Antiplatelets, Anticoagulants and Thrombolysis

1. Introduction
2. Haemostasis Recap
3. Arterial and Venous Thrombi
4. Antiplatelet Drugs
   • Aspirin
   • P2Y₁₂ Inhibitors
   • Glycoprotein IIb/IIIa Inhibitors
   • Dipyridamole
5. Anticoagulants
   • Warfarin
   • Heparins
   • DOACs
   • Fondaparinux
6. Thrombolysis
7. Reversal of Anticoagulation
8. Risk Stratification: CHA₂DS₂-VASc and HAS-BLED
9. Summary
10. Drug Summary Table
11. Quiz

• Arterial thrombi are platelet-rich ("white") and form on ruptured atheromatous plaques (fatty deposits in the artery wall); venous thrombi are fibrin-rich ("red") and form where blood flow is slow or still (stasis). Antiplatelet drugs target arterial thrombi; anticoagulants target venous thrombi.
• The major antiplatelet classes are aspirin (COX-1 inhibitor), P2Y₁₂ inhibitors (clopidogrel, ticagrelor, prasugrel), GPIIb/IIIa inhibitors (tirofiban, eptifibatide) and dipyridamole.
• The major anticoagulant classes are warfarin (vitamin K antagonist; monitored with a blood clotting test, the International Normalised Ratio or INR), heparins (unfractionated and low-molecular-weight), DOACs (direct oral anticoagulants: apixaban, rivaroxaban, edoxaban, dabigatran), and fondaparinux.
• Thrombolytics (alteplase, tenecteplase, streptokinase) dissolve established thrombus and are used for acute ischaemic stroke, ST-elevation myocardial infarction (STEMI: a heart attack with ST-segment elevation on the ECG heart tracing) when primary PCI (percutaneous coronary intervention: opening the blocked artery through a thin tube passed in from the wrist or groin) is unavailable, and massive pulmonary embolism.

Introduction

Thromboembolic disease (a clot blocking a vessel where it forms, or after breaking off and travelling) is one of the largest causes of morbidity and mortality in the UK. Ischaemic stroke (from a blocked brain artery), myocardial infarction (MI, a heart attack), deep vein thrombosis (DVT), pulmonary embolism (PE) and the embolic complications of atrial fibrillation (AF, an irregular heart rhythm) are all consequences of inappropriate clot formation. The pharmacology of preventing and treating these clots divides cleanly into three groups of drugs: antiplatelets, anticoagulants, and thrombolytics.

The anatomy of the cardiovascular system is covered in Anatomy of the Cardiovascular System, the disease processes in Artery and Vein Disease, and the haematology of clotting in Full Blood Count and Bloodfilms.

Haemostasis Recap

Normal haemostasis is conventionally divided into:

• Primary haemostasis: platelet adhesion, activation and aggregation. Triggered by exposure of subendothelial collagen (collagen beneath the vessel lining) and von Willebrand factor (vWF, a protein that helps platelets stick to damaged vessel wall). Aggregation is mediated by the glycoprotein IIb/IIIa receptor on activated platelets, which binds fibrinogen to crosslink platelets together. Platelets release thromboxane A₂ (a chemical that makes platelets stick together) and ADP (adenosine diphosphate, another platelet-activating chemical), recruiting more platelets in a positive feedback loop.
• Secondary haemostasis: the coagulation cascade, ending in conversion of fibrinogen to fibrin by thrombin (factor IIa, the enzyme that carries out this step). Activated factor X (Xa) is the convergence point of the intrinsic and extrinsic pathways (the two routes that start the cascade) and is therefore a key drug target.
• Fibrinolysis: the dissolution of clot by plasmin (the enzyme that digests fibrin), generated from its inactive precursor plasminogen by tissue plasminogen activator (tPA).

Diagram: The coagulation cascade and the principal sites of action of antiplatelet, anticoagulant and thrombolytic drugs.

Arterial and Venous Thrombi

The composition of a thrombus determines which drug class works best. This is one of the most useful ideas in thrombosis pharmacology:

• Arterial thrombi ("white" thrombi) form on ruptured atherosclerotic plaques in high-flow vessels. They are platelet-rich and have relatively low fibrin content. Acute coronary syndromes (ACS: a sudden drop in blood supply to the heart muscle, including heart attack) and many ischaemic strokes are caused by arterial thrombi. Antiplatelets are the cornerstone of treatment.
• Venous thrombi ("red" thrombi) form in low-flow conditions (immobility, surgery, pregnancy) and have a high fibrin and red-cell content with relatively few platelets. DVT, PE and the cardio-embolic strokes of AF (from clots that form in the heart and travel to the brain) are caused by venous-pattern thrombi. Anticoagulants are the cornerstone of treatment.

The simple memory hook: "white → antiplatelet, red → anticoagulant". In practice antiplatelets and anticoagulants are commonly combined, particularly after acute MI and percutaneous coronary intervention (PCI).

Antiplatelet Drugs

Aspirin

Aspirin (acetylsalicylic acid) irreversibly acetylates cyclo-oxygenase-1 (COX-1) in platelets (the enzyme is permanently switched off by an added acetyl group), blocking the production of thromboxane A₂, the major platelet aggregator. Because platelets have no nucleus they cannot synthesise new enzyme, so the antiplatelet effect lasts for the entire 7-10 day lifespan of the platelet. This is far longer than the drug's half-life (the time taken for its blood level to fall by half) of around 20 minutes.

The dose for antiplatelet effect is much lower than the analgesic dose: typically 75 mg once daily for chronic use. In acute coronary syndromes a one-off 300 mg loading dose (a larger first dose to get the drug working quickly) is also given.

Indications:

• Secondary prevention (preventing a further event in someone who has already had one) after MI.
• Ischaemic stroke and transient ischaemic attack (TIA, a temporary stroke-like episode): aspirin is started as soon as possible (for ischaemic stroke, only once a brain scan has excluded bleeding in the brain) and continued short term, sometimes with clopidogrel. For long-term prevention clopidogrel is usually recommended. If clopidogrel is contraindicated or not tolerated, NICE recommends aspirin combined with modified-release dipyridamole (a second antiplatelet drug, described below).
• Acute coronary syndromes (with a second antiplatelet).
• Following primary percutaneous coronary intervention (PCI) and stenting.
• Stable angina (chest pain on exertion caused by narrowed heart arteries).

Aspirin is no longer routinely recommended for primary prevention (preventing a first event) of cardiovascular disease: NICE NG238 says not to offer it routinely. The bleeding risk outweighs the modest absolute benefit.

Side effects:

• Gastrointestinal (GI) bleeding and peptic ulceration (ulcers in the stomach or duodenum): aspirin reduces the prostaglandins (local chemical messengers) that protect the stomach lining (covered in non-steroidal anti-inflammatory drugs (NSAIDs)).
• Haemorrhagic stroke: small absolute risk.
• Bronchospasm (sudden narrowing of the airways) in people with aspirin-sensitive asthma.
• Reye's syndrome (a very rare condition that can cause serious brain problems in children or young adults after an illness like flu or chickenpox): the reason aspirin should not be given to children under 16 unless specifically indicated, for example in Kawasaki disease (a childhood illness that inflames blood vessels).

P2Y₁₂ Inhibitors

The P2Y₁₂ receptor on platelets is activated by ADP and triggers activation of the platelet surface GPIIb/IIIa complex, accelerating aggregation. Three oral drugs block it (a fourth, cangrelor, is given intravenously during PCI when oral treatment is not suitable):

• Clopidogrel: recommended for long-term prevention after an ischaemic stroke and in peripheral arterial disease (narrowed leg arteries). In acute coronary syndromes it is the P2Y₁₂ inhibitor offered to people who also need an oral anticoagulant. It is a pro-drug (converted in the body into its active form) and needs a liver enzyme, cytochrome P450 2C19 (CYP2C19), to activate it. Its effect develops slowly and is unpredictable in CYP2C19 "poor metabolisers" (people whose version of this enzyme works poorly).
• Ticagrelor: not a pro-drug, faster onset, more potent, reversible. For non-ST-elevation myocardial infarction (NSTEMI) or unstable angina (new or worsening angina, including at rest), NICE NG185 offers prasugrel or ticagrelor with aspirin to people having coronary angiography (an X-ray dye test of the heart arteries) who do not need an oral anticoagulant for another reason. When PCI is not indicated, it offers ticagrelor with aspirin, unless the person has a high bleeding risk.
• Prasugrel: pro-drug with more reliable activation than clopidogrel; NICE NG185 first-line for STEMI undergoing primary PCI in patients not on an oral anticoagulant. Contraindicated after stroke or TIA. Age 75 or over is not an absolute contraindication: assess whether bleeding risk outweighs benefit and consider ticagrelor or clopidogrel as alternatives.

After acute coronary syndrome, P2Y₁₂ inhibitors are usually combined with aspirin for up to 12 months (dual antiplatelet therapy, DAPT), with duration reviewed according to bleeding risk and clinical circumstances. Having a stent does not by itself set a fixed 12-month course. P2Y₁₂ inhibitors are also used on their own for long-term prevention: clopidogrel after an ischaemic stroke, and after an MI when aspirin is not tolerated.

Glycoprotein IIb/IIIa Inhibitors

Tirofiban and eptifibatide block the final common pathway of platelet aggregation by occupying the GPIIb/IIIa receptor. They are given intravenously in the catheter laboratory at the time of high-risk PCI. The principal hazard is bleeding. An older drug, abciximab (a monoclonal antibody Fab fragment: the binding part of a laboratory-made antibody), works the same way but has been discontinued in some countries, including the USA.

Dipyridamole

Dipyridamole inhibits platelet phosphodiesterase, the enzyme that breaks down cAMP (cyclic AMP, a signalling molecule inside the platelet). The rise in cAMP indirectly inhibits platelet aggregation. It is used in combination with aspirin for secondary prevention after ischaemic stroke or TIA in patients who do not tolerate clopidogrel. Common side effects are flushing and headache.

Anticoagulants

Warfarin

Warfarin inhibits vitamin K epoxide reductase (the enzyme that recycles vitamin K), preventing the regeneration of reduced vitamin K. Reduced vitamin K is required as a cofactor for γ-carboxylation, a chemical step in the liver that activates clotting factors II, VII, IX and X (and proteins C and S, the body's natural anticoagulants). Without active carboxylation these clotting factors are inactive.

A useful memory aid: warfarin blocks the "1972" factors (10, 9, 7, 2).

Pharmacokinetics (how the body handles the drug):

• Excellent oral bioavailability (the share of a swallowed dose that reaches the blood): about 100%.
• Highly protein bound (~99%), although displacement from plasma proteins rarely matters clinically.
• Metabolised by CYP2C9; substantial inter-individual variability.
• Half-life 36-48 hours.
• Slow onset: full anticoagulation takes 3-5 days because circulating active factors must be cleared. Heparin is used as a "bridge" (cover in the meantime) until the INR reaches its target range.
• Teratogenic (harmful to the developing baby): should not be given in the first trimester, the first 3 months of pregnancy (warfarin embryopathy, a pattern of birth defects). It should also be avoided if at all possible later in pregnancy, especially in the last few weeks and at delivery, because of bleeding in the baby. Difficult decisions are needed in some women, for example those with mechanical heart valves.

Indications:

• Atrial fibrillation in patients unsuitable for DOACs (notably mechanical heart valves and moderate-severe mitral stenosis, a narrowed mitral valve, where DOACs are contraindicated).
• DVT and PE (largely replaced by DOACs).
• Prevention of recurrent venous thromboembolism (VTE: DVT or PE) in selected patients.

Monitoring: by International Normalised Ratio (INR), the prothrombin time (how long the patient's plasma takes to clot in a laboratory test) compared with a standardised control. Targets:

• INR 2.5 (range 2-3): AF, first VTE.
• INR 3.5 (range 3-4): DVT or PE that recurs despite anticoagulation with an INR above 2.
• Mechanical heart valves: the target depends on the type and position of the valve and on patient risk factors.

Side effects:

• Bleeding: the principal adverse drug reaction (ADR), ranging from minor bruising to fatal intracranial haemorrhage (bleeding inside the skull).
• Skin necrosis (death of patches of skin): rare, in the first days of treatment. The risk is higher in people with protein C or protein S deficiency.
• Purple toe syndrome: rare, from cholesterol microemboli (tiny fragments of cholesterol that block small arteries).

Drug interactions are vast and central to safe prescribing. They can raise or lower the INR, and some add to bleeding risk without changing it. For many of them the British National Formulary (BNF), the UK prescribing reference, advises monitoring the INR:

• Drugs that increase INR (increase warfarin's effect): enzyme inhibitors, which slow the liver's breakdown of warfarin (amiodarone, fluconazole, metronidazole, ciprofloxacin, sulphonamides), and antibiotics that reduce gut bacterial vitamin K production (cephalosporins).
• Drugs that add to bleeding risk without acting mainly on the INR: aspirin (via platelets) and other NSAIDs.
• Drugs that decrease INR: enzyme inducers, which speed up the liver's breakdown of warfarin. Mnemonic "PC BRAS": phenytoin, carbamazepine, barbiturates, rifampicin, alcohol [chronic], St John's wort. Phenytoin is less predictable: the BNF says it can alter warfarin's effect.

Heparins

Heparins are negatively charged glycosaminoglycans (long chains of sugar units) that bind antithrombin (ATIII), a natural clotting inhibitor in the blood, increasing the activity of antithrombin by around 1000-fold. ATIII inactivates several coagulation factors, principally thrombin (IIa) and factor Xa.

Two clinical preparations are used:

• Unfractionated heparin (UFH): large polysaccharide. Inactivates both IIa and Xa. Given intravenously, monitored by activated partial thromboplastin time (APTT), a laboratory test of clotting time. Short half-life (1-2 hours), so easily reversed by stopping the infusion. The standard choice when fine control is needed (e.g. cardiac surgery, intra-procedural anticoagulation).
• Low-molecular-weight heparin (LMWH): enoxaparin, dalteparin, tinzaparin. Smaller, preferentially inhibits Xa rather than IIa. Given subcutaneously, more predictable dose response, longer half-life (~4 hours), no routine monitoring needed (anti-Xa levels in selected patients). The standard drug for hospital inpatients and for prophylaxis (preventing clots before they form).

Indications:

• VTE prophylaxis in hospital inpatients (NICE recommends LMWH first line for acutely ill medical patients, with fondaparinux if LMWH is contraindicated).
• Treatment of DVT and PE: NICE recommends apixaban or rivaroxaban first. If neither is suitable, there are two options. One is LMWH for at least 5 days, followed by dabigatran or edoxaban. The other is LMWH alongside warfarin for at least 5 days or until the INR is at least 2 on 2 consecutive readings.
• Acute coronary syndromes: NICE recommends unfractionated heparin during primary PCI for STEMI when the catheter goes in through the wrist (radial access). For unstable angina or NSTEMI it recommends fondaparinux (see below) unless bleeding risk is high or immediate angiography is planned.
• Anticoagulation in pregnancy (heparins do not cross the placenta): LMWH is the standard.

Side effects:

• Bleeding.
• Heparin-induced thrombocytopenia (HIT): an immune-mediated reaction occurring 5-14 days after starting heparin, characterised by a fall in platelet count and, paradoxically, a high risk of thrombosis. Higher risk with UFH than LMWH. Treatment is to stop heparin and switch to a non-heparin anticoagulant (e.g. argatroban, fondaparinux).
• Osteoporosis with prolonged use, particularly in pregnancy.
• Hyperkalaemia (high blood potassium): heparin reduces secretion of aldosterone, the hormone that makes the kidneys excrete potassium.

Reversal: protamine sulfate reverses UFH almost completely and partially reverses LMWH. Protamine has no effect on fondaparinux.

DOACs

The direct oral anticoagulants (DOACs), sometimes still called NOACs ("novel oral anticoagulants"), have largely replaced warfarin for most indications since 2010. They are easier to use because they have predictable pharmacokinetics, fixed dosing, and no routine monitoring requirement.

Two mechanisms:

• Direct factor Xa inhibitors: apixaban, rivaroxaban, edoxaban. Memory hook: the "-xaban" suffix tells you they block Xa.
• Direct thrombin (IIa) inhibitor: dabigatran.

Indications:

• Non-valvular atrial fibrillation, meaning AF without a mechanical valve or moderate-to-severe mitral stenosis (first-line in NICE guidance).
• Treatment and prevention of DVT and PE.
• Post-orthopaedic surgery prophylaxis.

Contraindications (where warfarin is still required):

• Mechanical heart valves.
• Moderate-to-severe mitral stenosis.
• Antiphospholipid syndrome (an autoimmune condition that makes the blood clot too easily). The MHRA (the UK medicines regulator) advises that DOACs are not recommended, particularly in high-risk people who test positive on all 3 antiphospholipid tests ("triple-positive"), because of a higher risk of recurrent clots.

DOACs are also generally avoided in pregnancy and in advanced renal impairment.

Reversal:

• Idarucizumab: specific antidote for dabigatran.
• Andexanet alfa: specific antidote for apixaban and rivaroxaban. NICE recommends it only for life-threatening or uncontrolled bleeding in the gastrointestinal tract, and could not make a recommendation for bleeding inside the skull (intracranial haemorrhage).
• Prothrombin complex concentrate (PCC) (a concentrate of clotting factors): non-specific reversal where a specific antidote is unavailable or not recommended.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide (a chain of five sugar units) that selectively inhibits factor Xa via antithrombin. Given subcutaneously, it does not require routine anticoagulant-effect monitoring, but renal function and bleeding risk still need clinical assessment. It is sometimes used to treat HIT, with specialist advice, although rare cases of HIT have been reported with fondaparinux itself. Its licensed uses include preventing and treating DVT and PE. In unstable angina and NSTEMI, NICE recommends it unless bleeding risk is high or immediate angiography is planned.

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