Chapter 24 – Drugs Affecting Coagulation


This has three elements: platelets, the coagulation cascade and fibrinolysis. The first two are involved in preventing haemorrhage by thrombus formation, while fibrinolysis is an essential limiting mechanism.

Chapter 24 Drugs Affecting Coagulation


Haemostasis is complicated. Two models are currently used to explain what is thought to occur.

The Classical Model

This has three elements: platelets, the coagulation cascade and fibrinolysis. The first two are involved in preventing haemorrhage by thrombus formation, while fibrinolysis is an essential limiting mechanism.

Thrombus formation is initially dependent on platelet adhesion, which is triggered by exposure to subendothelial connective tissue. The von Willebrand factor, which is part of the main fraction of factor VIII, is essential in this process. Subsequent platelet aggregation and vasoconstriction is enhanced by the release of thromboxane A2 (TXA2) from platelets. Adjacent undamaged vascular endothelium produces prostacyclin (PGI2), which inhibits aggregation and helps to localise the platelet plug to the damaged area. The localised primary platelet plug is then enmeshed by fibrin, converting it to a stable haemostatic plug.

The coagulation cascade is formed by an intrinsic and extrinsic pathway, which converge to activate factor X and the final common pathway (see Figure 24.1). The intrinsic pathway is triggered by the exposure of collagen, thereby activating factor XII, while the extrinsic pathway is triggered by leakage of tissue factors, activating factor VII.

Figure 24.1 Final common pathway of the coagulation cascade.

Venous thrombus consists mainly of a fibrin web enmeshed with platelets and red cells. Arterial thrombus relies more on platelets and less on the fibrin mesh.

A crucial part of this process is its limitation to the initial site of injury. Circulating inhibitors, of which anti-thrombin III is the most potent, perform this function. In addition, a fibrinolytic system is activated by tissue damage, converting plasminogen to plasmin, which converts fibrin into soluble degradation products.

The Cell-Based Model

The cell-based model has been developed more recently in light of the perceived failings of the classical model, in particular its failure to explain haemostatic mechanisms in vivo.

For example, factor XII deficiency does not result in an increased bleeding tendency in vivo despite abnormal in vitro tests; the bleeding tendency surrounding factor XI deficiency is not closely related to in vitro tests.

The cell-based model places greater importance on the interaction between specific cell surfaces and clotting factors. Haemostasis is proposed to actually occur on the cell surface, the type of cell with its specific range of surface receptors allowing different cells to play specific roles in the process.

The cell-based model proposes that coagulation is the sum of three processes each occurring on different cell surfaces rather than as a cascade. The three processes are initiation, amplification and propagation. Following vascular injury cells that bear tissue factor are exposed to the circulation and to circulating clotting factors thereby initiating the process. The limited amount of thrombin generated is crucial in amplifying the procoagulant signal and causes platelets to become covered in activated co-factors. The whole process is propagated by the activation of clotting factors on the surface of the tissue factor bearing cells and platelets. As a result, large amounts of thrombin are formed leading to the formation of fibrin from fibrinogen, which consolidates the platelet plug and forms a stable clot. It is this propagation phase that is so deficient in haemophilia despite relatively normal initiation and amplification phases because of insufficient platelet surface thrombin production.

Antiplatelet Drugs

Cyclo-Oxygenase I Inhibition Aspirin


Aspirin reduces the risk of unstable angina progressing to acute myocardial infarction (MI) and reduces mortality following acute MI. The risk of stroke is also reduced for patients with transient ischaemic attacks.

Mechanism of Action

Aspirin acts by irreversible inhibition of cyclo-oxygenase (by acetylation) within the platelet, resulting in reduced production of TXA2. This may be achieved with only 75 mg daily. Its effects and kinetics are discussed in Chapter 10.

Platelet Phosphodiesterase Inhibition Dipyridamole


Dipyridamole has been used with limited success in conjunction with warfarin to prevent thrombus formation on prosthetic valves. There is some evidence that when combined with aspirin, dipyridamole may further reduce the risk of stroke, compared to aspirin alone.

Mechanism of Action

Dipyridamole inhibits platelet adhesion to damaged vessel walls (by inhibiting adenosine uptake), potentiates the effects of prostacyclin and at high doses inhibits platelet phosphodiesterase activity resulting in increased cAMP levels and lower intraplatelet calcium levels. Compared to aspirin it inhibits platelet adhesion to vessel walls more than platelet aggregation.

It is a potent coronary artery vasodilator and may be used in conjunction with thallium-201 during myocardial imaging.

Inhibition of ADP Binding Clopidogrel

Clopidogrel is a prodrug, requiring hepatic CYP450 to convert it into its active form.


It is used to prevent atherothrombotic events in patients with peripheral vascular disease and when combined with aspirin it is also used to treat ST-elevation myocardial infarction (STEMI) and NSTEMI. It also forms a crucial part of post-coronary stent therapy with aspirin to prevent stent failure.

Mechanism of Action

Clopidogrel irreversibly binds to the P2Y12 receptor (an ADP receptor) on platelets, which prevents the glycoprotein IIb/IIIa receptor from transforming into its active form and facilitating platelet activation and cross-linking.


An oral loading dose of 300 mg is followed by a maintenance dose of 75 mg. Antiplatelet effects are seen within 2 hours. Due to the irreversible binding to the P2Y12 receptor its effects last for 7 days which is the recommended interval between the last dose and insertion of a neuraxial block. The majority of clopidogrel is hydrolysed by esterases to inactive derivatives, leaving only a small fraction to be oxidised by hepatic CYP450. This oxidation is a two-stage reaction, the final product being the active moiety that forms a disulfide bond with the P2Y12 receptor. CYP3A4 and CYP3A5 are the primary isoenzymes but CYP2C19 is also involved. There are many genetic variants of CYP2C19 resulting in reduced or increased amounts of active drug and hence variable antiplatelet effect. In addition omeprazole, which is often prescribed alongside clopidogrel, has a CYP2C19 inhibitory effect and reduces the conversion of clopidogrel to its active form.


Prasugrel, like clopidogrel, is also a prodrug. However, it is only licensed for percutaneous coronary intervention (PCI) in acute coronary syndrome and may be continued for 12 months with aspirin. It has a faster onset of action compared to clopidogrel and is more effective but also associated with more serious bleeding episodes. It appears to be less susceptible to the genetic polymorphism of the CYP450 system than clopidogrel, and is not affected by CYP450 inhibitors.


Ticagrelor is used in acute coronary syndrome in combination with aspirin. It has a bioavailability of 40%, is metabolised by CYP3A4 to active metabolites and excreted mainly in the bile. Other drugs that are metabolised by CYP3A4 or inhibit CYP3A4 may increase its plasma concentrations. It is an allosteric antagonist of ADP in that it antagonises ADP’s binding to the P2Y12 receptor by binding to a different site.

Glycoprotein IIb/IIIa-Receptor Antagonists

Abciximab is a monoclonal antibody with a high affinity for the platelet glycoprotein IIb/IIIa receptor. It has a plasma half-life of 20 minutes but remains bound in the circulation for up to 15 days with some residual activity.

Eptifibatide is a cyclic heptapeptide with a lower receptor affinity and a plasma half-life of 200 minutes. Fifty percent undergoes renal clearance.

Tirofiban has intermediate receptor affinity and undergoes renal (65%) and faecal (25%) clearance.


These drugs are used around the time of acute coronary events. They are used intravenously for a short duration during concurrent unfractionated heparin therapy with close control of the activated partial thromboplastin time (APTT) and/or the activated clotting time (ACT). They carry the rare but serious complication of thrombocytopenia.

Mechanism of Action

They act by inhibiting the platelet glycoprotein IIb/IIIa receptor and as such block the final common pathway of platelet aggregation. However, they do not block platelet adhesion, secretion of platelet products, inflammatory effects or thrombin activation.

Miscellaneous Dextran 70

Dextran 70 is a polysaccharide that contains chains of glucose. It is produced by the fermentation of sucrose by the bacterium Leuconostoc mesenteroides.


It is used as prophylaxis against peri-operative venous thrombosis and as a plasma volume expander.

Mechanism of Action

The anticoagulant activity appears to depend on reducing platelet adhesiveness and a specific inhibitory effect on the von Willebrand factor. It also reduces red cell aggregation and provides a protective coat over vascular endothelium and erythrocytes. The dilution of clotting factors and volume expansion also improves micro-circulatory flow.

Other Effects

These include fluid overload, allergic reactions and anaphylaxis. Dextran 70 can impair cross-matching by rouleaux formation. Renal failure is a rare complication.

Epoprostenol (prostacyclin – PGI2)

This is a naturally occurring prostaglandin.


Epoprostenol is used to facilitate haemofiltration by continuous infusion into the extracorporeal circuit.

Mechanism of Action

Epoprostenol causes inhibition of platelet adhesion and aggregation by stimulating adenylate cyclase. The ensuing rise in cAMP reduces intracellular Ca2+, effecting the change. It may also have a fibrinolytic effect. The recommended dose range is 2–12−1.min−1.

Side Effects

These relate to its vasodilator properties (hypotension, tachycardia, facial flushing and headache).

Heparins and Protamine

Unfractionated Heparin

Heparin is an anionic, mucopolysaccharide, organic acid containing many sulfate residues. It occurs naturally in the liver and mast cell granules and has a variable molecular weight (5000–25,000 Da).


Unfractionated heparin is used by continuous intravenous infusion to treat deep vein thrombosis (DVT), pulmonary embolus (PE), unstable angina and in critical peripheral arterial occlusion. Subcutaneous administration to prevent venous thrombosis peri-operatively and in the critically ill has largely been superseded by fractionated heparin, except in renal failure. It is also used in the priming of extracorporeal circuits. There has been limited use in disseminated intravascular coagulation (DIC).

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Mar 7, 2021 | Posted by in ANESTHESIA | Comments Off on Chapter 24 – Drugs Affecting Coagulation
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