🏃 Physiology
Let’s review our coagulation cascade once again (primary haemostasis can be revisited in the CCC on patient on anti-platelet therapy).
We have 3 pathways to consider…
- Intrinsic pathway - activated primarily by collagen which in turn activates factor XII → factor XIIa which then activates factor XI → factor XIa which then activates factor IX → IXa. This finally activates factor VIII to activate factor X in the common pathway.
- Extrinsic pathway - this is activated by subendothelial tissue which releases tissue factor (TF). TF then activates factor VII which then activates factor X in the common pathway.
- Common pathway - kicks off with factor Xa (activated by either intrinsic or extrinsic pathway). This then activates prothrombin (factor II) → thrombin (IIa) with the help of factor Va.
Remember the intrinsic has 12, 11, 9 and 8.
Thrombin is used to convert factor I (fibrinogen) to factor Ia (fibrin). This then activates factor XIII → factor XIIIa which crosslinks fibrin which becomes incorporated into the platelet plug to stabilise the clot.
Vitamin K is also an essential cofactor that actives inactive forms of prothrombin (factor II), factor VII, IX, and X. It also helps synthesis protein C and protein S which are important regulators of the clotting cascade through negative feedback.
💊 Drugs
We will first discuss oral anticoagulation and then parenteral anticoagulation will be discussed separately.
When it comes to oral anticoagulants, there are 2 main types to consider:
- Vitamin K antagonists (VKAs) - they inhibit vitamin K dependent clotting factors (II, VII, IX, X) [remember the mnemonic 1972]. Some drugs included in this class are:
- Warfarin
- Direct oral anticoagulants (DOACs) - they are direct, reversible inhibitors of factor Xa, therefore subsequently inhibiting the formation of thrombin. Drugs included in this category are:
- Apixaban
- Dabigatran
- Edoxaban
- Rivaroxaban
Vitamin K antagonists
MOA
It inhibits the enzyme epoxide reductase which prevents vitamin K from being reduced into its active form. This then inhibits the co-activation of factors II, VII, IX, X.
Indications
Warfarin is licensed for:
- Rheumatic heart disease
- Prophylaxis after insertion of prosthetic heart valve
- Prophylaxis and treatment of VTE and PE
- AF
Contraindications
- Haemorrhagic stroke
- Significant bleeding
- Severe liver impairment
- Within 72 hours of major surgery
- Within 48 hours postpartum
- Pregnancy (teratogenicity) - should not be given for the first trimester of pregnancy. However can be used when breastfeeding.
Adverse effects
- Bleeding - one should seek advice if there is spontaneous bleeding that does not stop or recurs. If they get severe back pain suddenly, it may indicate spontaneous retroperitoneal bleeding.
- Vitamin K1 (phytomenadione) is the antidote for warfarin when treating haemorrhage.
- Skin necrosis - rare but very serious side effect that may occur. It will present with painful, localised lesions within the subcutaneous fat. This is because when we start warfarin, protein C is inhibited and thus a pro-coagulant state is temporarily induced. This may lead to thrombosis of venules and capillaries which causes the subsequent necrosis.
- Blue toe syndrome
Monitoring
We measure warfarin using the international normalised ratio (INR). This is calculated based on the ratio between prothrombin times ( and the control samples used in the laboratory (INR = patient PT/control PT).
For a normal patient, not on anticoagulation, the INR is usually 1.0. However, for patients on anticoagulation the therapeutic range for INR is 2.0 - 3.0. Anything less than 2.0 means the patient is thromboembotic and requires more warfarin. Anything higher than 3.0 means the patient is at risk of haemorrhage and requires a dose reduction.
For prosthetic heart valves, the target INR is 3-4.
- When initiating warfarin treatment, it should be measured daily/on alternate days until it is in the therapeutic range on two consecutive occasions.
- It is then measured twice weekly for 1-2 weeks to ensure that it is within the therapeutic range.
- After which it is measured less frequently (for example, every 3 months).
People who are at risk of overcoagulation (severe hypertension, liver disease or renal failure) or at risk of bleeding (>65 years old or on high-intensity anticoagulation.
Patients on warfarin will have a “yellow book” with their dose instructions and appointment times. All their results should be recorded in this book as well.
INR/Situation | What to do? |
Major bleed | 1. Stop warfarin
2. Give IV vitamin K (5mg)
3. Give prothrombin complex concentrate if not available we can give fresh frozen plasma. |
INR >8.0 and minor bleed | 1. Stop warfarin
2. Give IV vitamin K (1-3mg)
3. Repeat dose of vitamin K if INR still too high after 24 hours
4. Restart warfarin when INR < 5.0 |
INR >8.0 and no bleeding | 1. Stop warfarin
2. Give oral vitamin K (1-5mg)
3. Repeat dose of vitamin K if INR still too high after 24 hours
4. Restart warfarin when INR < 5.0 |
INR 5.0-8.0 and minor bleed | 1. Stop warfarin
2. Give IV vitamin K (1-3mg)
3. Restart when INR < 5.0 |
INR 5.0-8.0 and minor bleed | 1. Withhold 1 or 2 doses
2. Reduce maintenance dose |
Interactions
- P450 inhibitors - such as amiodarone, ciprofloxacin
- Cranberry juice
- NSAIDs as they can displace warfarin from plasma albumin.
- Platelet inhibitors such as aspirin and NSAIDs.
- Liver disease may also potentiate warfarin’s effect.
- Direct-acting antivirals
Direct oral anticoagulants (DOACs)
Direct inhibitor of factor Xa.
It is mainly excreted faecally and therefore is preferred in patients with renal impairment.
Indications
- Prophylaxis of stroke and systemic embolism in adults with non-valvular AF and at least one risk factor such as:
- Stroke/TIA
- Symptomatic HF
- DM
- Hypertension
- >75 years old
- Treatment of PE or DVT
- Prophylaxis of recurrent PE or DVT
- VTE prophylaxis in patients who have undergone knee/hip replacement
Contraindications
- Creatinine clearance (CrCl) <15ml/min
- Liver disease
- Prosthetic heart valve
- Antiphospholipid syndrome
- Active bleeding
- Risk of major bleed such as
- GI ulceration
- Oesophageal varices
- Recent brain/spinal injury or surgery
- Recent ICH
- Malignancy
Adverse effects
- Bleeding
- Andexanet alfa may be used as a reversal agent in life-threatening bleeds.
- Anaemia
- Bruising
- Nausea
- Skin reactions
Interactions
- NSAIDs
- Other anticoagulants
- Antiplatelets
- CYP3A4 inhibitors - such as itraconazole, ketoconazole, protease inhibitors.
- CYP3A4 inducers - such as carbamazepine, phenytoin, rifampicin, St John’s Wort.
- SSRIs
MOA
It is a direct thrombin inhibitor and has a rapid onset of action. It is mainly excreted renally.
Indications
- Prophylaxis of stroke and systemic embolism in adults with non-valvular AF and at least one risk factor such as:
- Stroke/TIA
- Symptomatic HF
- DM
- Hypertension
- >75 years old
- Treatment of PE or DVT
- Prophylaxis of recurrent PE or DVT
- VTE prophylaxis in patients who have undergone knee/hip replacement
Contraindications
- CrCl <30ml/min
- Active bleeding
- Antiphospholipid syndrome
- Severe liver impairment
- Prosthetic heart valves
- Risk of major bleed
Adverse effects
- Bleeding
- Idarucizumab is the reversal agent for dabigatran (for the Dab - give the mab).
- Anaemia
- Diarrhoea
- GI upset
- Abnormal hepatic function
- Nausea
Interactions
- NSAIDs
- Anticoagulants and antiplatelets
- P-glycoprotein inhibitors - such as ciclosporin, dronedarone, itraconazole, ketoconazole, amiodarone, verapamil, qunidine.
- P-glycoprotein inducers - such as carbamazepine, phenytoin, rifampicin, St John’s Wort.
- SSRIs
MOA
Direct and reversible inhibitor of factor Xa. It is mainly excreted faecally.
Indications
- Prevention of stroke and systemic embolism in non-valvular AF with at least one risk factor, such as:
- CHF
- Hypertension
- >75 years and older
- DM
- Previous stroke/TIA
- Treatment of DVT and PE
- Prophylaxis for recurrent DVT and PE
Contraindications
- Creatinine clearance (CrCl) <15ml/min
- Liver disease
- Prosthetic heart valve
- Antiphospholipid syndrome
- Active bleeding
- Uncontrolled, severe hypertension
- Risk of major bleed
Adverse effects
- Bleeding
- Anaemia
- Dizziness
- GI upset
- Pruritus
- Rash
- Abnormal LFTs
Interactions
- NSAIDs
- Anticoagulants and antiplatelets
- P-glycoprotein inhibitors - such as ciclosporin, dronedarone, itraconazole, ketoconazole, amiodarone, verapamil, qunidine.
- P-glycoprotein inducers - such as carbamazepine, phenytoin, rifampicin, St John’s Wort.
- SSRIs
There is no licensed reversal agent as of yet, but andexanet alfa has been studied.
MOA
Direct inhibitor of factor Xa. It is mainly excreted through liver metabolism.
Indications
- Prevention of stroke and systemic embolism in non-valvular AF with at least one risk factor, such as:
- CHF
- Hypertension
- >75 years and older
- DM
- Previous stroke/TIA
- Treatment of DVT and PE
- Prophylaxis of recurrent DVT and PE
- Prophylaxis of VTE in patients who have had knee/hip replacement (preferred)
- Prophylaxis of atherothrombotic events after ACS
- Prophylaxis of atherothrombotic events with high-risk CAD or PAD
Contraindications
- CrCl <15ml/min
- Liver disease
- Prosthetic heart valve
- Antiphospholipid syndrome
- Active bleeding
- Risk of major bleed
- History of TIA/stroke when used following ACS or for PAD/CAD.
Adverse effects
- Bleeding
- Andexanet alfa is the reversal agent for rivaroxaban.
- Anaemia
- Fatigue
- Constipation
- GI upset
- Pruritus
- Rash
- Peripheral oedema
Interactions
- NSAIDs
- Other anticoagulants
- Antiplatelets
- CYP3A4 inhibitors - such as itraconazole, ketoconazole, protease inhibitors.
- CYP3A4 inducers - such as carbamazepine, phenytoin, rifampicin, St John’s Wort.
- SSRIs
Parenteral anticoagulants are used for VTE prophylaxis and for management of ACS.
In this section we will consider 4 aspects:
- Unfractionated heparin
- Low molecular weight heparin
- Fondaparinux
- Direct thrombin inhibitors
Also known as standard heparin. It is administered IV and only has a short duration of action.
MOA
It works by activating antithrombin III, forming a complex that inhibits thrombin, factor Xa, IXa, XIa and XIIa.
Indications
Situations where there is a high risk of bleeding, as it can be terminated rapidly and only has a short DOA.
For example, in PVD with critical limb ischaemia.
Monitoring
Done by using the activated partial thromboplastin time (aPTT).
Adverse effects:
- Heparin-induced thrombocytopenia (HIT) - we will discuss this below
- Bleeding
- Osteoporosis
- Hyperkalaemia
It is administered subcutaneously and has a long duration of action.
These include familiar names such as dalteparin, enoxaparin, tinzaparin.
MOA
It works by activating antithrombin III, forming a complex that inhibits factor Xa.
Indications
For treatment of DVT and PE.
They may also be used in ACS treatment but other agents are preferred (see notes on ACS).
Monitoring
Routine monitoring is not required for LMWHs. However, anti-factor Xa may be used (with patients that have a very high body weight as they need a very large dose).
Adverse effects:
- Bleeding
- Hyperkalaemia
- They have a lower risk of HIT and osteoporosis.
Given subcutaneously and also works by potentiating antithrombin III to inhibit factor Xa.
Is advantageous as the dose is fixed (not according weight) - for ACS 2.5mg OD.
For example bivalirudin. Generally given IV.
1st choice for ACS and licensed alternative for DVT/PE.
HIT is a potential adverse effect following heparin administration. It is caused by the formation of antibodies against complexes of platelet factor 4 (PF4) and heparin.
The antibodies bind to the PF4-heparin complexes and induce platelet activation → prothrombotic state. This uses up the platelets and results in thrombosis, >50% reduction in platelets (thrombocytopenia), and skin allergy.
Management includes:
- 🥇 Cessation of heparin and LMWH
- Start a direct thrombin inhibitor
- Argatroban
- Danaparoid or fondaparinux can be used as well.