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Anticoagulation
BASIC SCIENCE
co-factors on phospholipid surfaces.3 The vitamin K-dependent factors are: pro-coagulant factors (II, VII, IX and X) anticoagulant factors (protein C and S). Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract, with peak concentrations reached at 90 minutes following oral administration. Once absorbed it binds strongly to albumin and has a half life of 36e72 hours, with the peak therapeutic effect occurring at between 24 and 72 hours. Warfarin is metabolized in the liver via the cytochrome P450 enzyme system.3
Anticoagulation Paul Batty Graham Smith
Abstract The increasing incidence of thrombosis in hospitalized patients in the 21st century is due to improved awareness by clinicians and more sophisticated forms of imaging. Thromboprophylaxis is now an imperative in the NHS of the UK and this combined with new, improved and safer forms of anticoagulation means that post-operative deaths from venous thromboembolic disease should become a thing of the past. In the following paper the authors review the up-to-date literature with emphasis on the newer anticoagulants that do not require blood test monitoring. We fully accept that this is a developing field and that the recognized indications for certain of these agents will change with the accumulation of further evidence.
Commencement and monitoring of warfarin treatment On commencement of warfarin treatment the intensity of loading is dependent on the indication for anticoagulation and patientrelated factors, such as age and haemorrhagic risk. Where anticoagulation is required rapidly, as in the case of acute VTE, a regimen involving a single dose of 10 mg on day 1 with subsequent doses determined by the international normalized ratio (INR) is recommended (e.g. Fennerty regimen).4 The INR is a ratio of the patient’s prothrombin time compared to a normal prothrombin time.3,5 In this case heparin (unfractionated or low molecular weight) should be co-administered until the INR is greater than 2.0 for 2 days to reduce the incidence of warfarininduced skin necrosis. In the situation where rapid anticoagulation is not required (e.g. atrial fibrillation) a slow loading protocol that does not require heparin is recommended (e.g. Janes protocol).4 In this, warfarin is commenced at 3 mg daily and subsequent doses are determined on the basis of weekly INR measurements. The majority of patients require a dose of 3e8 mg/day, but this may vary from 0.5 mg/week to in excess of 50 mg/day in patients with inherited warfarin resistance. The therapeutic target ranges recommended for various indications for warfarin are shown in Table 1.4
Keywords Anticoagulation; aspirin; bleeding; heparin; novel anticoagulants; pregnancy; surgery; thromboprophylaxis; warfarin
Introduction It is estimated that one million people in the UK are currently taking oral anticoagulation in the form of warfarin, representing approximately 1.6% of the population of the country.1 Venous thromboembolic (VTE) disease is responsible for around 25,000 deaths annually with 50% of fatal pulmonary emboli following hospital admission.2 Anticoagulation can be used either to prevent clot propagation or to reduce the risk of developing venous thrombosis. In this article we review the current forms of anticoagulant therapy in use in the UK and specifically discuss how this impacts on peri-operative management.
British Committee for Standards in Haematology (BCSH) guidelines on recommended target INR based on indication for anticoagulation4
TYPES OF ANTICOAGULANTS Warfarin
Indication Acute DVT/PE Recurrence of VTE on warfarin Recurrence of VTE after warfarin Antiphospholipid syndrome Atrial fibrillation Mural thrombus Cardiomyopathy Prosthetic valves Aortic bileaflet Aortic tilting disk Mitral bileaflet Mitral tilting disk Caged ball or caged disk (aortic or mitral)
Warfarin is the most common form of oral anticoagulant used in the UK. It is a synthetic derivative of 4-hydroxycoumarin, acting via inhibition of the enzyme vitamin K epoxide reductase (VKOR). This prevents formation of vitamin K hydroquinone which is required for gamma-carboxylation of the vitamin Kdependent factors. This reduces the coagulant activity of these factors, as they are no longer able to undergo Ca2þ-dependent changes in their structure required to bind to
Paul Batty BSc(Hons) MBBS MRCP is a Specialist Registrar in Haematology at the Royal Surrey County Hospital, Guildford, Surrey, UK. Conflicts of interest: none declared.
2.5 3.0 3.0 3.0 3.5
DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; VTE, venous thromboembolic.
J Graham Smith BSc MD FRCP FRCPath is a Professor of Haematology at the University of Surrey, Guildford and Consultant in Haematology at Frimley Park Hospital, Frimley, Surrey, UK. Conflicts of interest: none declared.
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Table 1
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BASIC SCIENCE
Factors affecting warfarin dosage Many factors can influence the warfarin requirements of an individual patient. These are discussed below.
haemorrhage increases substantially when the INR is greater than 4.5.7 On encountering an elevated INR reading the requirement for reversal of warfarin is dependent on whether there is active bleeding. The BCSH Guidelines for management of bleeding and excessive anticoagulation for patients on warfarin are shown in Figure 1.
Drug interactions Due to warfarin being metabolized via the cytochrome P450 systems, many drugs can affect its metabolism. It is recommended that on commencement of new medications the British National Formulary (BNF) is consulted as a dose adjustment of warfarin may be required. Examples of some of the interactions seen with commonly prescribed drugs are shown below: Potentiate warfarin effect: amiodarone, non-steroidal antiinflammatory drugs (NSAIDs), antibiotics (cephalosporins, erythromycin, ciprofloxacin and metronidazole), antifungals, paracetamol, allopurinol, omeprazole, thyroxine, alcohol (chronic excess ingestion), corticosteroids. Inhibit warfarin effect: antiepileptics (carbamazepine), rifampicin, oral contraceptive pill, St John’s wort.
Non-haemorrhagic toxicities Non-haemorrhagic side-effects of warfarin are uncommon. These include warfarin-induced skin necrosis, hypersensitivity, skin rashes, alopecia and diarrhoea. Warfarin-induced skin necrosis This is a rare complication of warfarin therapy occurring in less than 0.1% of newly warfarinized patients. It tends to occur within the first 10 days of treatment, is more common in women and with higher loading doses of warfarin.8 It is thought to occur due to levels of protein C falling faster than the other vitamin Kdependent factors leading to thrombus formation and subsequent necrosis. Treatment involves stopping warfarin therapy and some patients may require surgical intervention. Warfarininduced skin necrosis is considered a contraindication for future warfarin therapy.
Genetic factors Genetic mutations in the vitamin K epoxide reductase (VKOR) complex 1 lead to warfarin resistance and polymorphisms for cytochrome P450 2C9 can lead to reduced warfarin requirements.6
Other vitamin K antagonists Although warfarin is the most common vitamin K antagonist used in the UK, other oral vitamin K antagonists in use include phenindione, acenocoumarol and phenprocoumon.
Dietary factors Increased dietary intake of foods containing high levels of vitamin K1 can lead to higher warfarin dose requirements or resistance. Foods that are rich in vitamin K1 are the leafy green vegetables (e.g. spinach, cabbage, broccoli), parsley and some fruits (e.g. avocado and kiwi fruit).
Heparin Heparin, either in the form of unfractionated or low-molecularweight heparin (LMWH), is the most common parentally administered anticoagulant used in the UK. It is a naturally occurring anionic glycosaminoglycan produced by mast cells, with all heparin in the UK being of porcine origin. LMWH is produced from unfractionated heparin by controlled depolymerization.
Management of excessive anticoagulation and bleeding Warfarin, even when closely monitored, increases the risk of major bleeding by 0.3e0.5% per year. The risk of major
Management of excessive anticoagulation and bleeding associated with warfarin therapy 4,5 Is the patient having major bleeding?
No/minor bleeding
INR 4.5–6.0
INR 6.0–8.0
Yes
INR 8.0
Stop Warfarin Give 5–10 mg intravenous vitamin K
Reduce dose of Warfarin or stop Restart when INR 5.0
Stop Warfarin
Stop Warfarin
Restart when INR 5.0
Restart when INR 5.0 Consider 0.5–2.5 mg oral vitamin K
Give intravenous prothrombin complex concentrate (PCC) e.g. Beriplex or Octaplex up to 50 units/kg (based on INR) or 15 ml/kg fresh frozen plasma if PCC not available
Figure 1
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infused over 10 min. The maximum dose of protamine sulphate infused over this time should not exceed 50 mg.9
Unfractionated heparin ranges in molecular weight from 5000 to 35,000 Da and LMWH from 3000 to 5000 Da.9 Unfractionated heparin and LMWH form a complex with antithrombin-III, greatly potentiating its effect on the inactivation of various clotting factors. The unfractionated heparineantithrombin complex most notably inactivates factors Xa and thrombin (factor IIa), but to a lesser extent factors IXa, XIa and XIIa. The LMWHeantithrombin complex has its main activity through inactivation of factor Xa, although different preparations have varying degrees of activity on thrombin also. The heparins are not absorbed orally, so must be given intravenously or subcutaneously. The half-life of intravenous unfractionated heparin is approximately 60 min when given at a rate of 100 U/kg. The half-life of subcutaneous LMWH is significantly higher at around 4 hours.9 Unfractionated heparin is metabolized by two distinct mechanisms. The first is saturable, occurring via binding of heparin to endothelial cell receptors and macrophages. It is subsequently internalized and depolymerized. The second non-saturable mechanism is via renal clearance. LMWH is cleared entirely by the kidneys so its dose should be adjusted according to renal function.
Low-molecular-weight heparin: in major haemorrhage, protamine sulphate can be given within 8 hours of administration of LMWH, although this incompletely reverses the anticoagulant effect. The recommended dose for protamine sulphate is 1 mg/ 100 anti-Xa units. Fresh frozen plasma is ineffective in the reversal of the anticoagulant effect of LMWH.9
Non-haemorrhagic toxicities Osteoporosis In patients on long-term unfractionated heparin therapy (>1 month) significant reduction in bone density is seen in around 30% of patients and vertebral fractures in 2%.9 The risk of osteoporosis is much lower with LMWH.9 Heparin-associated thrombocytopenia/heparin-induced immune thrombocytopenia (HIT) A small decrease in platelet count (not <100), with no clinical sequelae is common in the first few days of commencement of heparin treatment. This resolves spontaneously without need for stopping heparin. A more serious complication is heparin-induced thrombocytopenia (HIT). This clinical syndrome develops between 5 and 10 days of commencement of heparin (sooner if heparin exposure within the previous 100 days).10 The risk is higher for unfractionated heparin, but may also occur with LMWH. It occurs as a result of formation of IgG antibodies to the complex formed between heparin and platelet factor-4. Antibody binding to this complex leads to platelet activation and thrombin generation, resulting in thrombosis in 50% and mortality in 20e30% of patients. Treatment of HIT involves stopping all heparin and commencing an alternative anticoagulant such as danaparoid or lepirudin.9
Commencement and monitoring of heparin Unfractionated heparin: unfractionated heparin therapy is monitored by the activated partial thromboplastin time (aPTT). Generally a target aPTT ratio of 1.5e2.5 (patient’s aPTT compared to a normal aPTT) is used in the treatment of VTE, although this can vary depending on the aPTT reagent used. In the treatment of VTE heparin should be commenced with a bolus dose of 5000e7500 units (75 U/kg) followed by an intravenous infusion of 18 U/kg/h.9 An aPTT should be taken 4 hours after commencement of an IV heparin infusion and following any subsequent dose adjustments. Please refer to local protocols for target aPTT and recommended dose adjustments. In the treatment of VTE unfractionated heparin can also be given subcutaneously at a dose of 15,000 units twice daily with adjustments made on the basis of the aPTT. Unfractionated heparin when used for thromboprophylaxis is given subcutaneously at a dose of 5000 units either 12-hourly or 8-hourly dependent on thrombotic risk.
New anticoagulants There has been much interest in the novel anticoagulants recently as generally they do not require monitoring and are not associated with complications such as HIT. These novel anticoagulants act either directly or indirectly (via antithrombin) to inhibit factor Xa or thrombin. 1) Indirect factor Xa inhibitors (fondaparinux/idraparinux) a. Fondaparinux is given as a once-daily subcutaneous injection. It has been approved by NICE as an alternative to LMWH for thromboprophylaxis in orthopaedic and general surgery.11 b. Idraparinux is given as a once weekly subcutaneous injection. Trials to date have been disappointing and its development has been halted. A biotinylated form of idrapariunx (idrabiotaparinux) which is rapidly reversible by administration of avidin is currently in development. 2) Direct factor Xa inhibitors (rivaroxaban/apixaban) These are orally administered direct factor Xa inhibitors. Large double-blind trials comparing rivaroxaban with enoxaparin thromboprophylaxis in total hip arthroplasty (RECORD 1) or total knee arthroplasty (RECORD 3) have shown non-inferiority for rivaroxaban.11 Rivaroxaban has NICE approval as an option for thromboprophylaxis in these settings.
Low-molecular-weight heparin: LMWH generally does not require monitoring, although this may be desirable in circumstances such as in pregnancy, renal failure, with children or in patients with very low or high body mass indices. In these situations monitoring is via the anti-factor Xa assay taken 3e4 hours after LMWH administration. The therapeutic range is between 0.5 and 1.0 IU/ml. LMWH is given as a subcutaneous injection on either a once daily or 12-hourly basis. There are a variety of different LMWHs available including dalteparin, enoxaparin and tinzaparin with dosage dependent on the indication and drug used. Management of excessive anticoagulation and bleeding Major haemorrhage is seen in 0e2% of patients therapeutically anticoagulated on heparin or LMWH.7 Unfractionated heparin: if major haemorrhage occurs whilst on unfractionated heparin the infusion should be stopped. The anticoagulant effect of heparin can be rapidly reversed with protamine sulphate at a dose of 1 mg/100 units of heparin
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contraindicated during pregnancy as it is associated with teratogenicity (between 6 and 12 weeks of gestation), spontaneous abortion, fetal wastage and maternal haemorrhage. In the postnatal period both warfarin and heparin are safe with the choice of anticoagulant used dependant on the indication and patient choice.13
3) Direct thrombin inhibitors (lepirudin/dabigatran etexilate) a. Lepirudin is an intravenously administered direct thrombin inhibitor licensed for use in patients with HIT.10 Monitoring of this drug is required with aPTT measurements. b. Dabigatran etexilate is a once-daily orally administered direct thrombin inhibitor. Large-scale double-blind trials of thromboprophylaxis with dabigatran etexilate in comparison to enoxaparin in total hip replacement (RENOVATE Trial) and total knee replacement (RE-MODEL Trial) have shown non-inferiority to enoxaparin.11 The recently published RE-LY study comparing dabigatran to warfarin in atrial fibrillation has shown non-inferiority of dabigatran to warfarin.12 This currently has NICE approval as an option for thromboprophylaxis in patients undergoing elective total hip or knee replacement.
Anticoagulation in the context of surgery Thromboprophylaxis for elective surgical patients: postoperative venous thrombosis is a significant cause of morbidity in surgical patients. It is estimated that deep vein thrombosis occurs in more than 20% of patients having major surgery with this number rising to greater than 40% for major orthopaedic surgery.14 The choice of thromboprophylaxis must be assessed on the basis of patient-related risk factors, listed below:14 active malignancy age > 60 years history of VTEepersonal/1st degree relative inherited thrombophilia/antiphospholipid syndrome pregnancy/puerperium acute surgical admission with inflammatory/intra-abdominal condition use of OCP/HRT recent myocardial infarction/stroke obesity (BMI > 30 kg/m2) inflammatory bowel disease (ulcerative colitis/Crohn’s disease)
Contraindications to anticoagulation There are no absolute contraindications to anticoagulation. If a patient is actively bleeding anticoagulation should be withheld until this is controlled. Relative contraindications include recent cerebral haemorrhage, ulceration in the gastrointestinal tract, known bleeding disorders and uncontrolled hypertension. Anticoagulation in pregnancy/breastfeeding In patients requiring anticoagulation during pregnancy for acute VTE treatment with twice-daily LMWH dosed according to the booking weight is recommended.13 Warfarin is
The National Institute for Health and Clinical Excellence recommendations for thromboprophylaxis in patients with increased risk of VTE and low risk of major bleeding based on type of surgery
Table 2
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immobility active heart failure/respiratory failure pro-thrombotic haematological disorder (paraproteinaemia, myeloproliferative disorder) central venous catheter in-situ anaesthetic plus surgical time >90 min nephrotic syndrome. NICE recommendations with regard to thromboprophylaxis in different surgical contexts are shown in Table 2.
2 3
4
Aspirin thromboprophylaxis Aspirin thromboprophylaxis in the post-operative period is appealing as it can be simply administered, is cheap and has no requirement for monitoring. Trials carried out comparing aspirin to LMWH have shown aspirin to be inferior in reduction of VTE risk and associated with significantly higher risks of bleeding. As a result aspirin is not recommended for use as VTE thromboprophylaxis.2
5
6
7
Elective surgery in patients on warfarin In patients undergoing major surgery warfarin should be stopped at least 3 days prior to surgery.5 The choice of bridging regimen required during the peri-operative period is dependent on the risk of bleeding associated with the procedure weighed against the risk of thrombosis. In patients on warfarin who are at low risk of thrombosis a prophylactic dose of LMWH alongside mechanical measures may be sufficient. Patients with higher risk for thrombotic complications may be managed with either prophylactic or therapeutic LMWH or less commonly, unfractionated heparin.
8 9 10
11
Oral surgery For most outpatient dental surgery (including extractions) warfarin should be continued if INR < 4 as the risk of significant bleeding is low. Local haemostatic treatments should also be used (oxidized cellulose, collagen sponges or tranexamic acid mouth wash).15
12
13
Emergency surgery in patients on warfarin Patients requiring emergency surgery whilst taking warfarin may need full reversal of anticoagulation. In this context reversal is generally with intravenous vitamin K and prothrombin complex concentrate infusions. A
14
15
REFERENCES 1 Connock M, Stevens C, Fry-Smith A, et al. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral
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anticoagulation therapy: a systematic review and economic modelling. Health Technol Assess 2007; 11. iiieiv, ixe66. Hunt BJ. The prevention of hospital-acquired venous thromboembolism in the United Kingdom. Br J Haematol 2009; 144: 642e52. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133(suppl 6): 160Se98. British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition e 2005 update. Br J Haematol 2006; 132: 277e85. British Committee for Standards in Haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101: 374e87. Francis CW. New issues in oral anticoagulants. Hematology; 2008. American Society of Hematology Education Book. American Society of Hematology, 2008. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 257Se98. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000; 87: 266e72. British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19e34. British Committee for Standards in Haematology. The management of heparin induced thrombocytopenia. Br J Haematol. 2006; 133: 259e69. Bounameaux H. The novel anticoagulants: entering a new era. Swiss Med Wkly 2009; 139: 60e4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139e51. Royal College of Obstetricians and Gynaecologists (RCOG). Thromboembolic disease in pregnancy and the puerperium: acute management. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG), 2007 Feb. (Green-top guideline; no. 28). The National Institute for Health and Clinical Excellence CG92. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. January 2010. British Committee for Standards in Haematology. Guidelines of the management of patients on oral anticoagulants requiring dental surgery. Br Dent J 2007; 203: 389e93.
Ó 2010 Elsevier Ltd. All rights reserved.
co-factors on phospholipid surfaces.3 The vitamin K-dependent factors are: pro-coagulant factors (II, VII, IX and X) anticoagulant factors (protein C and S). Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract, with peak concentrations reached at 90 minutes following oral administration. Once absorbed it binds strongly to albumin and has a half life of 36e72 hours, with the peak therapeutic effect occurring at between 24 and 72 hours. Warfarin is metabolized in the liver via the cytochrome P450 enzyme system.3
Anticoagulation Paul Batty Graham Smith
Abstract The increasing incidence of thrombosis in hospitalized patients in the 21st century is due to improved awareness by clinicians and more sophisticated forms of imaging. Thromboprophylaxis is now an imperative in the NHS of the UK and this combined with new, improved and safer forms of anticoagulation means that post-operative deaths from venous thromboembolic disease should become a thing of the past. In the following paper the authors review the up-to-date literature with emphasis on the newer anticoagulants that do not require blood test monitoring. We fully accept that this is a developing field and that the recognized indications for certain of these agents will change with the accumulation of further evidence.
Commencement and monitoring of warfarin treatment On commencement of warfarin treatment the intensity of loading is dependent on the indication for anticoagulation and patientrelated factors, such as age and haemorrhagic risk. Where anticoagulation is required rapidly, as in the case of acute VTE, a regimen involving a single dose of 10 mg on day 1 with subsequent doses determined by the international normalized ratio (INR) is recommended (e.g. Fennerty regimen).4 The INR is a ratio of the patient’s prothrombin time compared to a normal prothrombin time.3,5 In this case heparin (unfractionated or low molecular weight) should be co-administered until the INR is greater than 2.0 for 2 days to reduce the incidence of warfarininduced skin necrosis. In the situation where rapid anticoagulation is not required (e.g. atrial fibrillation) a slow loading protocol that does not require heparin is recommended (e.g. Janes protocol).4 In this, warfarin is commenced at 3 mg daily and subsequent doses are determined on the basis of weekly INR measurements. The majority of patients require a dose of 3e8 mg/day, but this may vary from 0.5 mg/week to in excess of 50 mg/day in patients with inherited warfarin resistance. The therapeutic target ranges recommended for various indications for warfarin are shown in Table 1.4
Keywords Anticoagulation; aspirin; bleeding; heparin; novel anticoagulants; pregnancy; surgery; thromboprophylaxis; warfarin
Introduction It is estimated that one million people in the UK are currently taking oral anticoagulation in the form of warfarin, representing approximately 1.6% of the population of the country.1 Venous thromboembolic (VTE) disease is responsible for around 25,000 deaths annually with 50% of fatal pulmonary emboli following hospital admission.2 Anticoagulation can be used either to prevent clot propagation or to reduce the risk of developing venous thrombosis. In this article we review the current forms of anticoagulant therapy in use in the UK and specifically discuss how this impacts on peri-operative management.
British Committee for Standards in Haematology (BCSH) guidelines on recommended target INR based on indication for anticoagulation4
TYPES OF ANTICOAGULANTS Warfarin
Indication Acute DVT/PE Recurrence of VTE on warfarin Recurrence of VTE after warfarin Antiphospholipid syndrome Atrial fibrillation Mural thrombus Cardiomyopathy Prosthetic valves Aortic bileaflet Aortic tilting disk Mitral bileaflet Mitral tilting disk Caged ball or caged disk (aortic or mitral)
Warfarin is the most common form of oral anticoagulant used in the UK. It is a synthetic derivative of 4-hydroxycoumarin, acting via inhibition of the enzyme vitamin K epoxide reductase (VKOR). This prevents formation of vitamin K hydroquinone which is required for gamma-carboxylation of the vitamin Kdependent factors. This reduces the coagulant activity of these factors, as they are no longer able to undergo Ca2þ-dependent changes in their structure required to bind to
Paul Batty BSc(Hons) MBBS MRCP is a Specialist Registrar in Haematology at the Royal Surrey County Hospital, Guildford, Surrey, UK. Conflicts of interest: none declared.
2.5 3.0 3.0 3.0 3.5
DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; VTE, venous thromboembolic.
J Graham Smith BSc MD FRCP FRCPath is a Professor of Haematology at the University of Surrey, Guildford and Consultant in Haematology at Frimley Park Hospital, Frimley, Surrey, UK. Conflicts of interest: none declared.
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Table 1
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Factors affecting warfarin dosage Many factors can influence the warfarin requirements of an individual patient. These are discussed below.
haemorrhage increases substantially when the INR is greater than 4.5.7 On encountering an elevated INR reading the requirement for reversal of warfarin is dependent on whether there is active bleeding. The BCSH Guidelines for management of bleeding and excessive anticoagulation for patients on warfarin are shown in Figure 1.
Drug interactions Due to warfarin being metabolized via the cytochrome P450 systems, many drugs can affect its metabolism. It is recommended that on commencement of new medications the British National Formulary (BNF) is consulted as a dose adjustment of warfarin may be required. Examples of some of the interactions seen with commonly prescribed drugs are shown below: Potentiate warfarin effect: amiodarone, non-steroidal antiinflammatory drugs (NSAIDs), antibiotics (cephalosporins, erythromycin, ciprofloxacin and metronidazole), antifungals, paracetamol, allopurinol, omeprazole, thyroxine, alcohol (chronic excess ingestion), corticosteroids. Inhibit warfarin effect: antiepileptics (carbamazepine), rifampicin, oral contraceptive pill, St John’s wort.
Non-haemorrhagic toxicities Non-haemorrhagic side-effects of warfarin are uncommon. These include warfarin-induced skin necrosis, hypersensitivity, skin rashes, alopecia and diarrhoea. Warfarin-induced skin necrosis This is a rare complication of warfarin therapy occurring in less than 0.1% of newly warfarinized patients. It tends to occur within the first 10 days of treatment, is more common in women and with higher loading doses of warfarin.8 It is thought to occur due to levels of protein C falling faster than the other vitamin Kdependent factors leading to thrombus formation and subsequent necrosis. Treatment involves stopping warfarin therapy and some patients may require surgical intervention. Warfarininduced skin necrosis is considered a contraindication for future warfarin therapy.
Genetic factors Genetic mutations in the vitamin K epoxide reductase (VKOR) complex 1 lead to warfarin resistance and polymorphisms for cytochrome P450 2C9 can lead to reduced warfarin requirements.6
Other vitamin K antagonists Although warfarin is the most common vitamin K antagonist used in the UK, other oral vitamin K antagonists in use include phenindione, acenocoumarol and phenprocoumon.
Dietary factors Increased dietary intake of foods containing high levels of vitamin K1 can lead to higher warfarin dose requirements or resistance. Foods that are rich in vitamin K1 are the leafy green vegetables (e.g. spinach, cabbage, broccoli), parsley and some fruits (e.g. avocado and kiwi fruit).
Heparin Heparin, either in the form of unfractionated or low-molecularweight heparin (LMWH), is the most common parentally administered anticoagulant used in the UK. It is a naturally occurring anionic glycosaminoglycan produced by mast cells, with all heparin in the UK being of porcine origin. LMWH is produced from unfractionated heparin by controlled depolymerization.
Management of excessive anticoagulation and bleeding Warfarin, even when closely monitored, increases the risk of major bleeding by 0.3e0.5% per year. The risk of major
Management of excessive anticoagulation and bleeding associated with warfarin therapy 4,5 Is the patient having major bleeding?
No/minor bleeding
INR 4.5–6.0
INR 6.0–8.0
Yes
INR 8.0
Stop Warfarin Give 5–10 mg intravenous vitamin K
Reduce dose of Warfarin or stop Restart when INR 5.0
Stop Warfarin
Stop Warfarin
Restart when INR 5.0
Restart when INR 5.0 Consider 0.5–2.5 mg oral vitamin K
Give intravenous prothrombin complex concentrate (PCC) e.g. Beriplex or Octaplex up to 50 units/kg (based on INR) or 15 ml/kg fresh frozen plasma if PCC not available
Figure 1
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infused over 10 min. The maximum dose of protamine sulphate infused over this time should not exceed 50 mg.9
Unfractionated heparin ranges in molecular weight from 5000 to 35,000 Da and LMWH from 3000 to 5000 Da.9 Unfractionated heparin and LMWH form a complex with antithrombin-III, greatly potentiating its effect on the inactivation of various clotting factors. The unfractionated heparineantithrombin complex most notably inactivates factors Xa and thrombin (factor IIa), but to a lesser extent factors IXa, XIa and XIIa. The LMWHeantithrombin complex has its main activity through inactivation of factor Xa, although different preparations have varying degrees of activity on thrombin also. The heparins are not absorbed orally, so must be given intravenously or subcutaneously. The half-life of intravenous unfractionated heparin is approximately 60 min when given at a rate of 100 U/kg. The half-life of subcutaneous LMWH is significantly higher at around 4 hours.9 Unfractionated heparin is metabolized by two distinct mechanisms. The first is saturable, occurring via binding of heparin to endothelial cell receptors and macrophages. It is subsequently internalized and depolymerized. The second non-saturable mechanism is via renal clearance. LMWH is cleared entirely by the kidneys so its dose should be adjusted according to renal function.
Low-molecular-weight heparin: in major haemorrhage, protamine sulphate can be given within 8 hours of administration of LMWH, although this incompletely reverses the anticoagulant effect. The recommended dose for protamine sulphate is 1 mg/ 100 anti-Xa units. Fresh frozen plasma is ineffective in the reversal of the anticoagulant effect of LMWH.9
Non-haemorrhagic toxicities Osteoporosis In patients on long-term unfractionated heparin therapy (>1 month) significant reduction in bone density is seen in around 30% of patients and vertebral fractures in 2%.9 The risk of osteoporosis is much lower with LMWH.9 Heparin-associated thrombocytopenia/heparin-induced immune thrombocytopenia (HIT) A small decrease in platelet count (not <100), with no clinical sequelae is common in the first few days of commencement of heparin treatment. This resolves spontaneously without need for stopping heparin. A more serious complication is heparin-induced thrombocytopenia (HIT). This clinical syndrome develops between 5 and 10 days of commencement of heparin (sooner if heparin exposure within the previous 100 days).10 The risk is higher for unfractionated heparin, but may also occur with LMWH. It occurs as a result of formation of IgG antibodies to the complex formed between heparin and platelet factor-4. Antibody binding to this complex leads to platelet activation and thrombin generation, resulting in thrombosis in 50% and mortality in 20e30% of patients. Treatment of HIT involves stopping all heparin and commencing an alternative anticoagulant such as danaparoid or lepirudin.9
Commencement and monitoring of heparin Unfractionated heparin: unfractionated heparin therapy is monitored by the activated partial thromboplastin time (aPTT). Generally a target aPTT ratio of 1.5e2.5 (patient’s aPTT compared to a normal aPTT) is used in the treatment of VTE, although this can vary depending on the aPTT reagent used. In the treatment of VTE heparin should be commenced with a bolus dose of 5000e7500 units (75 U/kg) followed by an intravenous infusion of 18 U/kg/h.9 An aPTT should be taken 4 hours after commencement of an IV heparin infusion and following any subsequent dose adjustments. Please refer to local protocols for target aPTT and recommended dose adjustments. In the treatment of VTE unfractionated heparin can also be given subcutaneously at a dose of 15,000 units twice daily with adjustments made on the basis of the aPTT. Unfractionated heparin when used for thromboprophylaxis is given subcutaneously at a dose of 5000 units either 12-hourly or 8-hourly dependent on thrombotic risk.
New anticoagulants There has been much interest in the novel anticoagulants recently as generally they do not require monitoring and are not associated with complications such as HIT. These novel anticoagulants act either directly or indirectly (via antithrombin) to inhibit factor Xa or thrombin. 1) Indirect factor Xa inhibitors (fondaparinux/idraparinux) a. Fondaparinux is given as a once-daily subcutaneous injection. It has been approved by NICE as an alternative to LMWH for thromboprophylaxis in orthopaedic and general surgery.11 b. Idraparinux is given as a once weekly subcutaneous injection. Trials to date have been disappointing and its development has been halted. A biotinylated form of idrapariunx (idrabiotaparinux) which is rapidly reversible by administration of avidin is currently in development. 2) Direct factor Xa inhibitors (rivaroxaban/apixaban) These are orally administered direct factor Xa inhibitors. Large double-blind trials comparing rivaroxaban with enoxaparin thromboprophylaxis in total hip arthroplasty (RECORD 1) or total knee arthroplasty (RECORD 3) have shown non-inferiority for rivaroxaban.11 Rivaroxaban has NICE approval as an option for thromboprophylaxis in these settings.
Low-molecular-weight heparin: LMWH generally does not require monitoring, although this may be desirable in circumstances such as in pregnancy, renal failure, with children or in patients with very low or high body mass indices. In these situations monitoring is via the anti-factor Xa assay taken 3e4 hours after LMWH administration. The therapeutic range is between 0.5 and 1.0 IU/ml. LMWH is given as a subcutaneous injection on either a once daily or 12-hourly basis. There are a variety of different LMWHs available including dalteparin, enoxaparin and tinzaparin with dosage dependent on the indication and drug used. Management of excessive anticoagulation and bleeding Major haemorrhage is seen in 0e2% of patients therapeutically anticoagulated on heparin or LMWH.7 Unfractionated heparin: if major haemorrhage occurs whilst on unfractionated heparin the infusion should be stopped. The anticoagulant effect of heparin can be rapidly reversed with protamine sulphate at a dose of 1 mg/100 units of heparin
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contraindicated during pregnancy as it is associated with teratogenicity (between 6 and 12 weeks of gestation), spontaneous abortion, fetal wastage and maternal haemorrhage. In the postnatal period both warfarin and heparin are safe with the choice of anticoagulant used dependant on the indication and patient choice.13
3) Direct thrombin inhibitors (lepirudin/dabigatran etexilate) a. Lepirudin is an intravenously administered direct thrombin inhibitor licensed for use in patients with HIT.10 Monitoring of this drug is required with aPTT measurements. b. Dabigatran etexilate is a once-daily orally administered direct thrombin inhibitor. Large-scale double-blind trials of thromboprophylaxis with dabigatran etexilate in comparison to enoxaparin in total hip replacement (RENOVATE Trial) and total knee replacement (RE-MODEL Trial) have shown non-inferiority to enoxaparin.11 The recently published RE-LY study comparing dabigatran to warfarin in atrial fibrillation has shown non-inferiority of dabigatran to warfarin.12 This currently has NICE approval as an option for thromboprophylaxis in patients undergoing elective total hip or knee replacement.
Anticoagulation in the context of surgery Thromboprophylaxis for elective surgical patients: postoperative venous thrombosis is a significant cause of morbidity in surgical patients. It is estimated that deep vein thrombosis occurs in more than 20% of patients having major surgery with this number rising to greater than 40% for major orthopaedic surgery.14 The choice of thromboprophylaxis must be assessed on the basis of patient-related risk factors, listed below:14 active malignancy age > 60 years history of VTEepersonal/1st degree relative inherited thrombophilia/antiphospholipid syndrome pregnancy/puerperium acute surgical admission with inflammatory/intra-abdominal condition use of OCP/HRT recent myocardial infarction/stroke obesity (BMI > 30 kg/m2) inflammatory bowel disease (ulcerative colitis/Crohn’s disease)
Contraindications to anticoagulation There are no absolute contraindications to anticoagulation. If a patient is actively bleeding anticoagulation should be withheld until this is controlled. Relative contraindications include recent cerebral haemorrhage, ulceration in the gastrointestinal tract, known bleeding disorders and uncontrolled hypertension. Anticoagulation in pregnancy/breastfeeding In patients requiring anticoagulation during pregnancy for acute VTE treatment with twice-daily LMWH dosed according to the booking weight is recommended.13 Warfarin is
The National Institute for Health and Clinical Excellence recommendations for thromboprophylaxis in patients with increased risk of VTE and low risk of major bleeding based on type of surgery
Table 2
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immobility active heart failure/respiratory failure pro-thrombotic haematological disorder (paraproteinaemia, myeloproliferative disorder) central venous catheter in-situ anaesthetic plus surgical time >90 min nephrotic syndrome. NICE recommendations with regard to thromboprophylaxis in different surgical contexts are shown in Table 2.
2 3
4
Aspirin thromboprophylaxis Aspirin thromboprophylaxis in the post-operative period is appealing as it can be simply administered, is cheap and has no requirement for monitoring. Trials carried out comparing aspirin to LMWH have shown aspirin to be inferior in reduction of VTE risk and associated with significantly higher risks of bleeding. As a result aspirin is not recommended for use as VTE thromboprophylaxis.2
5
6
7
Elective surgery in patients on warfarin In patients undergoing major surgery warfarin should be stopped at least 3 days prior to surgery.5 The choice of bridging regimen required during the peri-operative period is dependent on the risk of bleeding associated with the procedure weighed against the risk of thrombosis. In patients on warfarin who are at low risk of thrombosis a prophylactic dose of LMWH alongside mechanical measures may be sufficient. Patients with higher risk for thrombotic complications may be managed with either prophylactic or therapeutic LMWH or less commonly, unfractionated heparin.
8 9 10
11
Oral surgery For most outpatient dental surgery (including extractions) warfarin should be continued if INR < 4 as the risk of significant bleeding is low. Local haemostatic treatments should also be used (oxidized cellulose, collagen sponges or tranexamic acid mouth wash).15
12
13
Emergency surgery in patients on warfarin Patients requiring emergency surgery whilst taking warfarin may need full reversal of anticoagulation. In this context reversal is generally with intravenous vitamin K and prothrombin complex concentrate infusions. A
14
15
REFERENCES 1 Connock M, Stevens C, Fry-Smith A, et al. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral
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anticoagulation therapy: a systematic review and economic modelling. Health Technol Assess 2007; 11. iiieiv, ixe66. Hunt BJ. The prevention of hospital-acquired venous thromboembolism in the United Kingdom. Br J Haematol 2009; 144: 642e52. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133(suppl 6): 160Se98. British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition e 2005 update. Br J Haematol 2006; 132: 277e85. British Committee for Standards in Haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101: 374e87. Francis CW. New issues in oral anticoagulants. Hematology; 2008. American Society of Hematology Education Book. American Society of Hematology, 2008. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 257Se98. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000; 87: 266e72. British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19e34. British Committee for Standards in Haematology. The management of heparin induced thrombocytopenia. Br J Haematol. 2006; 133: 259e69. Bounameaux H. The novel anticoagulants: entering a new era. Swiss Med Wkly 2009; 139: 60e4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139e51. Royal College of Obstetricians and Gynaecologists (RCOG). Thromboembolic disease in pregnancy and the puerperium: acute management. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG), 2007 Feb. (Green-top guideline; no. 28). The National Institute for Health and Clinical Excellence CG92. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. January 2010. British Committee for Standards in Haematology. Guidelines of the management of patients on oral anticoagulants requiring dental surgery. Br Dent J 2007; 203: 389e93.
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