Indications for Anticoagulation

In most indications for anticoagulation (Table 103.1), there is broadly equal efficacy and safety of different anticoagulants, and choice may be based on patient and clinician preference. For some indications, and in some clinical contexts, one form of anticoagulation is preferred.

Table 103.4 provides a regimen for administering unfractionated heparin by infusion, and Table 103.5 shows enoxaparin (a LMWH) dosing by body weight for the treatment of deep vein thrombosis/pulmonary embolism and acute coronary syndrome.

Warfarin and Other Vitamin K Antagonists

As vitamin-K dependent activation occurs at the time of protein synthesis, VKAs do not affect the function of clotting factors that have already been synthesized. While factor VII has a short half-life (around 4–6h), other factors, for example prothrombin, have a longer half-life (around three days). This means that although the INR may reach therapeutic levels, warfarin does not have a fully effective anticoagulant effect until at least five days after the drug has been started and must be given with LMWH/UFH cover.

The CHA₂DS₂VASc score (Table 103.6) estimates annual risk of stroke or systemic thromboembolism in nonvalvar AF (Table 103.7). All patients with AF, whether paroxysmal, persistent or permanent are at increased risk of thromboembolism. Anticoagulation should be considered with a score of ≥2 depending on concurrent risks including the HASBLED score (Table 103.8) which estimates the annual risk of major bleeding for patients on warfarin for atrial fibrillation (Table 103.9). ‘Major bleeding’ in the original study was defined as bleeding requiring hospitalization and/or blood transfusion and/or a drop in haemoglobin >20g/L. Unfortunately, patients at the highest risk of stroke in AF are often also at the highest risk of bleeding. A risk score of 3 or more is considered high risk for bleeding and use of anticoagulation is cautioned.

Table 103.10 lists some of the more common clinical conditions affecting the anticoagulant response to warfarin and Table 103.11 shows a practical method of starting warfarin.

Duration of Anticoagulation Following Vte and Predicting Risk of Recurrence

At least three months of anticoagulation is advised following of deep venous thrombosis (DVT) and pulmonary embolism (PE). In general, VTE provoked by a reversible risk factor (see Chapter 56) has a low probability of recurrence and anticoagulation can be safely stopped after this point. Conversely, if there is an irreversible risk factor, for example incurable disseminated malignancy, indefinite anticoagulation should be considered.

Discuss with a haematologist whether to continue anticoagulation beyond 3 months in unprovoked VTE is a difficult one and the advice of a haematologist should be sought. Various factors are normally taken into account, including whether this was a recurrent event; the age and sex of the patient (increased chance of recurrence in patients under the age of 50 years and in males); and post-treatment D-dimer (increased risk of recurrence if elevated). Thrombophilia testing may be considered, once the patient has completed three months of anticoagulation, in individuals with a strong family history of VTE or in young patients with recurrent events, but is not recommended in unselected individuals as it is a poor determinant of risk of recurrence. Thrombophilia testing in the acute setting is not recommended as results may be affected by acute VTE and by anticoagulation.

National guidelines currently recommend a CT chest/abdomen/pelvis to investigate potential underlying malignancy in all patients over the age of 50 who present with apparently unprovoked VTE, and those under the age of 50 with any index of suspicion raised by clinical history and examination, chest X-ray and urine dipstick testing. Indiscriminate CT scanning of older patients has recently been challenged on the basis of more up-to-date evidence. Hospitals will often have their own local policy.

Direct-Acting Oral Anticoagulants (DOACs)

DOACs are becoming increasingly popular and widely available. They are known as direct-acting oral anticoagulants as they act through direct inhibition of procoagulant factors in the clotting cascade.

They combine the advantages of a convenient oral preparation without need for monitoring, because of a wide therapeutic range and similar pharmacokinetic and pharmacodynamic effects in different individuals. Disadvantages include difficulties in monitoring anticoagulant effect and the fact that they remain harder to reverse than VKAs and heparins, although this is changing as reversal agents are being rapidly developed. They are not recommended for all anticoagulation indications (see Table 103.1). The properties of dabigatran, rivaroxaban and apixaban are compared in Table 103.12.

There are circumstances in which monitoring of DOAC levels may be required (see Table 103.13) and all hospital laboratories should have this capacity. It should be noted that the prothrombin time (PT) and activated partial thromboplastin time (APTT) cannot be used to reliably assess the intensity of anticoagulation.

DOACs can be switched to and from heparin on the next scheduled dose. When converting from a DOAC to warfarin, a two-day overlap period should be ensured. When converting from warfarin to a DOAC, the INR should be less than 2.

DOACs have fewer clinically significant drug interactions than warfarin. However, concomitant use of certain drugs should be avoided. Dabigatran, rivaroxaban and apixaban are substrates for the P-gp efflux transporter and the CYP3A4 enzyme complex. Strong inhibitors of these metabolic pathways, such as azole antifungals, HIV protease inhibitors and the immunosuppressants, cyclosporine and tacrolimus are contraindications to use of the DOACs. Use in patients taking weaker inhibitors, for example amiodarone, pozaconazole, quinidine, verapamil and ticagrelor is cautioned. Strong inducers, such as St John's Wort, carbamazepine and phenytoin are also contraindicated. The advice of a pharmacist should be sought.

The dosing of DOACs by indication is shown in Table 103.14.

Management of Bleeding in a Patient Taking an Anticoagulant or Antiplatelet Drug

General measures are summarized in Table 103.15, and specific measures in Tables 103.16, 103.17, 103.18.

Warfarin and Other Vitamin K Antagonists

Bleeding complications increase significantly when the international normalized ratio (INR) is >5, and rise exponentially above this. Management depends on the INR and according to the presence and severity of bleeding.

The risk of bleeding for patients on warfarin is increased by trauma, age, instability in INR, alcohol-use disorder and organ failure.

Full reversal of anticoagulation in a patient with a mechanical prosthetic heart valve carries a risk of valve thrombosis: discuss management with a haematologist and cardiologist.

If there is unexpected bleeding at therapeutic INR, a structural lesion (e.g. carcinoma of bladder or large bowel) should be investigated for.

Direct-Acting Oral Anticoagulants (DOACs)

Because of the short half-life of these agents, minor bleeding occurring on DOACs can normally be managed by withholding further doses and following general supportive measures. However, more serious or life-threatening bleeding is harder to manage and the advice of a haematologist should be sought.

If bleeding occurs within two hours of the last dose, activated charcoal may be used to prevent intestinal adsorption. Haemodialysis may be partially effective in removing dabigatran but not the other DOACs, because of dabigatran's relatively low binding to plasma proteins.

Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) and recombinant FVIIa have all been used in in vitro and in animal studies, with partial reversal of anticoagulant effect of the DOACs, but their efficacy in human subjects is not confirmed.

Idaracizumab (Praxbind) is a newly developed and approved monoclonal antibody fragment that binds to and rapidly reverses the anticoagulant effects of dabigatran. Specific antidotes to anti-Xa inhibitors are in development.

Antiplatelet Agents

Antiplatelet agents, for example the COX inhibitor, aspirin, and P2Y12 antagonists such as clopidogrel, prasugrel and ticagrelor, cause irreversible platelet inhibition, and therefore, despite their short half-lives, have a prolonged inhibitory effect (up to seven days).

Glycoprotoein IIb/IIIa inhibitors, that block fibrinogen mediated platelet aggregation, for example abcixamab and tirofiban, have a much shorter duration of action (<1 day). Abcixamab can cause profound thrombocytopenia.

Some types of elective surgery, especially cardiac surgery, are performed with the patient still on aspirin, because of the risk of adverse events when the drug is stopped.

Platelet transfusion of 2–3 units should be considered to treat major bleeding that occurs while on antiplatelet agents, or to prevent this during surgery.

Safe Timing of Invasive Procedures in Patients on Anticoagulation

Apart from in an emergency, for example insertion of a central line in a critically unwell patient, it is safer to allow anticoagulants to be metabolized/excreted rather than attempting to reverse them before a planned invasive procedure (e.g. lumbar puncture, chest drain, ascitic drain), as reversal agents are potentially pro-thrombotic and may expose the patient unnecessarily to plasma products. Safe timing of a procedure requires a knowledge of when the last dose of anticoagulant was taken, the half-life of the drug, the excretion pathway, and any factors in the patient that may alter this, for example deranged renal function.