The UK Haemophilia Doctors Organisation triennial audit of UK Comprehensive Care Haemophilia Centres.

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.

UKHCDO guidelines on the management of HCV in patients with hereditary bleeding disorders 2011.

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 among UK patients with bleeding disorders, known to have received potentially contaminated plasma products.

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 10-20 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.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.

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.

Spontaneous resolution of acquired factor V inhibitor associated with ovarian carcinoma.

A 74-year-old lady who presented initially with loin pain and haematuria, then melaena was found to have a prothrombin time ratio (PTR) > 10 and activated partial thromboplastin time ratio (APTTR) > 7. A factor V inhibitor was diagnosed. She was managed with supportive care and the FV inhibitor resolved. A few weeks later she developed abdominal swelling and ascites and was found to have an ovarian tumour. This is the first case, as far as we are aware, of a malignancy-associated FV antibody that has spontaneously remitted before overt presentation of the tumour and illustrates the value of adopting an expectant approach to the management of acquired FV inhibitors.

The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.

The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K-dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers-Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

HIV and HCV coinfection in haemophilia.

A substantial number of haemophilic patients are infected with both human immunodeficiency virus (HIV) and hepatitis C (HCV). HIV has been shown to accelerate the course of HCV chronic liver disease and there is evidence that HCV infection may worsen the prognosis of HIV. As many HIV infected patients are stable on highly active antiretroviral therapy (HAART) HCV should be actively managed in coinfected individuals. Pegylated interferon (Peg-IFN)/ribavirin combination therapy is the treatment of choice for HCV infection and should be considered in patients with stable HIV on or off HAART with CD4 counts >200 x 10(6)/l. Results of on-going trials of combination therapy in coinfected individuals are awaited. For coinfected patients with end stage liver disease who are stable on HAART liver transplantation should be considered.

Evidence for the use of activated prothrombin complex concentrates (aPCCs) in the treatment of patients with haemophilia and inhibitors.

FEIBA and Autoplex T have been used to control bleeding in patients with factor VIII or IX inhibitors for over 25 years. The major components of FEIBA are thought to be activated factor X and prothrombin, whereas the main active components in Autoplex T are thought to be activated factors IX and VII. Both products have been found to effectively control approximately 80% of bleeds involving joints and soft tissues. Published experience of their use in surgery is limited. Thrombotic complications have been reported with high dose FEIBA therapy and have led to maximum dosage guidelines for this product.

Haemophilia 2002: emerging risks of treatment.

Haemophilia care and treatment products have greatly improved over the past 2 decades. Transitions in treatment produced by these changes were accompanied by the emergence of unexpected risks and new complications. In order to provide the best comprehensive care to patients with haemophilia, healthcare providers periodically need to re-evaluate and adjust their management and therapeutic products to prevent or minimize the effects produced by the emerging issues. For example, reducing the effects of infectious agents remains the highest priority for the haemophilia community because of the high level of morbidity and mortality that has resulted from earlier therapeutic agents. In many countries, the goal has been to achieve absolute zero risk for infectious agents. In some instances, the screening procedures to achieve these goals reduced the availability of plasma needed for manufactured derivatives and produced another emerging risk, shortages of clotting factor preparations. Similarly, better diagnostic methods identified other potential agents that were not inactivated by current technology. Likewise, immune tolerance regimens and the prophylactic management of haemophilia introduced different therapeutic delivery systems with their own risks. The drugs used to manage diseases such as human immunodeficiency virus (HIV), which were transmitted by products manufactured before mid-1980, create their own set of risks for this community. Topical emerging risks of treatment, including variant Creutzfeldt-Jakob disease, an assessment of its risks and impact, the complications of using indwelling catheters, and the role of protease inhibitors used to treat HIV may have on bleeding complications of haemophilia are discussed.

Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding.

We examined recombinant activated factor VII (rVIIa) administered by continuous infusion to eight patients with inhibitors to factor VIII, undergoing elective surgery. rVIIa was infused at a fixed rate of 16.5 microg/kg/h for a median of 13.5 days (range 1-26). There was effective haemostasis at this infusion rate in only one of two minor procedures and two of six major operations. Three patients experienced excessive bleeding despite plasma factor VII activity around 10 IU/ml. Serious bleeding occurred in two other patients caused by procedural errors unrelated to rVIIa and required re-operation. The median rVIIa clearance on day 1 was 57 ml/h/kg (range 18-100) and on day 3 was 100 ml/h/kg (range 61-200). Clearance on the final infusion day was not significantly different from day 3. The infusion did not induce pathological activation of the coagulation mechanism. The only thrombotic adverse events were two episodes of superficial thrombophlebitis of the infused vein in one subject. In conclusion, the 16.5 microg/kg/h infusion rate reliably achieves plasma factor VII activity levels of 10 IU/ml, but this level does not provide reliable haemostasis.

Protease inhibitor therapy and bleeding.

Shortly after the introduction of protease inhibitor drugs (PIs) for the treatment of human immunodeficiency virus infection an association between these drugs and an increased bleeding tendency in patients with hereditary bleeding disorders was observed. Not only do patients experience an increased bleed frequency in usual sites, but bleeds can also occur in unusual places such as the finger joints. Mucus membrane bleeding and haematuria are also common. Ritonavir appears to be associated with the highest risk of bleeding followed by indinavir. As yet there has not been enough experience with the newer PIs to assess fully their potential to induce increased bleeding, although nelfinavir seems to pose less of a risk than the original PIs. PI-associated bleeds tend to be more resistant to factor concentrate treatment and periods of prophylaxis may be required in individuals with frequent persistent bleeds. Patients continuing on PI therapy tend to develop a tolerance to this adverse effect with time. The mechanism of the bleeding tendency has not been elucidated. There is no consistent evidence of a disturbance of coagulation, fibrinolysis or platelet function which raises the possibility that PIs may exert a direct local effect on blood vessels. It is very important that this class-specific side-effect is recognized and understood by both treaters and patients.

Deficiency of natural anticoagulant proteins C, S, and antithrombin in portal vein thrombosis: a secondary phenomenon?

BACKGROUND: Hereditary deficiencies of natural anticoagulant proteins are implicated in the pathogenesis of portal vein thrombosis (PVT). Secondary deficiencies of these proteins have also been reported in PVT, making interpretation of concentrations difficult. AIMS: To characterise the coagulation profiles in adult patients with PVT and to investigate the possible mechanisms of natural anticoagulant protein deficiency. PATIENTS: Twenty nine adult patients with portal hypertension caused by PVT, and normal biochemical liver function tests. METHODS: Routine coagulation profiles and concentrations of proteins C, S, and antithrombin were measured; where indicated, corresponding concentrations in parents were also measured. Synchronous peripheral and hepatic or splenic vein concentrations were compared in seven patients undergoing interventional procedures, as were peripheral concentrations before and after shunt surgery in three patients. RESULTS: Deficiencies of one or more of the natural anticoagulant proteins occurred in 18 patients (62%), with six patients having combined deficiency of all three proteins. There were strong correlations between prothrombin and partial thromboplastin time ratios and concentrations of natural anticoagulant proteins. Family studies in nine cases of anticoagulant protein deficiency revealed possible hereditary deficiency in only three cases, and significantly lower concentrations of anticoagulant proteins in all PVT cases compared with parents. Levels of anticoagulant proteins tended to be lower in hepatic veins but higher in splenic veins compared with peripheral vein concentrations. Peripheral concentrations decreased after shunt surgery. CONCLUSIONS: Deficiency of natural anticoagulant proteins is common in PVT and is probably a secondary phenomenon in most cases, occurring as part of a global disturbance of coagulation variables. The mechanism for this remains unclear but may result from a combination of reduced hepatic blood flow and portosystemic shunting itself.

Combined alpha interferon and ribavirin for the treatment of hepatitis C in patients with hereditary bleeding disorders.

Patients with hereditary bleeding disorders who received non-virally inactivated plasma-derived clotting factor concentrates before the mid-1980s invariably became infected with hepatitis C virus (HCV). Therapy with interferon alpha (IFN-alpha) alone has been disappointing in this group. We conducted an open-label study, using a combination of IFN-alpha2b (3 million units three times per week) and ribavirin 1-1.2 g/d in 28 patients with hereditary bleeding disorders. Twenty-one of the 28 patients had liver biopsy-confirmed chronic hepatitis (median histological activity index 5; range 1-10) and all patients were HCV RNA positive by PCR. Virological response rate to therapy at 3 months was 82% (23 out of 28). Three HIV co-infected patients showed an early virological response with loss of HCV RNA, but two subsequently relapsed after 3 and 6 months of therapy. Four patients stopped treatment early (one at 4, one at 7 and two at 9 months) because of treatment-related side effects, although three of these have maintained a virological response. Seventeen patients completed the 48-week course. Twenty of the 28 (71%) treated have had a durable virological response with a median follow-up of 16 months (range 1-24). Combination therapy represents a significant advance in the treatment of hepatitis C in patients with hereditary bleeding disorders.

Increased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders.

The use of protease inhibitor (PI) drugs in treatment regimens for HIV-infected patients with hereditary bleeding disorders has been associated with an increased bleeding tendency. To characterize the nature of this bleeding tendency, a retrospective case record analysis was performed on 67 HIV-positive patients with hereditary bleeding disorders who had been treated with PI therapy. 34 patients (51%) developed an increased bleeding tendency on PI therapy, usually within the first few weeks of treatment. As well as an increase in usual joint bleeds, patients developed spontaneous atypical small joint, soft tissue and muscle bleeds. Haematuria was also common. Bleeding episodes tended to respond suboptimally to factor concentrate replacement. Ritonavir was most likely to be associated with bleeding. Nine patients switched first-line PI therapy as a direct consequence of bleeding and seven had no further bleeding problem on their second PI. Factor concentrate usage was significantly increased during the first 6 months of PI therapy compared to the 6 months preceeding treatment. PI therapy is frequently associated with increased bleeding in patients with hereditary bleeding disorders. The mechanism of the bleeding tendency remains to be elucidated.

A novel ELISA-based primer extension assay for the detection of the factor V Leiden mutation.

We describe an enzyme-linked immunosorbent assay (ELISA) based primer extension method for the detection of the factor V Leiden (FVL) mutation. The wild-type nucleotide at position 1691 or the mutant nucleotide at the complementary position on the antisense strand were detected by the incorporation of biotinylated complementary bases onto fluorescein isothiocyanate (FITC) labelled mini-sequence primers with specificity for the sense and antisense gene segments downstream from the bases adjacent to position 1691. The reactions took place in pairs of tubes containing the complementary bases to either the wild-type or mutant nucleotide respectively. Primer extension products from each reaction tube pair which have incorporated biotinylated bases were then captured in streptavidin-coated microtitre plate wells and detected colourimetrically using an ELISA procedure. 200 patient samples were tested to validate the assay and there was complete genotypic agreement between the ELISA method and restriction site analysis using Mnl I (137 wild type, 55 FVL heterozygotes and eight homozygotes). The method utilizes non-radioactive reagents and does not require electrophoretic techniques. It is therefore a safe, simple and rapid assay which lends itself to automation.

Hepatitis C viral load, genotype and histological severity in patients with bleeding disorders.

We report the relationship between hepatitis C virus (HCV) titre, liver histology and HCV genotype in patients with bleeding disorders. One hundred and thirty-two RIBA-2-positive patients, including 56 who were also HIV positive, were identified at our centre. Fifty of these patients, including nine who were HIV infected, underwent percutaneous liver biopsy. Liver histology was assessed using a modified histological activity index (HAI). Qualitative serum HCV PCR was positive in 87 (87%) of the 101 patients tested including 43 of 50 biopsied patients. HCV RNA titres, measured by quantitative PCR, were significantly higher in HIV-positive patients compared with HIV-negative patients (P < 0.05) but were not related to HAI, mean factor concentrate usage, duration of HCV infection or HCV genotype. There was no relationship between HCV genotype and HAI. Qualitative HCV PCR was positive in 30 of 43 liver biopsies tested. Biopsy PCR-positive and -negative cohorts were not distinguished by HAI or serum HCV titre. We conclude that although serum HCV PCR is useful in confirming the presence of HCV infection in patients with bleeding disorders, little meaningful information concerning the severity of the disease can be obtained from serum HCV quantification.