Anticoagulants and antiplatelet agents

What are anticoagulants and antiplatelet agents?

Anticoagulants and antiplatelet agents are commonly known as 'blood thinners', although strictly speaking, they do not thin the blood. They are used to reduce excessive blood clot formation.

How are blood clots formed?

Blood clots are part of a complicated cascade of events, known as haemostasis, that prevents bleeding from an external or internal wound.

• The blood vessels constrict to reduce blood flow.
• Tiny fragments of blood cells called platelets clump together to seal the wound. They produce thromboxane, which attracts more platelets to the wound.
• The wound produces thromboplastin, which sets off the coagulation cascade.
• The coagulation cascade involves 12 coagulation factors (blood proteins) that convert fibrinogen into a network of fibrin filaments via the enzyme thrombin.
• Vitamin K and calcium are also needed for this process.
• Excessive clotting is prevented by antithrombin, protein C and protein S.

What happens if clotting is excessive?

Excessive clotting forms a thrombus, which can completely block a blood vessel and stop normal blood flow. This is known as thrombosis.

A portion of the thrombus can become dislodged (an embolus) and can travel via the blood vessels to block a smaller vessel.

Blood clots which form in arteries are mainly composed of platelets with a small amount of fibrin. They lead to:

• Stroke, transient ischaemic attack (TIA or mini-stroke)
• Heart attack
• Peripheral arterial clot and gangrene
• Infarcts in the internal organs (eg kidney, spleen, intestine).

Blood clots which form in the larger veins are mainly composed of fibrin, with a small number of platelets. They can lead to:

• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE).

Why do thrombosis and embolism occur?

Thromboembolic disease occurs for genetic and acquired reasons. These may include:

• Familial reduction of antithrombin, protein C or protein S
• Obesity and metabolic syndrome
• Smoking
• Slow blood flow due to atherosclerosis (cholesterol and calcium deposition on the walls of the arteries) or frostbite
• Prolonged bed rest, eg after surgery or during illness
• Major orthopaedic surgery, particularly hip and knee surgery
• Travel in an aeroplane or bus for a prolonged period
• Irregular heartbeat (eg, atrial fibrillation)
• Artificial heart valve or congenital heart defects
• Antiphospholipid syndrome
• Pregnancy or oestrogen medication (eg, oral contraceptive pill)
• Drugs that increase haemostasis (eg, tranexamic acid, aprotinin).

Patients prone to blood clots may be prescribed one or more oral anticoagulants and antiplatelet drugs to reduce their chances of stroke, heart attack and deep venous thrombosis.

• Antiplatelet agents prevent platelets from sticking together.
• Anticoagulants act against clotting factors.

The level of antiplatelet/anticoagulant needs to be within a desired range to reduce the risk of excessive bleeding.

More about antiplatelet agents

Antiplatelet agents inhibit the production of thromboxane. They are mainly used to prevent stroke and heart attack. The most common antiplatelet agent prescribed is a small dose of aspirin (Aspec®, Cartia®, Cardiprin® and others). Other antiplatelet agents include:

• Dipyridamole (Persantin®, Pytazen and others)
• Clopidogrel (Plavix®, Clopid® and others)
• Prasugrel (Effient®)
• Ticagrelor (Brilinta®)
• Ticlopidine (Ticlid®).

Aspirin irreversibly inhibits cyclooxygenase-1, which is needed for prostaglandin and thromboxane synthesis. It has a long half-life.

Clopidogrel, prasugrel, ticagrelor and ticlopidine antagonise the ADP receptor, interrupting platelet activation and cross-linking. These have shorter half-lives.

More about anticoagulants

Anticoagulants are used mainly to treat and prevent venous thrombosis and to prevent the complications of atrial fibrillation and artificial heart valves. Warfarin is a synthetic derivative of the plant material, coumarin. Use of warfarin (Coumadin®, Maravan®) for anticoagulation began with its approval in 1954, and it has been instrumental in lowering morbidity and mortality associated with thrombotic conditions.

Warfarin:

• Inhibits vitamin K epoxide reductase, reducing the hepatic synthesis of vitamin-K dependent clotting factors II, VII, IX and X.
• The level of anticoagulation is monitored by measurement of International Normalised Ratio (INR).
• It is metabolised by CYP2C9 and has high protein binding (99%), which means many other medications and supplements can change the physiologically active dose.
• In the emergency setting of uncontrollable bleeding in patients on warfarin, vitamin K and fresh frozen plasma can be administered to counter its effects and lower the INR.

Phenprocoumon (Marcoumar®, Marcumar®, Falithrom®) is used instead of warfarin in some countries, for example, Germany.

Novel oral anticoagulants (NOACs) include:

• Dabigatran (Pradaxa®): inhibits thrombin (factor IIa) preventing the conversion of fibrinogen to fibrin
• Rivaroxaban (Xarelto®): inhibits factor Xa, preventing the conversion of prothrombin to thrombin
• Apixaban (Eliquis®): inhibits factor Xa, preventing the conversion of prothrombin to thrombin.

Compared to warfarin, these novel anticoagulants:

• Are as good or better in preventing thromboembolism
• Have equal or reduced bleeding risk
• Have no reversal agent available at this time
• Have predictable pharmacokinetics and pharmacodynamics, so levels are not currently monitored
• Have fewer interactions with other medications. However, there are some important interactions with cytochrome P450 3A4 inhibitors and inducers, and with p-glycoprotein inhibitors
• Have a shorter half-life and time to reach peak levels in plasma.

Natural antiplatelet agents and anticoagulants

Some foods, supplements and natural medicines have antiplatelet and anticoagulant activity, including garlic, ginger, ginkgo, dong quai, feverfew, fish oil, vitamin E and many others. Good quality laboratory and human studies have not been performed on these agents and they are unregulated. Food supplements and herbal medicines with an uncertain effect on blood clotting should be avoided when taking prescribed antiplatelet and anticoagulant medication because the combination could be dangerous.

Other foods and food supplements contain vitamin K, for example, cabbage, Brussels sprouts, broccoli, asparagus and many other green vegetables. These can unpredictably reduce the effectiveness of antiplatelet and anticoagulant drugs.

How do antiplatelet agents and anticoagulants affect dermatological surgery?

Patients taking antiplatelet agents and anticoagulants have an increased risk of bleeding, particularly after trauma. Dermatological surgery in these patients may lead to complications such as:

• Increased perioperative bleeding
• Postoperative haematoma
• Loss of skin graft or skin flap.

But, if patients stop their anticoagulants prior to surgery, they face complications associated with thrombosis. This presents a dilemma – should anticoagulation be stopped or continued for dermatologic surgery?

In the past, dermatological surgeons were in favour of interrupting anticoagulants to reduce the risk of bleeding—warfarin increases the surgical bleeding risk ~7–9 fold. However:

• It is extremely uncommon for bleeding to be life-threatening
• The overall rate of perioperative and postoperative bleeding in cutaneous surgery is very low (0.89%)
• Bleeding can be easily controlled by electro-coagulation in theatre
• A postoperative haematoma can be managed in an outpatient setting.

It has become clear that the discontinuation of anticoagulants can lead to serious thromboembolic events.

• 24% of surveyed dermatologic surgeons recalled a patient that had a thromboembolic event.
• Retrospective studies have reported that patients have a higher than expected incidence of cerebrovascular accidents and pulmonary embolisms after stopping warfarin.

Limited data on dabigatran indicates that it follows a similar pattern to warfarin.

As the risks of thromboembolism outweigh the risk of bleeding, it is now recommended that anticoagulants be continued in low-risk operations, such as those encountered in dermatology. This recommendation may differ on a case by case basis. In the event of discontinuing a medication, pharmacokinetic and pharmacodynamic factors need to be considered to optimise the timing (see table below).

Anticoagulant pharmacokinetic properties

General guidelines for anticoagulant and antiplatelet medication during skin surgery

Suggested guidelines for perioperative management of oral anticoagulant and antiplatelet medication for dermatological surgery are provided by Brown et al (simplified below) [3].

• Anticoagulant or antiplatelet medication prescribed for prevention of thrombosis should be continued prior to the procedure.
• Careful intraoperative haemostatic measures should be taken, using electrocautery and topical haemostatics.
• Postoperative pressure dressings should be applied for 24–48 hours.

Warfarin

• International normalised ratio (INR) 1 month before surgery should be within therapeutic range.
• Surgery should be postponed if INR is >3.5.
• Should severe bleeding occur that cannot be stopped by pressure, reversal with fresh frozen plasma or vitamin K can be considered.

Aspirin/Non-steroidal anti-inflammatory drugs (NSAIDs)

Aspirin (10 days) or NSAIDs (3 days) may be discontinued prior to the procedure ONLY if the medication is for primary prevention of stroke or heart attack (ask your doctor), headaches or pain. They may be resumed 3 days after the procedure.

Other anticoagulants and antiplatelet agents

See general guidelines.

Dabigatran may be stopped 12 to 48 hours prior to surgery if the risk of bleeding is high. Severe surgical bleeding that cannot be stopped with pressure may require reversal using tranexamic acid or, in an emergency situation, using the specific reversal agent, idarucizumab.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).