Anticoagulants and antiplatelet agents.

Its relationship with dermatological surgery.

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 the excessive formation of blood clots.

How do blood clots form?

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

• the blood vessels they contract to reduce blood flow.
• Small fragments of blood cells called platelets bundle to seal the wound. They produce thromboxane, which attracts more platelets to the wound.
• The wound produces thromboplastin, which triggers the coagulation waterfall.
• The coagulation cascade involves 12 clotting factors (blood proteins) that convert fibrinogen in a network of fibrin filaments through enzyme thrombin
• Vitamin K and calcium are also necessary for this process.
• Antithrombin, protein C, and protein S. prevent excessive clotting.

What happens if the clotting is excessive?

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

A part of the thrombus may become dislodged (a plunger) and can travel through blood vessels to block a smaller vessel.

Blood clots that form in the arteries are mainly made up of platelets with a small amount of fibrin. Lead to:

• Stroke, transient ischemic attack (TIA or mini-stroke)
• Myocardial infarction
• Peripheral arterial clot and gangrene
• Heart attacks in internal organs (eg kidney, spleen, intestine).

Blood clots that form in larger veins are made up mostly 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 by genetic and acquired reasons. These may include:

• Family reduced antithrombin, protein C, or protein S
• Obesity and metabolism syndrome
• Of smoking
• Slow blood flow due to atherosclerosis (cholesterol and calcium statement on the walls of the arteries) or frostbite
• Prolonged bed rest, for example, after surgery or during illness.
• Higher orthopedic surgery, particularly hip and knee surgery
• Traveling on a plane or bus for an extended period
• Irregular heartbeat (eg, atrial fibrillation)
• Artificial heart valve or congenital heart defects
• Antiphospholipid syndrome
• Pregnancy or estrogen medication (eg, oral contraceptive pill)
• Medications that increase hemostasis (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 venous thrombosis.

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

The antiplatelet / anticoagulant level should 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 used primarily to prevent strokes and heart attacks. 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 necessary for the synthesis of prostaglandins and thromboxane. It has a long half life.

Clopidogrel, prasugrel, ticagrelor and ticlopidine antagonize ADP receiverinterrupting platelet activation and crosslinking. These have shorter half lives.

More about anticoagulants

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

Warfarin:

• Inhibits vitamin K epoxide reductase, reducing the hepatic synthesis of vitamin K dependent coagulation factors II, VII, IX and X.
• The level of anticoagulation is controlled by measuring the International Normalized Ratio (INR).
• It is metabolized by CYP2C9 and is highly protein bound (99%), which means that many other drugs and supplements can change the physiologically active dose.
• In emergency situations of uncontrollable bleeding in patients with warfarin, vitamin K and fresh frozen plasma it can be given to counteract its effects and lower the INR.

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

Newer 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 newer blood thinners:

• They are as good or better at preventing thromboembolism
• Have the same or lower risk of bleeding
• You have no reversion agent available at this time
• Have predictable pharmacokinetics and pharmacodynamics, so the levels are not currently controlled
• 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 plasma levels.

Natural antiplatelet and anticoagulant agents.

Some natural foods, supplements, and medications have antiplatelet and anticoagulant activity, such as garlic, ginger, ginkgo, dong quai, feverfew, fish oil, vitamin E, and many others. Good quality laboratory and human studies have not been performed with these agents and they are not regulated. Food supplements and herbal medicines with an uncertain effect on blood clotting should be avoided when taking prescription antiplatelet and anticoagulant medications 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 dermatologic surgery?

Patients taking antiplatelet and anticoagulant agents are at increased risk of bleeding, particularly after trauma. Dermatological surgery in these patients can cause complications such as:

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

But, if patients stop their blood thinners before surgery, they face complications associated with thrombosis. This presents a dilemma: should anticoagulation be stopped or continued for dermatologic surgery?

In the past, dermatologic surgeons were in favor of stopping anticoagulants to reduce the risk of bleeding; warfarin increases the risk of surgical bleeding ~ 7 to 9 times. But nevertheless:

• It is extremely rare 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 in-theater electrocoagulation.
• A postoperative hematoma can be managed in an outpatient setting.

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

• The 24% of the dermatologic surgeons surveyed recalled a patient who 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 indicate that it follows a similar pattern to warfarin.

As the risks of thromboembolism outweigh the risk of bleeding, it is now recommended that anticoagulants continue in low-risk operations, such as those found in dermatology. This recommendation may differ on a case-by-case basis. In case of stopping a medicine, pharmacokinetics and pharmacodynamics Factors need to be taken into account to optimize time (see table below).

General guidelines for anticoagulant and antiplatelet medication during skin surgery.

Brown et al provide suggested guidelines for perioperative treatment of oral anticoagulant and antiplatelet drugs for dermatologic surgery (simplified below) [3].

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

Warfarin

• The international normalized ratio (INR) 1 month before surgery should be within therapeutic rank.
• Surgery should be postponed if the INR is> 3.5.
• If severe bleeding occurs that cannot be stopped with pressure, reversal with fresh frozen plasma or vitamin K may be considered.

Aspirin / Anti- steroidalinflammatory drugs (NSAID)

Aspirin (10 days) or NSAIDs (3 days) can be stopped before the procedure ONLY if the medicine is for primary prevention of stroke or heart attack (consult your doctor), headaches or pain. They can be resumed 3 days after the procedure.

Other anticoagulants and antiplatelet agents

See general guidelines.

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

New Zealand approved data sheets are the official source of information for these prescription drugs, including approved uses and risk information. See the New Zealand individual data sheet on the Medsafe website.