David Keeling

Guidelines on oral anticoagulation (warfarin) : third edition - 2005 update

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.

Guidelines on oral anticoagulation with warfarin - fourth edition: Guideline

The writing group was selected to be representative of UK based experts. This guidance is an update of the previous guideline written in 2005 and published in 2006 (Baglin et al, 2006). The guidance is updated with reference to relevant publications since 2005. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 5 years using the key word warfarin and limits clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, and English language. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH (British Committee for Standards in Haematology), the British Cardiovascular Society and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the indications for and management of patients on warfarin. This guideline replaces the previous BCSH guidelines on oral anticoagulants (Baglin & Rose, 1998; Baglin et al, 2006).

Clinical guidelines for testing for heritable thrombophilia

Trevor Baglin, Elaine Gray, Mike Greaves, Beverley J. Hunt, David Keeling, Sam Machin, Ian Mackie, Mike Makris, Tim Nokes, David Perry, R. C. Tait, Isobel Walker and Henry Watson Addenbrooke’s Hospital, Cambridge, NIBSC, South Mimms, University of Aberdeen, Aberdeen, Guy’s and St Thomas’, London, Churchill Hospital, Oxford, University College Hospital, London, Royal Hallamshire Hospital, Sheffield, Derriford Hospital, Plymouth, Glasgow Royal Infirmary, Glasgow and Aberdeen Royal Infirmary, UK

Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors' Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology.

Summary.  Evidence‐based guidelines are presented on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. They include details of therapeutic products available in the UK and they update and replace previous United Kingdom Haemophilia Centre Doctors’ Organisation guidelines.

Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia

Summary.  All UK patients with bleeding disorders treated with any UK‐sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt–Jakob disease (vCJD). We describe a study to detect disease‐associated, protease‐resistant prion protein (PrPres) in 17 neurologically aysmptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrPres. The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrPres by Western blot analysis. This tissue came from a 73‐year‐old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD‐infected donor, and some 400 000 units not known to include donations from vCJD‐infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure through diet, surgery, endoscopy, blood transfusion and receipt of UK‐sourced plasma products suggest that by far the most likely route of infection in this patient was receipt of UK plasma products.

Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies

Thrombosis is a well‐recognized complication following insertion of central venous catheters and is associated with significant morbidity. In an attempt to reduce line‐associated thrombosis, 108 consecutive patients with haematological malignancies were commenced on prophylactic ‘minidose’ warfarin, 1 mg/d, at the time of line insertion. This group of patients were compared with a historic group of 115 consecutive patients who had not received warfarin. Clinically‐suspected venous thrombosis was confirmed by Doppler ultrasound or venography. Patients taking prophylactic warfarin had their prothrombin time measured three times per week with the aim of maintaining an INR < 1.6. Five (5%) of the 108 patients who received minidose warfarin developed a thrombosis, at a median of 72 d (range 5–166) from the time of catheter insertion. In the 115 patients who were not anticoagulated 15 (13%) developed a catheter‐associated thrombosis at a median of 16 d (range 1–35). There was a significant reduction in line‐associated thrombosis in patients receiving warfarin (P = 0.03). These data suggest that minidose warfarin reduces the incidence of central venous catheter related thrombosis in patients with haematological malignancies.

The management of heparin-induced thrombocytopenia.

The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology has produced a concise practical guideline to highlight the key issues in the management of heparin-induced thrombocytopenia (HIT) for the practicing physician in the UK. The guideline is evidence-based and levels of evidence are included in the body of the article. All patients who are to receive heparin of any sort should have a platelet count on the day of starting treatment. For patients who have been exposed to heparin in the last 100 d, a baseline platelet count and a platelet count 24 h after starting heparin should be obtained. For all patients receiving unfractionated heparin (UFH), alternate day platelet counts should be performed from days 4 to 14. For surgical and medical patients receiving low-molecular-weight heparin (LMWH) platelet counts should be performed every 2-4 d from days 4 to 14. Obstetric patients receiving treatment doses of LMWH should have platelet counts performed every 2-4 d from days 4 to 14. Obstetric patients receiving prophylactic LMWH are at low risk and do not need routine platelet monitoring. If the platelet count falls by 50% or more, or falls below the laboratory normal range and/or the patient develops new thrombosis or skin allergy between days 4 and 14 of heparin administration HIT should be considered and a clinical assessment made. If the pretest probability of HIT is high, heparin should be stopped and an alternative anticoagulant started at full dosage unless there are significant contraindications while laboratory tests are performed. Platelet activation assays using washed platelets have a higher sensitivity than platelet aggregation assays but are technically demanding and their use should be restricted to laboratories experienced in the technique. Non-expert laboratories should use an antigen-based assay of high sensitivity. Only IgG class antibodies need to be measured. Useful information is gained by reporting the actual optical density, inhibition by high concentrations of heparin, and the cut-off value for a positive test rather than simply reporting the test as positive or negative. In making a diagnosis of HIT the clinicians estimate of the pretest probability of HIT together with the type of assay used and its quantitative result (enzyme-linked immunosorbent assay, ELISA, only) should be used to determine the overall probability of HIT. Clinical decisions should be made following consideration of the risks and benefits of treatment with an alternative anticoagulant. For patients with strongly suspected or confirmed HIT, heparin should be stopped and full-dose anticoagulation with an alternative, such as lepirudin or danaparoid, commenced (in the absence of a significant contraindication). Warfarin should not be used until the platelet count has recovered. When introduced in combination with warfarin, an alternative anticoagulant must be continued until the International Normalised Ratio (INR) is therapeutic for two consecutive days. Platelets should not be given for prophylaxis. Lepirudin, at doses adjusted to achieve an activated partial thromboplastin time (APTT) ratio of 1.5-2.5, reduces the risk of reaching the composite endpoint of limb amputation, death or new thrombosis in patients with HIT and HIT with thrombosis (HITT). The risk of major haemorrhage is directly related to the APTT ratio, lepirudin levels and serum creatinine levels. The patients renal function needs to be taken into careful consideration before treatment with lepirudin is commenced. Severe anaphylaxis occurs rarely in recipients of lepirudin and is more common in previously exposed patients. Danaparoid in a high-dose regimen is equivalent to lepirudin in the treatment of HIT and HITT. Danaparoid at prophylactic doses is not recommended for the treatment of HIT or HITT. Patients with previous HIT who are antibody negative (usually so after >100 d) who require cardiac surgery should receive intraoperative UFH in preference to other anticoagulants that are less validated for this purpose. Pre- and postoperative anticoagulation should be with an anticoagulant other than UFH or LMWH. Patients with recent or active HIT should have the need for surgery reviewed and delayed until the patient is antibody negative if possible. They should then proceed as above. If deemed appropriate early surgery should be carried out with an alternative anticoagulant. We recommend discussion of these complex cases requiring surgery with an experienced centre. The diagnosis must be clearly recorded in the patients medical record.

The story of the discovery of heparin and warfarin

Heparin and coumarins have been the mainstay of anticoagulant therapy throughout our working lives. As we stand on the threshold of a new era of anticoagulants it is timely to look back upon their discovery and development. Both have fascinating stories to tell. Jay McLean claimed to have discovered heparin whilst a medical student, although this is disputed. The story of warfarin leads us from a mysterious haemorrhagic disease of cattle to the development of a rat poison which became one of the most commonly prescribed drugs in history. Many people were involved in both stories and we owe them all a debt of gratitude.

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Summary.  Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty‐eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1–6 months 13 of 51 (25%), 6–12 months 27 of 130 (21%), 12–18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma‐derived FVIII (P = 0.006) and in those with a major molecular defect (P = 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.

The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.

Summary.  von Willebrand disease (VWD) is the commonest inherited bleeding disorder. However, despite an increasing understanding of the pathophysiology of VWD, the diagnosis of VWD is frequently difficult because of uncertainty regarding the relationship between laboratory assays and function in vivo. The objective of this guideline is to provide contemporary advice on a rational approach to the diagnosis of VWD. This is the second edition of this UK Haemophilia Centre Doctors’ Organisation (UKHCDO) guideline and supersedes the previous edition which was published in 1997.