Henry G. Watson

Guidelines for the diagnosis and management of disseminated intravascular coagulation

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50u2003×u2003109/l transfusion of platelets should be considered. In non‐bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1u2003g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co‐existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half‐life and reversibility. Weight adjusted doses (e.g. 10u2003μ/kg/h) may be used without the intention of prolonging the APTT ratio to 1·5–2·5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non‐bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24u2003μg/kg/h for 4u2003d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30u2003×u2003109/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half‐life ≈20u2003min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1u2003g every 8u2003h).

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

Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures

Unselected coagulation testing is widely practiced in the process of assessing bleeding risk prior to surgery. This may delay surgery inappropriately and cause unnecessary concern in patients who are found to have ‘abnormal’ tests. In addition it is associated with a significant cost. This systematic review was performed to determine whether patient bleeding history and unselected coagulation testing predict abnormal perioperative bleeding. A literature search of Medline between 1966 and 2005 was performed to identify appropriate studies. Studies that contained enough data to allow the calculation of the predictive value and likelihood ratios of tests for perioperative bleeding were included. Nine observational studies (three prospective) were identified. The positive predictive value (0·03–0·22) and likelihood ratio (0·94–5·1) for coagulation tests indicate that they are poor predictors of bleeding. Patients undergoing surgery should have a bleeding history taken. This should include detail of previous surgery and trauma, a family history, and detail of anti‐thrombotic medication. Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.

A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin.

The role of oral Vitamin K administration in the reversal of anticoagulation is not yet clear because of a paucity of data on the early effects of treatment, apparent differences in efficacy between preparations and a lack of data comparing oral with intravenous administration. We have compared the effects on the International Normalized Ratio (INR) and activities of the Vitamin K‐dependent clotting factors II, VII, IX and X at 4u2003h and 24u2003h after administration of three oral Vitamin K preparations and of intravenous Vitamin K in 64 anticoagulated patients who required non‐urgent partial correction of anticoagulation. Our data confirm that correction of anticoagulation is more rapid after intravenous administration of Vitamin K than after oral administration of similar or larger doses. At 24u2003h, satisfactory correction of INR can be achieved using low‐dose Vitamin K given by either the intravenous or oral route. Our data, and that from previous studies, suggest that there may be differences in efficacy between orally administered products. Administration of Vitamin K by either route was accompanied by changes in the activities of the Vitamin K‐dependent clotting factors that reflected their respective biological half‐lives. In the 24u2003h after treatment, the relationship between the INR and the individual Vitamin K‐dependent clotting factors was similar to that described previously in stable anticoagulated patients. We conclude that the reversal of anticoagulation with warfarin is achieved more rapidly by intravenous administration of Vitamin K. Satisfactory, but slower, reversal of anticoagulation can be effected using oral Vitamin K, but there may be differences in efficacy between the products tested in our study.

Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young

Conditions which result in hypercoagulable blood or venous stasis may predispose to the development of deep vein thrombosis (DVT). Most of the recently described risk factors for DVT induce a hypercoagulable state. Over a 3‐year period we have observed anomaly of the inferior vena cava (IVC) in four young patients presenting with spontaneous unprovoked DVT. This is a greater than expected rate (5% observed versus 0·5% expected). Further, bilateral DVT, which constitutes less than 10% of cases in most series, was present in three of the four cases. Anomaly of the IVC is a rare example of a prevalent congenital condition that predisposes to DVT, presumably by favouring venous stasis. This diagnosis should be considered in young patients with spontaneous and bilateral DVT.

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 management of coumarin-induced over-anticoagulation

Over the last decade there has been a dramatic increase in the use of oral anticoagulants. This is primarily as a result of the demonstration of their benefit in atrial fibrillation (Laupacis et al, 1998). It has been estimated that 2 ́3% of people older than 40 years and 5 ́9% of those older than 65 years suffer from atrial fibrillation (Feinberg et al, 1995). In Cambridge, UK, 0 ́5% of the population take warfarin (Baglin, 1998), while the Dutch Thrombosis Service monitors the anticoagulation of 270 000 persons annually (1 ́8% of a population of 15 million) (Breukink-Engbers, 1999). Three oral anticoagulant drugs are in widespread use. Warfarin is the anticoagulant most frequently prescribed in the UK and North America, while acenocoumarol and phenprocoumon are more commonly used elsewhere. The half-lives of these drugs differ and recommendations given below refer to anticoagulation with warfarin, except in the last section in which the specific problems associated with acenocoumarol and phenprocoumon are addressed.

Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition

• Patients who are to receive any heparin should have a baseline platelet count (2C). • Post-operative patients including obstetric cases receiving unfractionated heparin (UFH) should have platelet count monitoring performed every 2–3 d from days 4 to 14 or until heparin is stopped (2C). • Post-cardiopulmonary bypass patients receiving low molecular weight heparin (LMWH) should have platelet count monitoring performed every 2–3 d from days 4 to 14 or until heparin is stopped (2C). • Post-operative patients (other than cardiopulmonary bypass patients) receiving LMWH do not need routine platelet monitoring (2C). • Post-operative patients and cardiopulmonary bypass patients who have been exposed to heparin in the previous 100 d and are receiving any type of heparin should have a platelet count determined 24 h after starting heparin (2C). • Medical patients and obstetric patients receiving heparin do not need routine platelet monitoring (2C). • If the platelet count falls by 30% or more and/or the patient develops new thrombosis or skin allergy or any of the other rarer manifestations of heparin-induced thrombocytopenia (HIT) between days 4 and 14 of heparin administration, HIT should be considered and a clinical assessment made (2C). • HIT can be excluded by a low pre-test probability score without the need for laboratory investigation (2B). • If the pre-test probability of HIT is not low, heparin should be stopped and an alternative anticoagulant started in full dosage whilst laboratory tests are performed (1C). • Platelet aggregation assays using platelet-rich plasma (PRP) lack sensitivity and are not recommended (2C). • Platelet activation assays using washed platelets [heparin-induced platelet activation assay (HIPA) and serotonin release assay (SRA)] have a higher sensitivity than platelet aggregation assays using PRP and are regarded as the reference standard, but are technically demanding and their use should be restricted to experienced laboratories (2C). • Non-expert laboratories should use an antigen assay of high sensitivity. Only the IgG class needs to be measured. Useful information is gained by reporting the actual optical density, degree of inhibition by high dose heparin, and the cut-off point for a positive test rather than simply reporting the test as positive or negative (1B). • In making a diagnosis of HIT, the clinician’s estimate of the pre-test probability of HIT, together with the type of assay used and its quantitative result [enzyme-linked immunosorbent assay (ELISA) only] and information on reversal using higher doses of heparin should be used to determine the post-test probability of HIT (2B). • HIT can be excluded in patients with an intermediate pre-test score who have a negative particle gel immunoassay (2B). • HIT can be excluded in all patients by a negative antigen assay of high sensitivity (1A). • Clinical decisions should be made following consideration of the risks and benefits of treatment with an alternative anticoagulant (1C). • For patients with suspected (non-low pre-test probability) or confirmed HIT, heparin should be stopped and full dose anticoagulation with an alternative anticoagulant commenced (1B). • LMWH should not be used in the treatment of HIT (1A). • Warfarin should not be used until the platelet count has recovered to the normal range. When introduced, an alternative anticoagulant must be continued until the International Normalized Ratio (INR) is therapeutic. Argatroban affects the INR and this needs to be considered when using this drug. A minimum overlap of 5 d between non-heparin anticoagulants and vitamin K antagonist (VKA) therapy is recommended (1B). Correspondence: Dr Henry Watson, British Society for Haematology, 100 White Lion Street, London, N1 9PF, UK. E-mail bcsh@b-s-h.org.uk