Vitamin K is required for the synthesis of coagulation factors II (prothrombin), VII, IX and X. Warfarin and other similar oral anticoagulants such as nicoumalone are competitive antagonists of vitamin K and reduce the synthesis of these coagulation factors, resulting in prolongation of the prothrombin time. The drugs are well absorbed from the gastrointestinal tract, but their effect on coagulation is delayed for up to 24 h. Unlike heparin, these anticoagulants are not active in vitro.

The prothrombin time is the laboratory test used to monitor warfarin therapy. The patient sample is compared with a normal sample and the result is expressed as the international normalised ratio (INR). The therapeutic range of INR for a patient on warfarin is between 2.0 and 4.5, but target values for specific conditions have been recommended. A target INR of 2.5 is appropriate for venous thromboembolism, atrial fibrillation, cardiac mural thrombosis, cardiomyopathy and prior to cardioversion. A higher target INR of 3.5 is suitable for subjects with a mechanical heart valve (long-term anticoagulation is not required with a biological valve) and patients who have experienced recurrent venous thromboembolism.

The delay in onset of its anticoagulation effect means heparin should be given at the start of treatment with warfarin. The usual induction dose for adults is 10 mg warfarin daily for two successive days. Treatment with heparin should continue in parallel with oral anticoagulation for 5 days or until the patient’s INR is more than 2.0 for two consecutive days, whichever is longer. The daily maintenance dose of warfarin in adults is usually in the range from 3 to 9 mg daily. The INR should be checked daily or on alternate days initially, but the interval can then be extended to a maximum of 12 weeks for patients who are stable on long-term warfarin. Many drugs interact with warfarin through a variety of pharmacodynamic mechanisms. It is prudent to check the INR again 1 week after starting any new medication.

The treatment of over-anticoagulated patients depends upon the INR and the clinical circumstances. Temporary suspension is often all that is required for minor bleeding problems. If the INR is eight or more and there are no significant bleeding complications, a small dose of 0.5–2.0 mg vitamin K may be given to reduce the INR. Correction of anticoagulation is not immediate and may be delayed for up to 24 h.

In the case of a major bleeding episode, such as intracranial haemorrhage or gastrointestinal bleeding, rapid and complete reversal is required. In such cases, coagulation factor concentrates known as prothrombin complex concentrates are the most effective treatment. These plasma-derived blood products contain coagulation factors II (prothrombin), VII, IX and X and can be given by rapid intravenous injection without regard to blood group. If they are not available, fresh frozen plasma should be infused. A reason for a prolonged INR should be sought (e.g. interaction with a new medication or confusion over the number of warfarin tablets to take). Haemorrhagic problems when the INR is in the therapeutic range may deserve investigation, particularly in the elderly, in order to exclude latent pathology. For example, haematuria may be associated with a tumour of the bladder and melaena may be the first manifestation of a peptic ulcer.

Although warfarin is still widely used, newer oral anticoagulant agents are increasingly being adopted for many clinical indications. Such drugs are referred to generically as direct-acting oral anticoagulants (DOACs) since they directly inhibit either thrombin in the case of dabigatran (‘Pradaxa’) or factor Xa in the case of rivaroxaban (‘Xarelto’) and apixaban (‘Eliquis’). The principal advantage of these drugs is that patients received a fixed daily dose and there is generally no need for any blood tests for monitoring. There are also far fewer drug interactions which have to be taken into consideration, by contrast with warfarin. These agents are widely used for the treatment and prevention of venous thromboembolism as well as in atrial fibrillation. They have not replaced warfarin for anticoagulation in children and subjects with valvular heart disease.

None of these new agents has been shown to be better than the others in head-to-head clinical trials. The dose of each DOAC is product specific, e.g. 20 mg rivaroxaban once daily is the usual maintenance dose for adults with venous thromboembolism whilst 5 mg twice daily is the usual dose of apixaban. All DOACs depend to a variable degree on renal excretion and dose adjustment will be required in patients with renal impairment. DOACs should not be used during pregnancy.

The half-lives of these drugs are all significantly shorter than warfarin: 12 h in the case of apixaban and 5–9 h in the case of rivaroxaban. Thus, mild bleeding episodes can usually be managed by suspending further treatment and applying pressure to the bleeding site. Idarucizumab (‘Praxbind’) is a humanised monoclonal antibody which is now licenced for reversal of the effect of dabigatran. At the time of writing, there is no licenced antidote for factor Xa inhibitors like apixaban and rivaroxaban, However, a specific antidote for these agents is at an advanced stage of clinical development. Andexanet alfa (‘AndexXa’) is a recombinant factor Xa inactive decoy protein which binds factor Xa inhibitors with a high affinity. The infusion of fresh frozen plasma or cryoprecipitate will not reverse the anticoagulant effect of any of these new agents. In the case of severe bleeds with factor Xa inhibitors, FEIBA (an activated prothrombin complex concentrate) and recombinant activated factor VII have been used ‘off label’.

Heparin is a polymeric glycosaminoglycan, consisting of alternating chains of uronic acid and glucosamine. Originally identified in liver extracts (hence the name), it is extracted for commercial production from porcine mucosa. The anticoagulant properties of heparin reside in a pentasaccharide sequence, which binds avidly to antithrombin. This antithrombin–heparin complex behaves as a serine protease inhibitor, inactivating both thrombin and factor X. Heparin is highly negatively charged and has to be given by intravenous or subcutaneous injection as it is not absorbed effectively from the gastrointestinal tract. Unlike warfarin, it exerts an immediate anticoagulant effect and so it is also effective in vitro. It may be used as an anticoagulant for renal dialysis and in cardiopulmonary bypass machines. The anticoagulant effect of standard, unfractionated heparin may be monitored in the laboratory by measuring the activated partial thromboplastin time (APTT). The APTT should be maintained between 1.5 and 2.5 times the value of normal control plasma for full therapeutic anticoagulation with standard heparin.

Standard, unfractionated heparin consists of molecules with a molecular weight varying between 3000 and 35,000 Da (mean approximately 15,000 Da). Low-molecular-weight heparins (LMWH) are produced by the chemical degradation of standard, unfractionated heparin to produce smaller molecules with a mean molecular weight of approximately 5000 Da. These smaller molecules are more readily and predictably absorbed from sites of injection and have pharmacokinetic profiles, which offer almost complete bioavailability as well as a longer plasma half-life. By contrast, the bioavailability of standard heparin is only approximately 50%. Full anticoagulation can thus be easily achieved with once-daily subcutaneous injection, which a patient can be trained to give, so that they can be discharged from hospital to the community more quickly. Furthermore, the greater predictability of response means that it is generally not necessary to monitor treatment with laboratory tests, and the dose is based merely on the weight of the patient.

LMWHs have relatively little inhibitory effect against thrombin and so the APPT cannot be used for laboratory monitoring. Monitoring, if necessary, is by anti-factor Xa assay because they inactivate factor X. The dosage of these preparations is expressed in anti-Xa units. Examples of when anti-Xa monitoring may be indicated include monitoring of treatment in children, pregnancy, renal failure, obesity and patients with active bleeding. Samples for anti-Xa assays should be drawn 4 h after the last subcutaneous injection. As a rough guideline, the therapeutic range for full anticoagulation is 0.5–1.0 anti-Xa units/ml. A lower range of 0.2–0.4 anti-Xa units/ml is suitable for prophylactic treatment.

The various LMWHs available commercially should not be considered to be identical. The doses are based upon body weight, and many preparations come in prefilled syringes both to facilitate treatment and also to minimise errors in dosage. LMWHs cost considerably more than standard heparin but are becoming increasingly adopted for the initial treatment of venous thromboembolism where full anticoagulation is required. By contrast, the cheaper standard heparin preparations are still widely used for prophylaxis of venous thromboembolism in the setting of surgery, where full anticoagulation is not necessary.

Most patients who require anticoagulation will only be exposed to heparin for a few days because it is used as short-term prophylaxis during an intervention or until full anticoagulation with warfarin is established. However, there are circumstances where prolonged anticoagulation with heparin may be required (e.g. prophylaxis against thromboembolism during pregnancy). Heparin-induced thrombocytopenia (HIT) is seen in approximately 5% of subjects who receive unfractionated heparin and around 0.5% of those who receive LMWH. This is due to the development of antibodies directed against a complex of heparin and platelet factor 4, which results in platelet activation. HIT typically develops within 5–10 days of starting treatment with heparin, but it can develop much more quickly in individuals who have been previously exposed. Once the problem has been identified, heparin treatment should be suspended and argatroban, fondaparinux or bivalirudin used as alternative anticoagulants if systemic anticoagulation is still required. Platelets should not be transfused as this can trigger intravascular thrombosis due to explosive activation of the transfused platelets by the circulating antibodies. Patients with a history of heparin-induced thrombocytopenia should never be re-exposed to this anticoagulant. Osteoporosis is a recognised complication of long-term heparin administration, and this can result in vertebral fractures.

Protamine sulphate can be used to reverse the anticoagulant effect of heparin when bleeding occurs. Titration in vitro may be useful to determine the required dose: 1 mg of protamine will neutralise approximately 100 units of heparin: Protamine is given by slow intravenous infusion as rapid administration can result in hypotension, bradycardia and dyspnoea. Protamine does not inactivate LMWH as effectively as it does unfractionated heparin.

Haematologists generally place considerable importance on whether an episode of thromboembolism was provoked or unprovoked when deciding whether long-term anticoagulation is required. Where there is a clear underlying cause, such as surgery or a long-haul flight, patients will generally only receive anticoagulation for few months. By contrast, a patient who has an unprovoked episode of thromboembolism will be considered for long-term treatment and in certain circumstances, screening for abnormalities in blood, which predispose to venous thromboembolism (thrombophilia).