Anticoagulants

Heparin

Overview

There are two main types of heparins which are both used parenterally (not by mouth). These types are:

• Standard heparin (unfractionated heparin, UFH) – administered intravenously
• Low molecular weight heparin (LMWH) – administered subcutaneously
  • Example drugs are dalteparin, enoxaparin, and tinzaparin

In general, LMWH has a longer duration of action than UFH:

• UFH is ideal for use in those at high risk of bleeding as its effects can be stopped more quickly by stopping the infusion.

Unfractionated heparin (UFH)

UFH has a relatively short duration of action compared to LMH. It works by activating antithrombin III and forms a complex with it leading to the inactivation of factors IIa, IX, Xa, XI, XII, and plasmin.

Key side effects are:

• Bleeding
• Bruising
• Heparin-induced thrombocytopenia (HIT)
• Skin reactions

Other notes:

• APTT can be used to monitor its effect
• Overdose can be reversed using protamine sulfate

Low molecular weight heparin (LMWH)

LMWH has a relatively longer duration of action compared to UFH. It works by potentiating the effect of antithrombin III and inhibiting the formation of factor Xa.

LMWH is preferred due to the lower risk of HIT and their convenience – in some patients, one single subcutaneous injection is sufficient, rather than in UFH where a continuous intravenous infusion would be required.

Key side effects are:

• Bleeding
• Bruising
• HIT – the risk is lower using LMWH

Other notes:

• Monitoring is not routinely done, but can be in patients who are at increased risk of bleeding – anti-factor Xa activity is monitored in these situations
• Overdose can be reversed using protamine sulfate, but this only partially reverses the effect of LMWH

Warfarin

Overview

Warfarin is a commonly used oral anticoagulant. It is a vitamin K antagonist, leading to a reduction in the synthesis of clotting factors dependent on vitamin K. As it takes 2-3 days to take its full effect, heparin is often used for immediate coagulation to get the international normalised ratio (INR) into range. 

Side effects

• Bleeding
• Bruising
• Skin necrosis
• Teratogenicity in pregnancy
• Blue toe syndrome – acute digital ischaemia

Interactions

Anything that affects the P450 enzyme system can interact with warfarin. Inducers reduce the effectiveness of warfarin, and inhibitors increase its effect.

Other factors that can interact with warfarin are:

• Cranberry, grapefruit, or pomegranate juice – increases its effect
• Oral contraceptives – increase its effect
• Liver disease – increases its effect
• Foods rich in vitamin K can decrease its effect

Monitoring

The INR is monitored daily when initiating treatment, and then the frequency of monitoring is spread at longer intervals depending on the response. Monitoring should be done at least every 12 weeks. 

Managing high INRs

• Any major bleeding:
  • Stop warfarin + give IV vitamin K 5 mg + prothrombin complex concentrate (PCC)
    • If PCC is not available, give fresh frozen plasma (FFP)
• INR >8.0 + minor bleeding:
  • Stop warfarin + give IV vitamin K 1-3 mg
    • If the INR is still too high after 24 hours, repeat the dose of vitamin K
    • Restart warfarin once the INR is <5.0
• INR >8.0 + no bleeding:
  • Stop warfarin + give oral vitamin K 1-5 mg
    • If the INR is still too high after 24 hours, repeat the dose of vitamin K
    • Restart warfarin once the INR is <5.0
• INR 5.0-8.0 + minor bleeding:
  • Stop warfarin + give IV vitamin K 1-3 mg
  • Restart warfarin once the INR is <5.0
• INR 5.0-8.0 + no bleeding:
  • Withhold 1-2 warfarin doses
  • Reduce the following maintenance dose

Direct Oral Anticoagulants

Overview

Previously called novel oral anticoagulants (NOACs), direct oral anticoagulants (DOACs) are newer anticoagulants that are slowly superseding the use of warfarin. They are more convenient as they do not require monitoring, however, they are not easily reversible in severe bleeding.

Characteristics

The main DOACs are as follows:

• Apixaban:
  • Mechanism of action: direct factor Xa inhibitor (apiXaban)
  • Excretion: mainly through the faeces
  • Reversal: Andexanet alfa (recombinant factor Xa)
• Rivaroxaban:
  • Mechanism of action: direct factor Xa inhibitor (rivaroXaban)
  • Excretion: mainly hepatic
  • Reversal: Andexanet alfa (recombinant factor Xa)
• Edoxaban:
  • Mechanism of action: direct factor Xa inhibitor (edoXaban)
  • Excretion: mainly through the faeces
  • Reversal: none at the moment
• Dabigatran:
  • Mechanism of action:
  • Excretion: mainly renal
  • Reversal: idarucizumab