10. Anticoagulants, antiplatelet drugs

Last updated on November 25, 2020 at 12:58


Thrombosis is the pathological formation of a “haemostatic” plug within the vasculature in the absence of bleeding. We wish to prevent thrombosis as much as possible, to prevent embolism and ischaemia. To do this must we understand the process of haemostasis.

Haemostasis is the process that causes bleeding to stop when blood vessels are damaged. The process involves three steps:

  1. Vasoconstriction
  2. Adhesion and activation of platelets to form a platelet plug
  3. Fibrin formation

In addition to this, the fibrin be will removed by fibrinolysis after the bleeding has stopped.

Haemostatic drugs affect haemostasis by interfering with step 2, 3 or by decreasing the rate of fibrinolysis. This topic will only cover drugs that interfere with platelet function and fibrin formation.

There are two pathways that lead to the formation of fibrin: the intrinsic pathway and the extrinsic pathway. Both end in the same pathway, the common pathway.

The intrinsic pathway is so named because all the components of it can be found in the blood. A better and more modern name of the pathway is the “contact activation pathway”, because it is activated when the blood comes into contact with a negative surface like glass or another foreign surface. Factor XII binds to the foreign surface and becomes activated to XIIa, which then converts XI into XIa which converts IX into IXa which converts X into Xa.

The extrinsic pathway is so named because it involves a factor that isn’t present in the blood, the tissue factor. Tissue factor is a protein that is found in subendothelial tissue. When there is a vessel damage will the subendothelial tissue and therefore tissue factor be exposed to the blood. Tissue factor activates factor VII to VIIa, which converts X into Xa.

Both pathways end when the common pathway starts, when Xa is formed. Xa converts prothrombin into thrombin, which again converts fibrinogen into fibrin. Fibrin then cross-links with the help of factor XIIIa to form a fibrin mesh that covers the vascular defect.

There are multiple laboratory tests that test the functions of these pathways. Prothrombin time and international normalized ratio (INR) both test the function of the extrinsic pathway while the partial thromboplastin time tests the function of the intrinsic pathway.

Vitamin K

Vitamin K is a fat-soluble vitamin that is essential for the production of clotting factors II, VII, IX, X and protein C and protein S in the liver. After the translation of these clotting factors they are post-translationally modified by γ-carboxylation. This enables them to bind Ca2+, which is essential for their function. In the absence of vitamin K will these clotting factors still be synthesized, but they won’t function as they can’t bind Ca2+.

Vitamin K isn’t strictly a cofactor for γ-carboxylation, as it is converted to an unusable form in the process. However it can be recycled so it can be reused. Recycling is done by the enzyme vitamin K epoxide reductase. When this enzyme works properly will vitamin K be continuously recycled and reused.

Vitamin K antagonists


  • Warfarin
  • Dicumarol

Most vitamin K antagonists (VKAs) are coumarins, so the terms are often used interchangeably. However, there exists some VKAs which are not coumarins. The most commonly used VKA by far is warfarin.


  • Atrial fibrillation
  • Artificial heart valve
  • Prophylaxis for DVT, PE

Mechanism of action:

VKAs inhibit vitamin K epoxide reductase, thereby decreasing the amount of “usable” vitamin K. This creates a condition similar to vitamin K deficiency, causing clotting factors II, VII, IX and X to be dysfunctional and therefore inactive.

Because VKAs act on the synthesis of clotting factors they have a slow onset of action. Immediately after the first administration there are still functioning clotting factors present in the blood – the anticoagulant effect comes only after these functioning clotting factors have been eliminated, which takes around 4 days.


Warfarin has good oral absorption, strong plasma protein binding (97%) and is inactivated by CYP450 in the liver. Its duration of action is 4-5 days and their half-life is 40 hours. It’s given orally.


The problem with coumarins is that people respond differently to the same dose. This is because polymorphisms in the gene for vitamin K epoxide reductase change the affinity of the VKAs to the enzyme.

It’s therefore important to start with a low dose and continuously test the INR of the patient to make sure that they’re not receiving too much (and therefore bleed too easily) or too little (and therefore have suboptimal anticoagulant effect). The dose should always be adjusted so that the INR of the patient is between 2 and 3. INR should be measured often, initially daily but later more rarely.


Coumarins are teratogenic and are therefore contraindicated in pregnancy. They’re also contraindicated in liver and kidney failure.


Certain drugs decrease the effect of coumarins. Vitamin K is the obvious one – in fact vitamin K is the antidote to warfarin poisoning. Drugs that induce CYP450 enzymes like rifampicin and barbiturates increase the elimination of coumarins. Colestyramine decreases the absorption of them.

Because coumarins have strong plasma protein binding they can be displaced by other drugs who also bind strongly to plasma proteins.


Warfarin inhibits the synthesis of protein C and protein S as well, and these factors are depleted more quickly than the clotting factors. This causes an initial hypercoagulable state which can cause tissue infarction and necrosis. Warfarin-induced skin necrosis is a severe complication which can occur with warfarin treatment.

To prevent warfarin-induced necrosis we can use heparin to prevent the initial hypercoagulable state.

Antithrombin III and unfractionated heparin


Unfractionated heparin (UFH)


Heparin is preferred over warfarin in cases where it is necessary that the anticoagulant effect begins immediately. It’s used to prevent deep vein thrombosis, pulmonary embolism and acute coronary syndromes.

Mechanism of action:

Antithrombin III is an endogenous molecule that inhibits factors II, IX, X, XI and XII and therefore the formation of fibrin. Heparin is a drug that increases the effect of antithrombin III and therefore has strong anticoagulant activity.

Heparin isn’t actually a single molecule but a family of large and sulphated glycosaminoglycans that all act on antithrombin III. Heparin is actually present endogenously in the body inside the granules of mast cells. To acquire heparin the pharmaceutical industry extracts them from beef lung or pig intestine. However, because heparin isn’t a single molecule can the biological activity of it differ depending on where it is extracted from. Because of this the dose of heparin is not given in units of mass but rather in units of activity.

The molecular weight of heparin is between 5 and 35 kDa, depending on where it was extracted from.


Given IV or subcutaneously. It acts immediately when given IV but has a 60-minute delay when given subcutaneously. Because of its large molecular size heparin would not be absorbed through the GI tract.

Heparin is eliminated by the liver and by phagocytosis by macrophages. It’s safe to use in pregnancy.


Like for warfarin must patients receiving heparins measure its effect frequently to ensure that they’re not overtreated or undertreated. Activated partial thromboplastin time (aPTT) should be measured daily and should be 1.5 – 2.5 times that of a control subject.

Side effects:

Heparin may paradoxically cause thrombosis. It’s an uncommon but serious side effect called heparin-induced thrombocytopaenia (HIT). It occurs if IgG and IgM antibodies are produced against heparin and platelet factor 4. The immune complexes that form activate platelets and cause thrombosis. Opsonized platelets are phagocytosed, causing thrombocytopaenia.

HIT is treated by taking the patient off heparins and giving another anticoagulant instead, most commonly either danaparoid or argatroban. Danaparoid is a so-called heparinoid, while argatroban is a direct thrombin inhibitor. Warfarin can not be used due to it’s slow onset of action.


The antidote of heparin is a drug called protamine sulphate, which can be used if there is excessive bleeding. It binds to and inactivates heparin.

Low molecular weight heparins


  • Enoxaparin
  • Dalteparin
  • Fondaparinux

The low molecular weight heparins (LMWH) are also called fractionated heparins to distinguish them from unfractionated heparin. These drugs are just fragments of the unfractionated heparin. They’re more predictable and have longer half-life than unfractionated heparin and are therefore preferred in many cases.

The LMWHs have a molecular weight of 3 – 4 kDa.

Advantages of LMWH vs unfractionated heparin:

  • No monitoring of APTT or other parameters is necessary as they’re more predictable
  • Patients can be taught to inject themselves subcutaneously at home
  • Lower risk of bleeding
  • Lower risk of heparin-induced thrombocytopaenia

Disadvantages of LMWH vs unfractionated heparin:

  • LMWH are excreted renally and therefore cannot be used in renal failure

LMWHs don’t inhibit all the coagulation factors that unfractionated heparin does; they only inhibit Xa. However that’s more than enough to ensure that LMWHs are at least as safe and effective as unfractionated heparin and are more convenient to use.

Direct oral anticoagulants

Some more recent drugs are available which can be used instead of the “older” drugs heparin and warfarin. They are called direct oral anticoagulants (DOACs). These drugs do not need monitoring. Their antidotes are not readily available or cheap. They should be used with care when there is decreased liver or kidney function.


  • Direct thrombin inhibitors
    • Dabigatran (Antidote: idarucizumab)
    • Argatroban
      • (NB! Not taken orally, so it’s not a DOAC)
  • Direct factor X inhibitors
    • Apixaban (Antidote: andexanet)
    • Rivaroxaban (Antidote: andexanet)
    • Edoxaban

Mechanism of action:

These drugs bind to and inhibit certain clotting factors directly. Dabigatran etexilate and argatroban bind to and inhibit thrombin (factor IIa). Rivaroxaban, apixaban, edoxaban are factor Xa inhibitors.

Idarucizumab is a monoclonal antibody which binds to and inactivates dabigatran.

Andexanet is a modified recombinant factor Xa. Apixaban and rivaroxaban bind to andexanet with the same affinity as factor Xa, which frees up endogenous factor Xa.

Advantages of DOACs vs other anticoagulants:

  • Don’t require regular monitoring
  • Can be taken orally

Disadvantages of DOACs vs other anticoagulants:

  • Antidotes are very expensive and not readily available

Because antidotes are not readily available these drugs should be used with care in people with liver or kidney failure, as these patients may have decreased elimination of DOACs.

Antiplatelet drugs

When there is a vascular damage receptors glycoprotein IIB/IIIA on the surface of platelets will bind to the subendothelial collagen with the help of von Willebrand factor. This causes the platelets to change shape and release their granules, which contain thromboxane A2, ADP and serotonin.

The molecules that were released from the granules bind to receptors on other platelets and activate them too. ADP will bind to P2Y12 receptor. Glycoprotein receptors also bind to fibrin, which aggregates the platelets by sticking them together.

By interfering with the platelet’s function in haemostasis can we also inhibit thrombosis. Different drugs act on different aspects of platelet activation and aggregation.

Aspirin (acetylsalicylic acid)


  • AMI
  • Ischaemic stroke
  • Angina pectoris
  • After coronary intervention
  • Prevention of cardiovascular disease
  • Prevention of colorectal cancer
  • Peripheral artery disease

Aspirin is such a good drug that basically anyone who has ever had a coronary or cerebral episode are put on low dose aspirin for the rest of their lives.

Mechanism of action:

Aspirin (acetylsalicylic acid) irreversibly inhibits the cyclooxygenase 1 (COX1) enzyme, which produces thromboxanes. By reducing the amount of thromboxane A2 in thrombocytes aspirin interferes with platelet activation and aggregation.


Aspirin is given in much lower dose for use as an antiplatelet drug than when used as an anti-inflammatory. Antiplatelet dose is 50 – 150 mg/day while anti-inflammatory dose is 500 mg/day. Aspirin has no anti-inflammatory effect in those low doses.

The onset of action is within minutes. The effect lasts for around a week.


The antidote of aspirin is platelet concentrate infusion.

Side effects:

  • GI symptoms
    • Peptic ulcer
  • Aspirin asthma
  • Reye syndrome

Reye syndrome is an encephalopathy that occurs in children who take aspirin for viral infections. Aspirin should therefore be used carefully in children.


Dipyridamole is often combined with aspirin.

Mechanism of action:

Dipyridamole is phosphodiesterase inhibitor. It increases the amount of cAMP in the platelets, which inhibits platelet aggregation.

P2Y12 receptor antagonists


  • Clopidogrel
  • Prasugrel
  • Ticagrelor


As part of dual antiplatelet therapy (in combination with aspirin):

  • AMI
  • Before coronary interventions
  • After stent insertion

Mechanism of action:

These drugs inhibit the P2Y12 receptor, an ADP receptor which is found on platelets. This receptor binds ADP which is released from other activated platelets. By blocking the P2Y12 receptor these drugs prevent platelet aggregation.


Clopidogrel and prasugrel are irreversible inhibitors, while ticagrelor is a reversible inhibitor. Despite this, they appear to have similar half-lives.

Glycoprotein IIb/IIIa inhibitors


  • Abciximab
  • Eptifibatide
  • Tirofiban


  • High-risk patients before and during coronary intervention

Mechanism of action:

These drugs bind to and inhibit the receptors glycoprotein IIB/IIIA, which prevents platelets from binding to each other and therefore preventing aggregation.

When to use what?

Both antiplatelet drugs and anticoagulants prevent blood from clotting, so when do we use which type?

The short version of it is that anticoagulants is to prevent thrombosis on the venous side (including the heart) and antiplatelets are used to prevent thrombosis on the arterial side.

Venous thrombi and thrombi forming inside the heart due to atrial fibrillation are mostly due to slow blood flow, or stasis. Stasis activates the coagulation cascade prematurely because the pro-coagulant factors in the blood aren’t exposed to as many anti-coagulant factors on the endothelial surface. In these cases is the best treatment to inhibit the coagulation cascade.

Arterial thrombi form mostly on foreign surfaces like atherosclerotic plaques and stents. This is because the platelets are mostly involved in this process. Antiplatelets decrease the incidents of strokes and coronary episodes like AMI because they prevent platelets from aggregating on the (ruptured) atherosclerotic plaque.

Anticoagulants are mostly used for:

  • Prevention of deep vein thrombosis
  • Prevention of thrombus formation in atrial fibrillation
  • Other venous thrombosis

Antiplatelets are mostly used for:

  • Acute treatment of acute coronary syndromes like NSTEMI, STEMI, unstable angina
  • Prophylaxis of acute coronary syndromes, cerebral stroke
  • Patients who have stents

However in some cases are both types of drugs used in combination.

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11. Fibrinolytics, antifibrinolytics, hemostatic agents

10 thoughts on “10. Anticoagulants, antiplatelet drugs”

    1. Notes are based mostly on the lectures and seminars. When I had pharma 2 the seminar included only one sentence about direct thrombin inhibitors:

      “Management of patients with thromboembolic disease who develop HIT is therefore usually with either danaparoid or with a direct thrombin inhibitor (argatroban).”

      Hirudin and bivalirudin are not mentioned at all, but argatroban is, so I’ve added that to the topic now.

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