this study was to provide practical guidance on patient management and selection and also to communicate a standardized approach to the dosing and monitoring of FEIBA during and after surgery. A consensus group was convened with the aims of (i) providing an overview of the efficacy and safety of FEIBA in surgery; (ii) sharing best practice; (iii) developing recommendations based on the outcome of (i) and (ii). To date there have been 17 publications reporting on the use of FEIBA in over 210 major and minor orthopaedic and non-orthopaedic surgical procedures. Haemostatic outcome was rated as 'excellent' or 'good' in 78-100% of major cases. The reporting of thromboembolic complications or anamnestic response to FEIBA was very rare. Key to the success of FEIBA as haemostatic cover in surgery is to utilize the preplanning phase to prepare the patient both for surgery and also for rehabilitation. Haemostatic control with FEIBA should be continued for an adequate period postoperatively to support wound healing and to cover what can in some patients be an extended period of physiotherapy. Published data have demonstrated that FEIBA can provide adequate, well tolerated, peri and postoperative haemostatic cover for a variety of major and minor surgical procedures in patients with haemophilia A. The consensus recommendations provide a standardized approach to the dosing and monitoring of FEIBA.

Treatment studies in haemophilia focus on joint bleeds; however, some 10-25% of bleeds occur in muscles. This review addresses management of muscle haematoma in severe haemophilia, defines gaps in the published evidence, and presents a combined clinician and physiotherapist perspective of treatment modalities. The following grade 2C recommendations were synthesized: (i) Sport and activity should be based on individual factor levels, bleeding history and physical characteristics, (ii) Musculoskeletal review aids the management of children and adults, (iii) 'Time to full recovery' should be realistic and based on known timelines from the healthy population, (iv) Diagnosis should be carried out by both a clinician and physiotherapist, (v) Severe muscle bleeds should be treated similarly to surgical patients: a 50% trough for 10-14 days followed by high-level prophylaxis, (vi) Protection, rest, ice, compression and elevation should be implemented in the acute stage, and (vii) Physiotherapy and rehabilitation should be divided into: control of haemorrhage (phase 1); restoration of Range of Movement (ROM) and strength (phase 2); functional rehabilitation and return to normal living (phase 3). Recommendations specifically for inhibitor patients include: (i) Minor to moderate bleeds should be managed by home-treatment within 1 h of bleed onset using either one injection of rFVIIa 270 μg kg(-1), or two to three injections of rFVIIa 90 μg kg(-1) (2-3 h intervals), or FEIBA 50-100 U kg(-1) (repeated at 12-hourly intervals, if necessary) and (ii) Severe muscle bleeds should be supervised by the treatment centre and include bypassing agents until clinical improvement is observed.

Summary. Total knee replacement (TKR) is a well recognized treatment for haemophilic arthropathy. Successful haemostasis can be achieved by bolus doses or continuous infusion (CI) using either recombinant (r) or plasma-derived (pd) factor IX (FIX). We retrospectively analysed our experience of factor replacement to cover TKR in haemophilia B patients and explored factors related to FIX use during surgery. Between 2000 and 2010, 13 primary TKRs were performed in 11 haemophilia B patients. Operations were performed by the same surgeon using standard techniques. Median age was 58 years (42–79). An adjusted CI protocol was used for 5 days followed by bolus doses. FIX:C was maintained at 100 IU dL−1 in the immediate postoperative period. There was no excess haemorrhage. There was no evidence of thrombosis or infection. All patients received mechanical thromboprophylaxis and only one chemical. CI was used in seven cases. Ten patients received pdFIX. Median hospital stay was 14 days (8–17). Median factor usage was 999 IU kg−1 (768–1248). During CI, factor consumption was 695 IU kg−1, 691 IU kg−1 and 495 IU kg−1 for BeneFix®, Replenine® and Haemonine, respectively. Clearance of both pdFIX and rFIX reduced during CI. All operations were uncomplicated. The decreased clearance in the CI setting reduced the amount of FIX required to maintain a therapeutic level. This reduction was greater with pdFIX and may be related to pharmacokinetic differences between pdFIX and rFIX. Given the excellent safety profile of the pdFIX products, CI of FIX and particularly pdFIX is safe, efficacious and convenient.

Increasing evidence indicates that factor VIII (FVIII) inhibitor bypassing agents (FEIBA® and NovoSeven®) can provide effective peri-operative haemostasis in haemophilia patients with high-responding inhibitors. We report the collected experience of all major and minor surgeries, conducted between December 1998 and September 2008, at four UK haemophilia Comprehensive Care Centres with FEIBA® as the first-line bypassing agent in patients with inhibitors. A total of 26 surgical procedures were performed in 18 patients of ages 34-83 years including five patients with acquired FVIII inhibitors. A single pre-operative infusion of FEIBA was followed by 6-12 h interval dosing for major surgeries at the discretion of the physician to approximate a maximum of 200 U kg(-1) day(-1), with tapering when postoperative haemostasis and wound healing permitted. Haemostatic outcomes were retrospectively reviewed against European consensus thresholds for blood loss and duration of treatment compared with expectations for equivalent procedures in non-inhibitor patients. Peri-operative haemostatic outcome with FEIBA was rated excellent or good in 78% of 18 major surgeries in 12 patients, including 11 major orthopaedic procedures. Haemostatic outcome was rated excellent in all seven procedures in five patients with acquired FVIII inhibitors and in all eight minor surgical procedures in six patients. FEIBA was well tolerated with no intra-operative haemostatic complications. A single, transient postoperative thrombotic adverse event occurred in a patient with cerebrovascular disease. This case series adds significantly to existing evidence that FEIBA can provide adequate, well-tolerated, peri-operative haemostatic cover for a wide variety of major and minor surgical procedures.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Background: Hepatitis C is a major co-morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long-term follow-up after treatment. Objectives: To assess the effect of interferon-based (IFN-based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end-stage liver disease (ESLD) after completing antiviral therapy. Patients and methods: In a multicenter cohort study, 295 treatment-naive hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan- Meier survival table. Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co-infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8-20.5], and combination therapy (IFN and ribavirin OR 3.7,95% CI: 1.7-8.4), PegIFN and ribavirin (OR 4.2,95% CI: 1.8-9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%. Conclusions., Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.

Summary Acquired haemophilia is a rare phenomenon and prompt diagnosis is essential for successful treatment. Early laboratory detection could minimize its potentially devastating consequences and reduce mortality but when a masking element such as anticoagulant therapy is present, delay in diagnosis is not uncommon. A prolonged activated partial thromboplastin time (APTT) may be falsely attributed to warfarin alone, particularly when it is associated with oral anticoagulant overdose. We describe two patients on treatment with warfarin who presented with a bleeding diathesis and disproportionately prolonged APTT, which led to the diagnosis of antibodies directed against factor VIII.

Prior to 1990, many patients with inherited bleeding disorders were infected with hepatitis C virus (HCV). This study assessed the risk of end-stage liver disease (ESLD) in patients with hemophilia with chronic hepatitis C. Patients were infected between 1961 and 1990 and were followed up to August 2005. Of 847 anti-HCV+ patients, 160 (19%) spontaneously cleared HCV and 687 (81%) developed chronic hepatitis C. Coinfection with HIV was present in 210 patients. After 35 years of infection the cumulative incidence of ESLD was 11.5% (95% CI, 8.2%-14.8%) in HIV− patients and 35.1% (95% CI, 29.2%-41.0%; P < .001) in patients coinfected with HIV. Independent risk factors of ESLD were HIV coinfection (hazard ratio 13.8; 95% CI, 7.5-25.3), older age at infection (hazard ratio 2.3 per 10 years; 95% CI, 2.0-2.8), alcohol abuse (hazard ratio 4.9; 95% CI, 2.5-9.6), and presence of HCV genotype 1 (hazard ratio 2.2; 95% CI, 1.1-4.2). With longer duration of HCV infection, the risk of developing ESLD is emerging in patients with inherited bleeding disorders. Risk factors for rapid progression to ESLD are alcohol abuse, coinfection with HIV, older age at infection, and presence of HCV genotype 1.

The practice of prophylactic treatment of boys with severe haemophilia has been evaluated in our centre. Prophylaxis was started at the median age of 3.7 years (range 0.4-12.7 years) in 38/41 children (93%) under 17 years of age. Median follow-up was 4.1 years (range 0.4-12.7 years). The criteria of primary prophylaxis according to the definition by the European Paediatric Network of Haemophilia Management was fulfilled by 9/38 (24%). Although a majority [76%, 29/38] of the children started prophylaxis after a median number of joint bleeds of 3.5, 70% of the children in this group had clinical joint scores of 0. Intravenous catheter insertion was required at a median age of 15.5 months (range 5-36 months) in 21% of the children, resulting in a catheter infection rate of 1.74 per 1000 catheter days. None developed an inhibitor on prophylaxis and three patients who had low-titre inhibitors (< 5 Bethesda units) prior to prophylaxis had undetectable inhibitors after prophylaxis. The home-treatment training programme required considerable time and cost. As a result, 87% of the children used peripheral venous access and hospital visits declined as prophylaxis became established. Parents' incentives for prophylaxis were that the children undertook many physical activities and sports previously not recommended, there was less parental anxiety and an overall improvement in the quality of life for the whole family.

AIM—This study describes the long term follow up of haemophilic patients infected with hepatitis C virus (HCV) between 1961 and 1985. METHODS—Clinical and treatment records from 310 patients with inherited coagulation disorders treated with blood product before 1985 were reviewed. Standard survival analysis methods were used to model progression to liver failure and death. RESULTS—A total of 298/305 (98%) patients tested were anti-HCV positive. Twenty seven (9%) individuals consistently HCV polymerise chain reaction negative were considered to have cleared the virus. By 1 September 1999, 223/310 (72%) were alive, 26 (8%) had died a liver related death, and 61 (20%) had died from other, predominantly human immunodeficiency virus (HIV) related, causes. Kaplan-Meier progression rates to death from any cause and liver related deaths 25 years after exposure to HCV were 47% (95% confidence intervals (CI) 34-60) and 19% (95% CI 10-27), respectively. After 13.3 years from 1985, by which time all patients had seroconverted to HIV, progression rates to death from any cause and liver related deaths were, respectively, 8% (95% CI 4-13) and 3% (95% CI 0.4-6) for those HIV negative, and 57% (95% CI 48-66) and 21% (95% CI 13-31) for those HIV positive (p=0.0001). Using Cox proportional hazard models, the adjusted relative hazard of death for individuals coinfected with HIV compared with those infected with HCV alone was 19.47 (95% CI 9.22-41.10), 0.99 (95% CI 0.39-2.53), 3.47 (95% CI 1.40-8.63), and 9.74 (95% CI 3.91-24.26) for the age groups at infection 10-19 years, 20-29 years, and >30 years, respectively, compared with the age group

OBJECTIVES: Many haemophilic individuals infected with HIV died before receiving antiretroviral therapy (ART). Most who remain alive are chronically infected with hepatitis C virus (HCV), which has implications for their prognosis and choice of ART. The clinical status of a cohort of HIV-positive haemophilic men is reported together with their response to highly active antiretroviral therapy (HAART). DESIGN: Longitudinal cohort study. SETTING: A comprehensive care haemophilia centre. PATIENTS: A group of 111 haemophilic men who seroconverted to HIV in the period 1979 to 1985. RESULTS: The cohort has been followed since 1979. By 30 April 1999, 57 of the 111 men had developed AIDS and 65 had died: Kaplan-Meier rates of 57.0% [95% confidence interval (CI) 46.9-67.0) and 65.1% (95% CI 52.7-77.4) by 19.5 years, respectively. AIDS rates have declined since 1997 but death rates have remained high, largely owing to deaths from non-HIV-related causes. Thirty-five patients remain alive and under follow-up at the clinic. The 28 men who had received ART had lower CD4 cell counts than the seven patients who had not received ART, but the two groups were otherwise similar. In total, 21 patients are known to have started HAART while under care at the centre. By 10-12 months after starting HAART, viral loads dropped by 2.06 log10 copies/ml and CD4 cell counts increased by 60 x 10(6) cells/l. In 10 out of 18 patients with viral loads initially > 400 copies/ml, a viral load below this level was attained; four had changed therapy at the time. CONCLUSIONS: While the decision to initiate HAART in haemophilic men should be made carefully because of the possible adverse events, our results suggest that a good response rate was achieved in this group of men.

A retrospective study of the natural history of factor VIII inhibitors in haemophilia A patients experienced in a single comprehensive haemophilia centre over three decades is reported. 431 haemophilia A patients of all severities have been followed-up for a total of 5626 patient-years. The frequency of inhibitors was 10% in the severe haemophilia A patients and 37% occurred in children 5 BU). An 8-year (1987–95) inhibitor-free period was seen during which all previously untreated patients were treated with an intermediate-purity factor VIII concentrate. A moderate haemophiliac with a misense mutation that has not been described in association with inhibitor is reported. Six HIV-positive patients preserved their antibody response to factor VIII even at the advanced stage of their disease.

Summary. Pegylated interferon (pegIFN)/ribavirin has been established as the treatment of choice for chronic hepatitis C in HIV co-infected individuals [1–3]. We report the case of an individual who was well prior to treatment, but was diagnosed with tuberculous adenitis after receiving 12 weeks of pegIFN/ribavirin therapy. The association of pegIFN and ribavirin therapy with tuberculosis (TB) has not been described previously.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

Background & Aims: Patients with inherited bleeding disorders are an interesting group to study the long-term course of chronic hepatitis C virus (HCV) infection, because of their uniform mode of infection and reliable follow-up. Our aim was to assess the long-term occurrence of adverse liver-related events in these patients. Methods: The occurrence and determinants of end-stage liver disease (ESLD) were assessed using retrospective data of 863 HCV infected patients with inherited bleeding disorders from the Netherlands and the UK. Results: Median follow-up since HCV infection was 31 years, while 30% of patients had > 35 follow-up years. Nineteen percent of patients spontaneously cleared the virus and 81% developed chronic HCV infection. Of the 700 patients with chronic HCV, 90 (13%) developed ESLD. Hepatocellular carcinoma (HCC) was diagnosed in 3% of patients with chronic HCV, 41% of which occurred in the last six years. Determinants of ESLD development were age at infection (hazard ratio (HR) 1.09 per year increase), HIV co-infection (HR 10.85), history of alcohol abuse (HR 4.34) and successful antiviral treatment (HR 0.14). Of the 487 patients who were still alive at the end of follow-up, 49% did not undergo optimal conventional antiviral treatment. Conclusions: After over 30 years of HCV infection, ESLD occurred in a significant proportion of patients with inherited bleeding disorders. HCC appears to be an increasing problem. There is a significant potential for both conventional and new antiviral treatment regimens to try and limit ESLD occurrence in the future.

Summary. Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group.

BackgroundIntervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/principal findingsWe have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-γ, IL-2, TNF-α production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8(+) T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.ConclusionsOur results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption.

In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.

SummaryUse of high purity and recombinant factor VIII (FVIII) concentrates has been thought to be associated with an increased incidence of FVIII inhibitors in patients with severe haemophilia A. Comparison with comparable historical control groups has suggested that the true incidence of inhibitors in patients with severe haemophilia A was ~20-25%, similar to the incidence seen with new high purity and recombinant FVIII products.We have conducted a study of inhibitor development in a cohort of 37 boys with severe haemophilia A (VIII: C

Treatment of patients with bleeding disorders (especially those with hemophilia) with blood products has been associated with infections with blood-borne viruses. Of these, hepatitis B and C viruses (HBV and HCV, respectively) and the human immunodeficiency virus (HIV) have created major health problems. Although virus-inactivation procedures have virtually eliminated these viruses from newer factor concentrates since 1985, the risk remains in developing countries where there is no ready access to these concentrates. Although a few of these countries have established their own fractionation facilities and in others the respective governments make concentrates available, the large majority of countries still face the problems of blood-borne infections. HCV will invariably lead to liver damage and many hemophiliacs who were exposed to the HCV virus will succumb to cirrhosis. Only approximately 10% of hemophilic patients infected with HCV will clear the infection naturally. Coinfection with HIV shortens the life expectancy. The HIV epidemic in hemophiliacs began in the mid-1980s. Patients in developed countries were especially affected because they were predominantly treated with factor concentrates that were manufactured from thousands of blood donors. Hemophiliacs in developing countries have considerably less HIV infection, although it does exist and depends largely on the source of the plasma fractions. Progress has been made not only in the purification of factor concentrates, but also in the understanding of the HIV virus and in the development of antiretroviral treatment modalities. However, there are still several challenges in delivering antiretroviral treatment that must be addressed before the full impact of these transmitted infections is known.

Summary Background Low serum albumin concentration is associated with short-term survival in individuals with HIV-1. However, few investigators have assessed whether individuals with a low serum albumin concentration have delayed progression to AIDS, or survive in the long term. We aimed to assess the relation between markers of liver function and progression to AIDS and death in individuals with haemophilia infected with HIV-1 and hepatitis C virus. Methods We measured markers of liver function and took CD4 counts every 3 months in 111 patients registered at the Royal Free Hospital Haemophilia Centre, London, UK. HIV RNA concentrations were measured yearly and then every 3–6 months from 1996. We used Cox's regression models to assess the independent prognostic value of these markers for AIDS and death. Findings As a fixed covariate, albumin concentrations measured shortly after HIV-1 seroconversion were associated with risk of AIDS (relative hazard 0·91 [95% CI 0·84–1·00], p=0·04) and death (0·89 [0·82–0·96], p=0·004) over a 15-year period. These findings were independent of the CD4 count and HIV-1 RNA concentration. As a time-updated covariate, after adjustment for CD4 count and HIV-1 RNA concentrations, albumin was not associated with progression to AIDS (0·96 [0·90–1·01], p=0·13), but was strongly associated with death (0·88 [0·84–0·93], p Interpretation Low concentrations of albumin in individuals infected with HIV-1 could indicate a poor outlook and should therefore prompt concern at any stage of infection.

The first HIV seroconversion in the United Kingdom in a man with haemophilia was in 1979.1 After HIV was identified, measures were taken to remove the risk of HIV transmission via blood products, and since 1986 no HIV infections have occurred through this route in the developed world. The epidemic is now 25 years old in haemophilic men. Although the introduction of highly active antiretroviral therapy (HAART) has altered the course of HIV infection, many haemophilic men died before this became available. It is important to monitor those remaining alive to determine their long term outcomes and to assess the impact of coinfection with hepatitis C virus. The Royal Free Hospital haemophilia cohort, consisting of 111 men with haemophilia infected with HIV after treatment with contaminated clotting factor concentrates (median age 22 (range 2-77) years at infection), has been described previously.2 All are coinfected with hepatitis C virus. Follow-up time—calculated from seroconversion date to the date of death, last clinic visit (for those lost to follow-up), …

The risk of acquiring diseases from transfusion of blood and blood products is well recognized and the issue of parvovirus in haemophiliacs is not a new one. We report two patients with haemophilia acquiring iatrogenic parvovirus B19 infection, resulting in life-threatening sepsis in one, and immunocompetent adult. Over the last 10 years there has been great progress in manufacturing safer products with regard to enveloped viruses such as HIV, hepatitis B and C. A recent outbreak across Europe of hepatitis A in haemophiliacs treated with plasma-derived factor VII concentrates has made haemophilic treaters concerned about the known (parvovirus B19 and hepatitis A) and the unknown non-lipid enveloped viruses that may be contained in the clotting factor concentrates, because these are resistant to the existing viral inactivating techniques. The possibility of HIV itself mutating into a non-lipid enveloped virus emphasizes the need to seek and use safer products.

Abstract 3160 Poster Board III-97 The major challenges in acquired bleeding disorders are accurate assessment of bleeding risk and subsequent effective correction of the haemostatic imbalance without increasing the risk of thrombotic complications. The response to Fresh Frozen Plasma (FFP) is extremely variable when used in acquired bleeding disorders. The administration of higher doses of FFP is more effective (Chowdhury et al., Br J Haematology. 2004 Apr; 125(1):69-73), but is limited by the potential risk of fluid overload. In addition, as with the use of all blood products, the risk of transmitting infection and concerns regarding allergic reactions, anaphylaxis and transfusion-related lung injury remain. With the increasing availability of prothrombin complex concentrates (PCCs), it has become possible to give a defined dose of factor II, VII, IX, X and proteins C & S in a small volume. Its efficacy has been well described in patients requiring warfarin reversal, but the indication for its use in other acquired bleeding disorders is less clear and data published on the subject is very limited. Concerns remain regarding the thrombotic risk associated with its use and, as a plasma-derived product, there is also the potential of transmitting blood borne infections. Here we present our two-year experience of the use of PCCs in a wide range of acquired coagulopathies. We collected retrospective data on a total of 200 (n=200) administration events, which we subdivided as follows: (1) Warfarin reversal (n=54), (2) Gastrointestinal bleeding on the background of coagulopathy secondary to chronic liver disease (n=62), (3) Liver transplantation complicated by massive blood loss or renal impairment requiring volume restriction (n=31), (4) Massive haemorrhage (n=10), (5) Coagulopathy due to underlying malignancy (n=10), (6) Correction of coagulopathy prior to procedures (n=20), (7) Miscellaneous (n=13). Dosing of PCCs was decided based on weight of patient, severity of acquired coagulopathy, rate of blood loss and underlying pathology. If required the PCCs were administered in conjunction with fibrinogen concentrate, blood products (packed red cells, platelets, FFP, cryoprecipitate) and antifibrinolytic agents such as aprotinin or tranexamic acid. Our PCC dosing regime of 20 -30 units/kg usually led to an improvement in prothrombin time (PT) and international normalised ratio (INR) in all the above listed clinical settings. No excessive blood loss was noted during the procedures for which PCCs were given. In addition, we did not see a significant increase in thrombotic complications in our cohort of patients, but these findings have to be confirmed in larger studies. At our institution, patients requiring warfarin reversal with an INR >4.0 receive a universal dose of 30u/kg of PCCs based on a previous study (Gatt et al., J. Thrombosis and Haemostasis. 2009 Jul; 7(7); 1123-7), which demonstrated that sufficient thrombin generation is achieved with this dose and the retrospective analysis of our clinical data supports this. In patients with acute and chronic liver failure, the capacity to generate thrombin is probably not significantly impaired in steady state despite a prolonged PT and INR (Gatt et al., Blood, vol.112, No. 11, abstract 1826). However, these patients are more vulnerable to disturbances caused by major blood loss requiring large volume transfusion. We found that administration of PCC in this setting led to improvement of prothrombin time/INR and clinical outcome. We were able to correlate these findings to improvement in the thromboelastogram curves in patients undergoing liver transplant. We conclude that use of PCCs and their dosing must be tailored to the clinical setting. Administration of PCCs can be considered when rapid correction of clotting factors to haemostatic levels is required and/or if there is a significant restriction to volume that can be safely transfused. A comprehensive approach to the management of acquired coagulopathies should also include the addition of FFP, cryoprecipitate, fibrinogen concentrate, antifibrinolytics and recombinant factor VIIa. The correlation between bleeding tendency and standard coagulation tests remains unclear and has to be further investigated to help with future changes of clinical practice. Disclosures No relevant conflicts of interest to declare.