HaemophiliaVolume 23, Issue 4 p. 511-520 Review Article Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia A United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) guideline J. Hanley, Corresponding Author J. Hanley john.hanley@nuth.nhs.uk Haemophilia Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK Correspondence: John Hanley, Haemophilia Centre, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. Tel.: 0191 282 4159; fax: 0191 282 0814; e-mail: john.hanley@nuth.nhs.ukSearch for more papers by this authorA. McKernan, A. McKernan Department of Haematology, Derby Hospitals NHS Foundation Trust, Derby, UKSearch for more papers by this authorM. D. Creagh, M. D. Creagh Haemophilia Centre, Royal Cornwall Hospitals NHS Trust, Truro, UKSearch for more papers by this authorS. Classey, S. Classey Haemophilia Centre, Guys and St. Thomas' NHS Foundation Trust, London, UKSearch for more papers by this authorP. McLaughlin, P. McLaughlin Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authorN. Goddard, N. Goddard Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authorP. J. Briggs, P. J. Briggs Haemophilia Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorS. Frostick, S. Frostick Institute of Translational Medicine, University of Liverpool, Liverpool, UKSearch for more papers by this authorP. Giangrande, P. Giangrande orcid.org/0000-0001-5408-3719 Haemophilia Centre, Churchill Hospital, Oxford, UKSearch for more papers by this authorJ. Wilde, J. Wilde Haemophilia Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UKSearch for more papers by this authorJ. Thachil, J. Thachil Haemophilia Centre, Manchester Royal Infirmary, Manchester, UKSearch for more papers by this authorP. Chowdary, P. Chowdary orcid.org/0000-0002-6690-8586 Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authoron behalf of the Musculoskeletal Working Party of the UKHCDO, the Musculoskeletal Working Party of the UKHCDOSearch for more papers by this author J. Hanley, Corresponding Author J. Hanley john.hanley@nuth.nhs.uk Haemophilia Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK Correspondence: John Hanley, Haemophilia Centre, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. Tel.: 0191 282 4159; fax: 0191 282 0814; e-mail: john.hanley@nuth.nhs.ukSearch for more papers by this authorA. McKernan, A. McKernan Department of Haematology, Derby Hospitals NHS Foundation Trust, Derby, UKSearch for more papers by this authorM. D. Creagh, M. D. Creagh Haemophilia Centre, Royal Cornwall Hospitals NHS Trust, Truro, UKSearch for more papers by this authorS. Classey, S. Classey Haemophilia Centre, Guys and St. Thomas' NHS Foundation Trust, London, UKSearch for more papers by this authorP. McLaughlin, P. McLaughlin Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authorN. Goddard, N. Goddard Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authorP. J. Briggs, P. J. Briggs Haemophilia Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorS. Frostick, S. Frostick Institute of Translational Medicine, University of Liverpool, Liverpool, UKSearch for more papers by this authorP. Giangrande, P. Giangrande orcid.org/0000-0001-5408-3719 Haemophilia Centre, Churchill Hospital, Oxford, UKSearch for more papers by this authorJ. Wilde, J. Wilde Haemophilia Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UKSearch for more papers by this authorJ. Thachil, J. Thachil Haemophilia Centre, Manchester Royal Infirmary, Manchester, UKSearch for more papers by this authorP. Chowdary, P. Chowdary orcid.org/0000-0002-6690-8586 Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UKSearch for more papers by this authoron behalf of the Musculoskeletal Working Party of the UKHCDO, the Musculoskeletal Working Party of the UKHCDOSearch for more papers by this author First published: 30 March 2017 https://doi.org/10.1111/hae.13201Citations: 57Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume23, Issue4July 2017Pages 511-520 RelatedInformation

HaemophiliaVolume 19, Issue 2 p. e96-e97 Letter to the Editor Orthotopic liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor from an antithrombin-deficient cadaveric donor R. Gregg, R. Gregg West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorW. Lester, W. Lester West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorS. Bramhall, S. Bramhall Liver Transplant Unit, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorJ. Wilde, Corresponding Author J. Wilde West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UK Correspondence: Jonathan Wilde, West Midlands Adult Haemostasis and Thrombosis Centre, 3rd Floor Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH Birmingham, UK. Tel.: 0121 627 2353; fax: 0121 697 8497; e-mail: [email protected]Search for more papers by this author R. Gregg, R. Gregg West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorW. Lester, W. Lester West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorS. Bramhall, S. Bramhall Liver Transplant Unit, Queen Elizabeth Hospital, Birmingham, UKSearch for more papers by this authorJ. Wilde, Corresponding Author J. Wilde West Midlands Adult Haemostasis and Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UK Correspondence: Jonathan Wilde, West Midlands Adult Haemostasis and Thrombosis Centre, 3rd Floor Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH Birmingham, UK. Tel.: 0121 627 2353; fax: 0121 697 8497; e-mail: [email protected]Search for more papers by this author First published: 18 February 2013 https://doi.org/10.1111/hae.12086Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume19, Issue2March 2013Pages e96-e97 RelatedInformation

til Steril 2004; 82: 735–7. 7 Battaglia C, Regnani G, Giulini S, Madgar L, Genazzani AD, Volpe A. Severe intraabdominal bleeding after transvaginal oocyte retrieval for IVF-ET and coagulation factor XI deficiency: a case report. J Assist Reprod Genet 2001; 18: 178– 81. 8 James AH. More than menorrhagia: a review of the obstetric and gynaecological manifestations of bleeding disorders. Haemophilia: J World Fed Hemophilia 2005; 11: 295–307. 9 Fatum M, Ozcan C, Simon A, Lewin A, Laufer N. The safety of ultrasound-guided oocyte pick-up in IVF patients with haemostatic disorders. Eur J Obstet Gynecol Reprod Biol 2008; 137: 259–61.

Prior to the introduction of viral inactivation procedures, people with haemophilia and other hereditary coagulation factor deficiencies were at substantial risk of acquiring hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection from factor concentrates. Usually, HBV infection is cleared by the host’s immunological response, but the majority of HCV and all HIV infections evade immune eradication and the host becomes chronically infected. In around 20–30% of cases, HCV infection can progress to cirrhosis, culminating in end-stage liver disease or hepatocellular carcinoma (HCC) [1]. Liver transplantation is the treatment of choice for patients with end-stage liver disease as well as for those with small HCC [2]. The outcomes of liver transplantation in general are good with 1-year survival approaching 90% and 5-year survival reaching 75% in some centres [3]. This successful outcome coupled with an increase in liver disease in general has led to an increased demand for transplantation. Indeed, the number of patients waiting for liver transplantation in the United Kingdom has increased from 202 in 2002 to 510 in 2011 [4]. However, as the number of patients needing transplantation increases, so does the mortality on the waiting list. An estimated 20% of patients assessed as suitable for transplantation will die whilst waiting for a new liver [4]. To address this problem, the transplant community has employed a number of strategies to increase the supply of donor livers, which would permit an increased rate of transplantation and reduce waiting list mortality [5]. This has included the use of older donors, donors with increasing degrees of liver steatosis, and donation after cardiac death. A further group of so-called ‘marginal’ donors are those that have evidence of previous, or indeed current, viral hepatitis. The suitability of using these donors, or donors with HIV infection, is discussed below and summarized in Table 1.

. Under the auspices of the United Kingdom Haemophilia Doctors Organisation (UKHCDO) the UK Comprehensive Care Haemophilia Centres (CCCs) have undergone a three yearly formal audit assessment since 1993. This report describes the evolution of the audit process and details the findings of the most recent audit round, the sixth since inception. The audit reports from the 2009 audit round were reviewed by the audit organizing group and a structured analysis of the data was compiled. CCCs in the UK offer a high standard of comprehensive care services. The main areas of concern were the state of the premises (seven centres), lack of dental services (seven centres), physiotherapy (seven centres) and social work support (11 centres). Major concerns were identified at eight centres requiring a formal letter from the chairman of UKHCDO to the chief executive of the host trust. Since inception of the triennial audit process centre report recommendations have resulted in major improvements in the services available at UK CCCs. The audit process is considered to be a highly effective means of improving the quality of care for patients with bleeding disorders and can be used as a model for the introduction of a similar process in other countries.

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.

. The risk of variant Creutzfeldt-Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed-up for 1020 years through the UK Haemophilia Centre Doctors Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 implicated clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch-manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is =1% for 595, =50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty-one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow-up of this cohort is needed.

doi:10.1160/TH11-02-0108 Thromb Haemost 2011; 106: 386–387 Dear Sirs, With a prevalence of up to 1% in the general population, pregnancy in women with von Willebrand’s disease (VWD) is a common clinical issue (1). A number of publications have specifically addressed the management of VWD in pregnancy, reporting the changes in laboratory parameters, treatment aspects and outcome in the subtypes of VWD (2–4). We report the pregnancies in three women with platelettype (pseudo-) VWD (PT-VWD), detailing the changes in factor VIII (FVIII) and von Willebrand factor (VWF) levels and the management and outcome of pregnancy and delivery in each case, providing useful information for the management of pregnancy in other females with this rare but under-recognised subtype of VWD (5). PT-VWD results from a mutation in the platelet glycoprotein Ibα gene (GP1BA), situated on chromosome 17, which increases platelet affinity for VWF (6). This leads to a reduction in high molecular weight multimers due to the formation of platelet-VWF aggregates and subsequent removal from the circulation, although the exact mechanism by which this occurs remains unclear (7, 8). The resulting reduction in VWF levels, combined with associated thrombocytopenia seen in some cases, produces a haemostatic defect with a phenotype similar to other subtypes of VWD. In particular, the clinical and laboratory findings are often indistinguishable from type 2B VWD, a disorder in which the VWF protein itself displays increased affinity for the platelet glycoprotein Ib (8). Reports in women with type 2B VWD have shown that pregnancy results in exacerbation of thrombocytopenia, presumably secondary to the increased circulating VWF levels associated with pregnancy (10–12). Indeed, VWF levels in these patients can rise into the normal range during late pregnancy. A single case report from a kindred with PTVWF noted a normal VWF level in the propositus during pregnancy with a reduced platelet count, initially misdiagnosed as immune thrombocytopenia (13). This patient developed post-partum bleeding despite being given a platelet transfusion in the first pregnancy and VWF concentrate in the second pregnancy. We report the management of three pregnancies in three females with PTVWD. All three women, two of whom are sisters, have the same mutation of the glycoprotein Ibα gene, Gly233Val (G233V), as previously reported in PT-VWD (14). Details of the three patients are shown in Table 1. All cases developed a worsening thrombocytopenia through pregnancy. In patient 1, a VWF:RCo level taken prior to pregnancy was mistakenly used to plan the management of the delivery. At the time of delivery obstetric indications meant the patient required an emergency caesarean section. The patient was treated, with two units of platelets and 2,500 units of Haemate P (CSL-Behring UK Ltd), equating to a 100 IU/dl/kg VWF:RCo increment. The delivery was uneventful, with no excessive blood loss. Pre-treatment levels subsequently became available, demonstrating normalisation of VWF:RCo and FVIII levels ( Table 1), suggesting treatment with VWF concentrate had been unnecessary. The experience in this pregnancy provided useful lessons to guide the management of subsequent pregnancies in two sisters with PT-VWD. As shown in Table 1, both patients followed a similar course to patient 1, with progressive thrombocytopenia through pregnancy. In both cases, monitoring demonstrated normalisation of VWF levels within the third trimester. Based on these results, it was felt that VWF concentrate was unnecessary and so both patients were treated solely with two units of HLA-selected platelets immediately prior to delivery. Both women had normal vaginal deliveries of healthy term infants. Blood loss was minimal in both cases with no delayed post partum bleeding reported. These three cases provide interesting information on the physiological changes in pregnancy in patients with PT-VWD. An increase in circulating VWF is well documented in pregnancy (15). It might be assumed that in patients with PT-VWD this would result in the observed worsening thrombocytopenia as the excess VWF binds to the platelets leading to increased clearance from the circulation. Our data show normalisation of VWF antigen and activity in the latter stages of pregnancy, with the VWF:Ag being higher than the VWF:RCo, particularly in patient 3. VWF:Ag multimers were not performed; however, we postulate that the pregnancy-related increase in VWF outstrips the rate of platelet production resulting in a shift in the equilibrium with accumulation of free VWF that has sufficient platelet binding capacity for adequate haemostasis. The physiological reduction in the platelet count, commonly seen in pregnancy, may exacerbate the thrombocytopenia. All three of our patients developed severe thrombocytopenia towards the end of pregnancy requiring platelet transfusion to cover the delivery. This is in contrast to the reports of pregnancies in type 2B VWD, which typically showed a milder reduction in platelets, with four of six patients having a count in excess of 45 x 10/l at the time of delivery (10–12). Whether the thrombocytopenia in pregnancy in type 2B VWD is truly milder than in PT-VWD is unclear as so few cases have been reported. We would advise monitoring of the platelet count and VWF antigen and activity throughout pregnancy in both PT-VWD and type 2B VWD, allowing informed use of platelet transfusions at delivery and possible avoidance of VWF concentrate which may theoretically increase the risk of

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.

Background The role and dose of anticoagulants in thromboprophylaxis for patients with cancer receiving chemotherapy through central venous catheters (CVCs) is controversial. We therefore assessed whether warfarin reduces catheter-related thrombosis compared with no warfarin and whether the dose of warfarin determines the thromboprophylactic effect.Methods In 68 clinical centres in the UK, we randomly assigned 1590 patients aged at least 16 years with cancer who were receiving chemotherapy through CVCs to no warfarin, fixed-dose warfarin 1 mg per day, or dose-adjusted warfarin per day to maintain an international normalised ratio between 1. 5 and 2. 0. Clinicians who were certain of the benefit of warfarin randomly assigned patients to fixed-dose or dose-adjusted warfarin groups. The primary outcome was the rate of radiologically proven, symptomatic catheter- related thrombosis. Analysis was by intention to treat. This trial is 14 registered as an International Standard Randomised Controlled Trial, number I SRCTN 50312145.Findings Compared with no warfarin (n=404), warfarin (n=408; 324 [79%] on fixed-dose and 84 [21%] on dose-adjusted) did not reduce the rate of catheter- related thromboses (24 [6%] vs 24 [6%]; relative risk 0 . 99, 95% Cl 0 . 57-1.72, p=0 . 98). However, compared with fixed-dose warfarin (n=471), dose-adjusted warfarin (n=473) was superior in the prevention of catheter- related thromboses (13 [3%] vs 34 [7%]; 0 . 38, 0.20-0.71, p=0 . 002). Major bleeding events were rare; an excess was noted with warfarin compared with no warfarin (7 vs 1, p=0. 07) and with dose-adjusted warfarin compared with fixed-dose warfarin (16 vs 7, p=0.09). A combined endpoint of thromboses and major bleeding showed no difference between comparisons. We did not note a survival benefit in either comparison.Interpretation The findings show that prophylactic warfarin compared with no warfarin is not associated with a reduction in symptomatic catheter- related or other thromboses in patients with cancer and therefore we should consider newer treatments.Funding Medical Research Council and Cancer Research UK.

Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

HaemophiliaVolume 14, Issue 1 p. 140-141 LETTER TO THE EDITOR Increased risk of bleeding with the use of tipranavir boosted with ritonavir in haemophilic patients C. ARBUTHNOT, C. ARBUTHNOT University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, West Midlands, UKSearch for more papers by this authorJ. T. WILDE, J. T. WILDE University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, West Midlands, UKSearch for more papers by this author C. ARBUTHNOT, C. ARBUTHNOT University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, West Midlands, UKSearch for more papers by this authorJ. T. WILDE, J. T. WILDE University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, West Midlands, UKSearch for more papers by this author First published: 31 August 2007 https://doi.org/10.1111/j.1365-2516.2007.01447.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Racoosin JA, Kessler CM. Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series. Haemophilia 1999; 5: 266–9. 2 Wilde JT. Protease inhibitor therapy and bleeding. Haemophilia 2000; 6: 487–90. 3 Yazdanpanah Y, Viget N, Cheret A et al. Increased bleeding in HIV-positive haemophiliac patients treated with lopinavir–ritonavir. AIDS 2003; 17: 2397–9. 4 Rusconi S, La Seta Catamancio S, Citterio et al. Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother 2000; 44: 1328–32. 5 Ryan CT. New black box warning for ritonavir–boosted tipranavir. AIDS Clin Care, 2006; 18: 72. Citing Literature Volume14, Issue1January 2008Pages 140-141 ReferencesRelatedInformation