Thromboembolism

Venous thromboembolism

Overview

Venous thromboembolism includes deep-vein thrombosis and pulmonary embolism, and occurs as a result of thrombus formation in a vein.

Prophylaxis of venous thromboembolism All patients admitted to hospital should undergo a risk assessment for venous thromboembolism on admission.

Patients considered to be at high risk include those anticipated to have a substantial reduction in mobility, those with obesity, malignant disease, history of venous thromboembolism, thrombophilic disorder, or patients over 60years. Patients with risk factors for bleeding (e.g. acute stroke, thrombocytopenia, acquired or untreated inherited bleeding disorders) should only receive pharmacological

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prophylaxis when the risk of bleeding does not outweigh the risk of venous thromboembolism. NICE clinical guideline92 (January2010) provides a full list of risk factors, and gives recommendations for prophylaxis. A venous

thromboembolism risk assessment checklist is also available from the Department of Health (www.gov.uk/dh).

Patients scheduled for surgery should be offered mechanical prophylaxis (e.g. anti-embolism stockings) on admission if appropriate; prophylaxis should continue until the patient is sufficiently mobile. Choice of mechanical prophylaxis will depend on factors such as the type of surgery, suitability for the patient, and their condition.

Patients undergoing general or orthopaedic surgery, who are considered to be at high risk of venous

thromboembolism, should be offered pharmacological prophylaxis. Choice of prophylaxis will depend on the type of surgery, suitability for the patient, and local policy. A low molecular weight heparin is suitable in all types of general and orthopaedic surgery; heparin (unfractionated) p.128is preferred for patients in renal failure. Fondaparinux sodium p.123is an option for patients undergoing hip or knee replacement surgery, hip fracture surgery, gastro-intestinal, bariatric, or day surgery procedures. The oral anticoagulants apixaban p.121, dabigatran etexilate p.131, and rivaroxaban p.123are indicated for thromboprophylaxis following hip or knee replacement surgery.

Pharmacological prophylaxis in general surgery should usually continue for5–7days, or until sufficient mobility has been re-established. Pharmacological prophylaxis should be extended to28days after major cancer surgery in the abdomen or pelvis. Hip or knee replacement surgery, and hip fracture surgery, require an extended duration of

pharmacological prophylaxis, depending on the preparation used (consult product literature).

General medical patients who are considered to be at high risk of venous thromboembolism should be offered pharmacological prophylaxis on admission. Choice of prophylaxis will depend on the medical condition, suitability for the patient, and local policy. Patients should receive either a low molecular weight heparin, heparin

(unfractionated) (if patient in renal failure), or fondaparinux sodium. Prophylaxis should continue until the patient is no longer considered to be at significant risk of venous thromboembolism. Mechanical prophylaxis (e.g. anti-embolism stockings) can be offered to medical patients in whom pharmacological prophylaxis is contra-indicated, and continued until the patient is sufficiently mobile.

Edoxaban

Edoxaban p.122, an inhibitor of factor Xa, is given orally for the treatment and prophylaxis of venous thromboembolism, although, it should not be used as an alternative to unfractionated heparin in pulmonary embolism in patients with haemodynamic instability, or who may receive thrombolysis or pulmonary embolectomy. Duration of therapy should be determined by balancing the benefit of treatment with the bleeding risk; shorter duration of treatment (at least3months) should be based on transient risk factors i.e. recent surgery, trauma, immobilisation, and longer durations should be based on permanent risk factors or idiopathic deep-vein thrombosis or pulmonary embolism.

Edoxaban is also licensed for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one other risk factor.

Treatment of venous thromboembolism For the initial treatment of deep-vein thrombosis and pulmonary embolism a low molecular weight heparin is used; alternatively, heparin (unfractionated) is given as an intravenous loading dose, followed by continuous intravenous infusion (using an infusion pump) or (for deep-vein thrombosis only) by intermittent subcutaneous

injection. Intermittent intravenous injection of heparin (unfractionated) is no longer recommended. An oral anticoagulant (usually warfarin sodium p.135is started at the same time as unfractionated or low molecular weight heparin (the heparin needs to be continued for at least5days and until the INR is2for at least24hours). Laboratory monitoring for heparin (unfractionated), preferably on a daily basis, is essential; determination of the activated partial thromboplastin time (APTT) is the most widely used measure (for heparin (unfractionated). A low molecular weight heparin or, in some circumstances, heparin (unfractionated) is also used in regimens for the management of myocardial infarction and unstable angina.

Management of venous thromboembolism in pregnancy

Heparins are used for the management of venous thromboembolism in pregnancy because they do not cross the placenta. Low molecular weight heparins are preferred because they have a lower risk of osteoporosis and of heparin-induced thrombocytopenia. Low molecular weight heparins are eliminated more rapidly in pregnancy, requiring alteration of the dosage regimen for drugs such as dalteparin sodium p.126, enoxaparin sodium p.127, and tinzaparin sodium p.129. Treatment should be stopped at the onset of labour and advice sought from a specialist on continuing therapy after birth.

Extracorporeal circuits

Heparin (unfractionated) is also used in the maintenance of extracorporeal circuits in cardiopulmonary bypass and haemodialysis.

Haemorrhage

If haemorrhage occurs it is usually sufficient to withdraw unfractionated or low molecular weight heparin, but if rapid reversal of the effects of the heparin is required, protamine sulfate p.1258is a specific antidote (but only partially reverses the effects of low molecular weight heparins).

Management of stroke

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Overview

Stroke is associated with a significant risk of morbidity and mortality. Patients presenting with acute symptoms should be immediately transferred to hospital for accurate diagnosis of stroke type, and urgent initiation of appropriate treatment; patients should be managed by a specialist multidisciplinary stroke team.

The following notes give an overview of the initial and long-term management of transient ischaemic attack, ischaemic stroke, and intracerebral haemorrhage.

Transient ischaemic attack

Patients suspected of having a transient ischaemic attack should immediately receive aspirin p.117(patients with aspirin hypersensitivity, or those intolerant of aspirin despite the addition of a proton pump inhibitor, should receive clopidogrel p.119[unlicensed use] as an alternative).

Following a confirmed diagnosis, patients should receive treatment for secondary prevention (see Long-term Management, under Ischaemic Stroke).

Ischaemic stroke Initial management

Alteplase p.210is recommended in the treatment of acute ischaemic stroke if it can be administered within4.5hours of symptom onset; it should be given by medical staff experienced in the administration of thrombolytics and the treatment of acute stroke, preferably within a specialist

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stroke centre. Treatment with aspirin should be initiated 24hours after thrombolysis (or as soon as possible within 48hours of symptom onset in patients not receiving thrombolysis); patients with aspirin hypersensitivity, or those intolerant of aspirin despite the addition of a proton pump inhibitor, should receive clopidogrel [unlicensed use]

as an alternative.

Anticoagulants are not recommended as an alternative to antiplatelet drugs in acute ischaemic stroke in patients who are in sinus rhythm. However, parenteral anticoagulants may be indicated in patients who are symptomatic of, or at high risk of developing, deep vein thrombosis or pulmonary embolism; warfarin sodium p.135should not be commenced in the acute phase of ischaemic stroke.

Anticoagulants should be considered after cardio-embolic ischaemic stroke in patients with atrialfibrillation, however patients presenting with atrialfibrillation following a disabling ischaemic stroke should receive aspirin before being considered for anticoagulant treatment. Patients already receiving anticoagulation for a prosthetic heart valve who experience a disabling ischaemic stroke and are at significant risk of haemorrhagic transformation, should have their anticoagulant treatment stopped for7days and substituted with aspirin.

Treatment of hypertension in the acute phase of ischaemic stroke can result in reduced cerebral perfusion, and should therefore only be instituted in the event of a hypertensive emergency, or in those patients considered for thrombolysis.

Long-term management

Patients should receive long-term treatment following a transient ischaemic attack or an ischaemic stroke to reduce the risk of further cardiovascular events.

Following atransient ischaemic attackor anischaemic stroke(not associated with atrialfibrillation), long-term treatment with clopidogrel [unlicensed in transient ischaemic attack] is recommended. If clopidogrel is contra-indicated or not tolerated, patients can receive modified-release dipyridamole p.120in combination with aspirin; if both aspirin and clopidogrel are contra-indicated or not tolerated, then modified-release dipyridamole alone is recommended; if both modified-release dipyridamole and clopidogrel are contra-indicated or not tolerated, then aspirin alone is recommended.

Patients with stroke associated with atrialfibrillation should be reviewed for long-term treatment with warfarin sodium or an alternative anticoagulant (see Initial Management under Ischaemic Stroke).

Anticoagulants are not routinely recommended in the long-term prevention of recurrent stroke, except in patients with atrialfibrillation.

A statin should be initiated48hours after stroke symptom onset, irrespective of the patient’s serum-cholesterol concentration.

Following the acute phase of ischaemic stroke, blood pressure should be measured and treatment initiated to achieve a target blood pressure of<130/80mmHg. Beta-blockers should not be used in the management of hypertension following a stroke, unless they are indicated for a co-existing condition.

All patients should be advised to make lifestyle modifications that include beneficial changes to diet, exercise, weight, alcohol intake, and smoking.

Intracerebral haemorrhage Initial Management

Surgical intervention may be required following intracerebral haemorrhage to remove the haematoma and relieve intracranial pressure. Patients taking anticoagulants should have this treatment stopped and reversed;

anticoagulant therapy has, however, been used in patients with intracerebral haemorrhage who are symptomatic of

deep vein thrombosis or pulmonary embolism; placement of a cavalfilter is an alternative in this situation.

Long-term management

Aspirin therapy should only be given to patients at a high risk of a cardiac ischaemic event. Anticoagulant therapy is not recommended following an intracerebral haemorrhage, even in those with atrialfibrillation, unless the patient is at very high risk of an ischaemic stroke or cardiac ischaemic events; advice from a specialist should be sought in this situation. Blood pressure should be measured and treatment initiated where appropriate, taking care to avoid

hypoperfusion. Statins should be avoided following intracerebral haemorrhage, however they can be used with caution when the risk of a vascular event outweighs the risk of further haemorrhage.

Oral anticoagulants

Overview

The main use of anticoagulants is to prevent thrombus formation or extension of an existing thrombus in the slower-moving venous side of the circulation, where the thrombus consists of afibrin web enmeshed with platelets and red cells.

Anticoagulants are of less use in preventing thrombus formation in arteries, for in faster-flowing vessels thrombi are composed mainly of platelets with littlefibrin.

Coumarins and phenindione

The oral anticoagulants warfarin sodium p.135, acenocoumarol p.134and phenindione p.134, antagonise the effects of vitamin K, and take at least48to72hours for the anticoagulant effect to develop fully; warfarin sodium is the drug of choice. If an immediate effect is required, unfractionated or low molecular weight heparin must be given concomitantly.

These oral anticoagulants should not be used in cerebral artery thrombosis or peripheral artery occlusion asfirst-line therapy; aspirin p.117is more appropriate for reduction of risk in transient ischaemic attacks. Unfractionated or a low molecular weight heparin (see under Parenteral anticoagulants p.115) is usually preferred for the prophylaxis of venous thromboembolism in patients undergoing surgery; alternatively, warfarin sodium can be continued in selected patients currently taking long-term warfarin sodium and who are at high risk of

thromboembolism (seek expert advice).

Dose

The base-line prothrombin time should be determined but the initial dose should not be delayed whilst awaiting the result.

Target INR

The following indications and target INRs for adults for warfarin take into account recommendations of the British Society for Haematology guidelines on oral anticoagulation with warfarin—fourth edition.Br J Haematol2011;154_: 311–324:

An INR which is within0.5units of the target value is generally satisfactory; larger deviations require dosage adjustment. Target values (rather than ranges) are now recommended.

INR2.5for:

.treatment of deep-vein thrombosis or pulmonary embolism (including those associated with

antiphospholipid syndrome or for recurrence in patients no longer receiving warfarin sodium)

.atrialfibrillation

.cardioversion—target INR should be achieved at least 3weeks before cardioversion and anticoagulation should

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continue for at least4weeks after the procedure (higher target values, such as an INR of3, can be used for up to 4weeks before the procedure to avoid cancellations due to low INR)

.dilated cardiomyopathy

.mitral stenosis or regurgitation in patients with either atrialfibrillation, a history of systemic embolism, a left atrial thrombus, or an enlarged left atrium

.bioprosthetic heart valves in the mitral position (treat for 3months), or in patients with a history of systemic embolism (treat for at least3months), or with a left atrial thrombus at surgery (treat until clot resolves), or with other risk factors (e.g. atrialfibrillation or a low ventricular ejection fraction)

.acute arterial embolism requiring embolectomy (consider long-term treatment)

.myocardial infarction INR3.5for:

.recurrent deep-vein thrombosis or pulmonary embolism in patients currently receiving anticoagulation and with an INR above2;

Mechanical prosthetic heart valves:

.the recommended target INR depends on the type and location of the valve, and patient-related risk factors .consider increasing the INR target or adding an

antiplatelet drug, if an embolic event occurs whilst anticoagulated at the target INR.

Duration

The risks of thromboembolism recurrence and

anticoagulant-related bleeding should be considered when deciding the duration of anticoagulation.

The following durations of warfarin sodium for the treatment of deep-vein thrombosis and pulmonary embolism reflect the recommendations of the British Society for Haematology (Guidelines on Oral Anticoagulation with Warfarin—fourth edition.Br J Haematol2011;154_: 311–324):

.6weeks for isolated calf-vein deep-vein thrombosis .3months for venous thromboembolism provoked by

surgery or other transient risk factor (e.g. combined oral contraceptive use, pregnancy, plaster cast)

.at least3months for unprovoked proximal deep-vein thrombosis or pulmonary embolism; long-term anticoagulation may be required.

Haemorrhage

The main adverse effect of all oral anticoagulants is haemorrhage. Checking the INR and omitting doses when appropriate is essential; if the anticoagulant is stopped but not reversed, the INR should be measured2–3days later to ensure that it is falling. The cause of an elevated INR should be investigated. The following recommendations (which take into account the recommendations of the British Society for Haematology Guidelines on Oral Anticoagulation with Warfarin—fourth edition.Br J Haematol2011;154_:311–324) are based on the result of the INR and whether there is major or minor bleeding; the recommendations apply to adults taking warfarin:

.Major bleeding—stop warfarin sodium; give

phytomenadione p.997(vitamin K1) by slow intravenous injection; give dried prothrombin complex p.108(factors II, VII, IX, and X); if dried prothrombin complex unavailable, fresh frozen plasma can be given but is less effective; recombinant factor VIIa is not recommended for emergency anticoagulation reversal

.INR>8.0, minor bleeding—stop warfarin sodium; give phytomenadione (vitamin K1) by slow intravenous injection; repeat dose of phytomenadione if INR still too high after24hours; restart warfarin sodium when INR

<5.0

.INR>8.0, no bleeding—stop warfarin sodium; give phytomenadione (vitamin K1) by mouth using the intravenous preparation orally [unlicensed use]; repeat dose of phytomenadione if INR still too high after 24hours; restart warfarin when INR<5.0

.INR5.0–8.0, minor bleeding—stop warfarin sodium; give phytomenadione (vitamin K1) by slow intravenous injection; restart warfarin sodium when INR<5.0 .INR5.0–8.0, no bleeding—withhold1or2doses of

warfarin sodium and reduce subsequent maintenance dose .Unexpected bleeding at therapeutic levels—always

investigate possibility of underlying cause e.g.

unsuspected renal or gastro-intestinal tract pathology Peri-operative anticoagulation

Warfarin sodium should usually be stopped5days before elective surgery; phytomenadione (vitamin K1) by mouth (using the intravenous preparation orally [unlicensed use]) should be given the day before surgery if the INR is1.5. If haemostasis is adequate, warfarin sodium can be resumed at the normal maintenance dose on the evening of surgery or the next day.

Patients stopping warfarin sodium prior to surgery who are considered to be at high risk of thromboembolism (e.g. those with a venous thromboembolic event within the last 3months, atrialfibrillation with previous stroke or transient ischaemic attack, or mitral mechanical heart valve) may require interim therapy (‘bridging’) with a low molecular weight heparin (using treatment dose). The low molecular weight heparin should be stopped at least24hours before surgery; if the surgery carries a high risk of bleeding, the low molecular weight heparin should not be restarted until at least48hours after surgery.

Patients on warfarin sodium p.135who require emergency surgery that can be delayed for6–12hours can be given intravenous phytomenadione p.997(vitamin K1) to reverse the anticoagulant effect. If surgery cannot be delayed, dried prothrombin complex p.108can be given in addition to intravenous phytomenadione (vitamin K1) and the INR checked before surgery.

Combined anticoagulant and antiplatelet therapy Existing antiplatelet therapy following an acute coronary syndrome or percutaneous coronary intervention should be continued for the necessary duration according to the indication being treated. The addition of warfarin sodium, when indicated (e.g. for venous thromboembolism or atrial fibrillation) should be considered following an assessment of the patient’s risk of bleeding and discussion with a cardiologist. The duration of treatment with dual therapy (e.g. aspirin p.117and warfarin sodium) or triple therapy (e.g. aspirin with clopidogrel p.119and warfarin sodium) should be kept to a minimum where possible. The risk of bleeding with aspirin and warfarin sodium dual therapy is lower than with clopidogrel and warfarin sodium Depending on the indications being treated and the patient’s risk of thromboembolism, it may be possible to withhold antiplatelet therapy until warfarin sodium therapy is complete, orvice versa(on specialist advice) in order to reduce the length of time on dual or triple therapy.

Parenteral anticoagulants

Overview

The main use of anticoagulants is to prevent thrombus formation or extension of an existing thrombus in the slower-moving venous side of the circulation, where the thrombus consists of afibrin web enmeshed with platelets and red cells.

Anticoagulants are of less use in preventing thrombus formation in arteries, for in faster-flowing vessels thrombi are composed mainly of platelets with littlefibrin.

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Heparin

Heparin initiates anticoagulation rapidly but has a short duration of action. It is often referred to as‘standard’or heparin (unfractionated) p.128to distinguish it from the low molecular weight heparins, which have a longer duration of action. Although a low molecular weight heparin is generally preferred for routine use, heparin

(unfractionated) can be used in those at high risk of bleeding because its effect can be terminated rapidly by stopping the infusion.

Low molecular weight heparins

Low molecular weight heparins (dalteparin sodium p.126, enoxaparin sodium p.127, and tinzaparin sodium p.129) are usually preferred over heparin (unfractionated) in the preventionof Venous thromboembolism p.112because they are as effective and they have a lower risk of heparin-induced thrombocytopenia. The standard prophylactic regimen does not require anticoagulant monitoring. The duration of action of low molecular weight heparins is longer than that of heparin (unfractionated) andonce-daily subcutaneous administration is possible for some indications, making them convenient to use.

Low molecular weight heparins are generally preferred over heparin (unfractionated) in thetreatmentof deep vein thrombosis and pulmonary embolism, and are also used in the treatment of myocardial infarction, unstable coronary artery disease (see under Acute coronary syndromes p.206) and for the prevention of clotting in extracorporeal circuits.

Dalteparin sodium and tinzaparin sodium (only 20 000unit/mL syringe) are also licensed for the extended treatment and prophylaxis of venous thromboembolism in patients with solid tumours; treatment is recommended for a duration of6months. Treatment should be initiated by healthcare professionals experienced in the treatment of venous thromboembolism.

Heparinoids

Danaparoid sodium p.125is a heparinoid used for prophylaxis of deep-vein thrombosis in patients undergoing general or orthopaedic surgery. Providing there is no evidence of cross-reactivity, it also has a role in patients who develop heparin-induced thrombocytopenia.

Argatroban

An oral anticoagulant can be given with argatroban monohydrate p.130, but it should only be started once thrombocytopenia has substantially resolved.

Hirudins

Bivalirudin, a hirudin analogue, is a thrombin inhibitor which is licensed for unstable angina or non-ST-segment elevation myocardial infarction in patients planned for urgent or early intervention, and as an anticoagulant for patients undergoing percutaneous coronary intervention (including patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention—see also Management of ST-segment elevation myocardial infarction (STEMI) in Acute coronary syndromes p.206).

Heparin flushes

The use of heparinflushes should be kept to a minimum. For maintaining patency of peripheral venous catheters, sodium chloride injection0.9% is as effective as heparinflushes. The role of heparinflushes in maintaining patency of arterial and central venous catheters is unclear.

Epoprostenol

Epoprostenol(prostacyclin) can be given to inhibit platelet aggregation during renal dialysis when heparins are unsuitable or contra-indicated. It is also licensed for the

treatment of primary pulmonary hypertension resistant to other treatment, usually with oral anticoagulation; it should be initiated by specialists in pulmonary hypertension.

Epoprostenol is a potent vasodilator. It has a short half-life of approximately3minutes and therefore it must be administered by continuous intravenous infusion.

Fondaparinux

Fondaparinux sodiumis a synthetic pentasaccharide that inhibits activated factor X.

Other drugs used for ThromboembolismStreptokinase, p.211

ANTIDOTES AND CHELATORS

Idarucizumab

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