Anticoagulation and thrombolytic therapy

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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Anticoagulation and thrombolytic therapy

Two major classes of drugs are commonly used in the management of thromboembolic disease. The anticoagulants heparin and warfarin are used to prevent thrombosis and limit the extension of an established clot, while thrombolytic agents such as streptokinase are used to dissolve thrombus.

Anticoagulation

Heparin

Unfractionated heparin is a naturally occurring glycosaminoglycan produced by mast cells. Low molecular weight (LMW) heparin is prepared by controlled depolymerisation of the unfractionated form. Both unfractionated and LMW heparin exert their anticoagulant properties by binding to antithrombin (AT) and potentiating its activity. AT is a normal circulating anticoagulant which inhibits the actions of factor Xa and thrombin. LMW heparin differs from unfractionated heparin in having a relatively greater anti-Xa than antithrombin activity.

Standard unfractionated heparin may be used therapeutically to treat established thrombosis (usually intravenously at higher dosage) or prophylactically to prevent thrombosis (usually subcutaneously at lower dosage). Most common indications for therapeutic use are deep vein thrombosis (DVT) and pulmonary embolism (PE) (Fig 40.1). A typical regimen is an intravenous loading dose of 5000 units followed by an infusion of 1000–2000 units/hour. The anticoagulant response varies as the drug binds non-specifically to plasma and cellular proteins. Laboratory monitoring using the APTT (see p. 20) is required; the therapeutic range is usually 1.5–2.5, these values being the ratio of the patient’s APTT to a control sample. As the half-life is short, high APTTs are managed by stopping the heparin but in the event of bleeding (in up to 7% of cases) the antidote protamine can be given. When the APTT is too low the heparin dose should be promptly increased. Heparin is normally continued until oral anticoagulation is therapeutic.

Fig 40.1 Large pulmonary embolus at the bifurcation of the main pulmonary trunk.

Prophylactic heparin is most commonly given to prevent DVT and PE in patients undergoing surgery. It is particularly indicated in patients with known risk factors for venous thrombosis (see p. 78) and in major procedures. A typical prophylactic regimen is 5000 units subcutaneously preoperatively and 5000 units 8- to 12-hourly after surgery, for 7 days or until the patient is mobile. No laboratory monitoring is necessary in routine cases – where required anti-X_a assays are used.

Apart from haemorrhage, patients on heparin may develop thrombocytopenia (see p. 69) and prolonged use can cause osteoporosis. It should be prescribed cautiously where there is any bleeding tendency.

LMW heparin

LMW heparins are now preferred for treatment of DVT and PE and prophylaxis. They appear to have superior efficacy, a better safety profile and to be more cost-effective than unfractionated heparin. LMW heparins cause less bleeding and a lower incidence of thrombocytopenia and osteoporosis. The more predictable dose response precludes the need for routine monitoring and the long half-life allows once or twice daily subcutaneous administration. Where monitoring is indicated (e.g. in renal failure), the anti-Xa effect is measured. LMW heparin treatment allows outpatient management of uncomplicated DVT.

Fondaparinux is a synthetic form of the heparin pentasaccharide molecule with a specific anti-Xa effect. It has similar indications to LMW heparin.

Warfarin

Oral anticoagulant drugs are derived from 4-hydroxycoumarin and the standard agent is warfarin. Warfarin works by antagonising vitamin K, which is needed for the gamma carboxylation of certain glutamic acid residues that facilitate calcium binding of coagulation factors II, VII, IX and X (Fig 40.2).

Fig 40.2 The vitamin K cycle and the action of warfarin.
The major site of warfarin action is not a direct effect on the carboxylation step needed for coagulation factor activation but on steps needed for resynthesis of active vitamin K from its epoxide form.

Some indications for warfarin are shown in Table 40.1. Where rapid anticoagulation is required a reasonable starting regimen is a single 10 mg dose and then protocol-guided adjustment according to the international normalised ratio (INR). A coagulation screen should always be checked before warfarin is prescribed. The maintenance dose is usually between 3 and 9 mg. Laboratory monitoring depends on the prothrombin time (see p. 20). As thromboplastin reagents used in this test vary, their sensitivity is labelled with an international sensitivity index (ISI) which permits reporting as an INR such that INR = (prothrombin time)^ISI.

Table 40.1

Warfarin: common indications and recommended INRs

Indication	Target INR¹
Deep vein thrombosis	2.5
Pulmonary embolus	2.5
Atrial fibrillation	2.5
Mural thrombosis	2.5
Cardioversion	2.5
Mechanical prosthetic heart valves	2.5–3.5²
Recurrent venous thromboembolism on warfarin therapy	3.5
Thrombosis in antiphospholipid antibody syndrome	2.5

¹ An INR within 0.5 units of the target is usually satisfactory.

² Depending on valve.

As it takes several days for warfarin to become therapeutic, the conventional treatment of established thrombosis is to start heparin and warfarin simultaneously and only to stop heparin when the desired INR has been achieved. Warfarin should be used with caution in patients with a bleeding tendency. The most common side-effect is haemorrhage, the risk of serious bleeding correlating with the height of the INR. Poor control of anticoagulation and bleeding may arise from poor prescribing or compliance, intercurrent illness and interaction with a potentiating drug (Table 40.2). A prolonged INR in a non-haemorrhagic patient may only require withdrawal of the drug for a few days. Where there is haemorrhage, warfarin can be reversed within hours by oral/intravenous vitamin K (0.5–5 mg) and instantly by infusion of a concentrate of prothrombin complex. Guidelines are complex and significant warfarin overdosage should be discussed with a haematologist. The duration of warfarin treatment depends on the indication. Anticoagulation may be needed for only 3 months in a patient with a limited DVT and reversible risk factors (e.g. post-surgery). Longer periods are indicated in idiopathic venous thrombosis, and lifelong warfarin treatment may be justified following recurrent episodes of venous thrombosis or where there is a known ongoing thrombotic risk such as a prosthetic heart valve, atrial fibrillation or a thrombophilic state.

Table 40.2

Drugs interacting with warfarin ¹

Potentiating	Antagonising
Alcohol	Oral contraceptives
Cimetidine	Spironolactone
Allopurinol	Antihistamines
Quinine	Barbiturates
Amiodarone	Rifampicin
Co-trimoxazole	Sucralfate
Metronidazole	Anti-epileptics
Tricyclics
Aspirin and salicylates
Anabolic steroids
Thyroxine
Sulfinpyrazone

¹ These are some commonly implicated agents – this is not a comprehensive list.

Community and outpatient warfarin treatment is best monitored in specialist clinics where control is audited and technologies such as computerisation exploited.

New oral anticoagulant agents

There is a need for oral anticoagulant agents with more predictable pharmacokinetics than warfarin. A number of new drugs have been tested in clinical trials and are now entering clinical practice for both prophylaxis and treatment of thromboembolic disease. Examples include the direct thrombin inhibitor dabigatran exilate and the factor X inhibitor rivaroxaban. This is a fast moving area of medicine and new anticoagulants are further discussed on page 102.

Thrombolytic therapy

Thrombolytic agents dissolve fresh clots and therefore restore vascular patency more quickly than anticoagulants. The commonly used agents – streptokinase, urokinase and tissue plasminogen activator (alteplase) – work by activating the fibrinolytic system (see p. 13 and Fig 40.3). They convert plasminogen, the inactive proenzyme of the system, to the proteolytic enzyme plasmin. Thrombolytic drugs are indicated in any patient with acute myocardial infarction in which the benefit is likely to outweigh the risk of treatment. Early administration gives the best results. Other possible uses for this class of drugs include treatment of complicated venous thrombosis, acute ischaemic stroke and the unblocking of occluded venous catheters. The major side-effect is excessive bleeding.