Antiplatelets, Anticoagulants and Thrombolysis

Core

Introduction

Thromboembolic disease is one of the largest causes of morbidity and mortality in the UK: ischaemic stroke, myocardial infarction, deep vein thrombosis (DVT), pulmonary embolism (PE) and the embolic complications of atrial fibrillation 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 and von Willebrand factor (vWF). Aggregation is mediated by the glycoprotein IIb/IIIa receptor on activated platelets, which binds fibrinogen to crosslink platelets together. Platelets release thromboxane A₂ and ADP, recruiting more platelets in a positive feedback loop.
• Secondary haemostasis: the coagulation cascade, ending in conversion of fibrinogen to fibrin by thrombin (factor IIa). Activated factor X (Xa) is the convergence point of the intrinsic and extrinsic pathways and is therefore a key drug target.
• Fibrinolysis: the dissolution of clot by plasmin, generated from 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 the most effective drug class; one of the most useful conceptual hooks 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 and most 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 are caused by venous-pattern thrombi. Anticoagulants are the cornerstone of treatment.

The simple memory hook: "white → antiplatelet, red → anticoagulant". In practice the two groups are commonly combined, particularly after acute MI and percutaneous coronary intervention.

Antiplatelet Drugs

Aspirin

Aspirin (acetylsalicylic acid) irreversibly acetylates cyclo-oxygenase-1 (COX-1) in platelets, 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: far longer than the drug's pharmacokinetic half-life of around 20 minutes.

The dose for antiplatelet effect is much lower than the analgesic dose; typically 75 mg once daily for chronic use, with a one-off 300 mg loading dose in acute coronary syndromes.

Indications:

• Secondary prevention after MI, ischaemic stroke or TIA.
• Acute coronary syndromes (with a second antiplatelet).
• Following primary percutaneous coronary intervention (PCI) and stenting.
• Stable angina.

Aspirin is no longer routinely recommended for primary prevention of cardiovascular disease in low-risk adults: the bleeding risk outweighs the modest absolute benefit.

Side effects:

• GI bleeding and peptic ulceration: from the inhibition of prostaglandin-mediated mucosal protection (covered in NSAIDs).
• Haemorrhagic stroke: small absolute risk.
• Bronchospasm in aspirin-sensitive asthmatics.
• Reye's syndrome: the reason aspirin is contraindicated in children under 16 with viral illness.

P2Y₁₂ Inhibitors

The P2Y₁₂ receptor on platelets is activated by ADP and triggers GPIIb/IIIa expression on the platelet surface, accelerating aggregation. Three drugs block it:

• Clopidogrel: the standard. Pro-drug requiring CYP2C19 activation; effect develops slowly and is unpredictable in CYP2C19 poor metabolisers.
• Ticagrelor: not a pro-drug, faster onset, more potent, reversible. NICE NG185 first-line for NSTEMI and unstable angina after coronary angiography.
• 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, and in patients aged 75 or over (use ticagrelor or clopidogrel instead).

P2Y₁₂ inhibitors are typically given for 12 months after acute coronary syndrome or stenting, on top of long-term aspirin (dual antiplatelet therapy, DAPT). They are also used for secondary prevention in patients intolerant of aspirin.

Glycoprotein IIb/IIIa Inhibitors

Abciximab (a monoclonal antibody Fab fragment), 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.

Dipyridamole

Dipyridamole inhibits platelet phosphodiesterase, raising cAMP and indirectly inhibiting 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, preventing the regeneration of reduced vitamin K. Reduced vitamin K is required as a cofactor for the γ-carboxylation of clotting factors II, VII, IX and X (and proteins C and S) in the liver. Without active carboxylation these clotting factors are inactive.

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

Pharmacokinetics:

• Excellent oral bioavailability (~100%).
• Highly protein bound (~99%): relevant to drug interactions.
• 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" until therapeutic INR is reached.
• Teratogenic: contraindicated in the first trimester (warfarin embryopathy) and in the third trimester (fetal intracranial bleeding).

Indications:

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

Monitoring: by International Normalised Ratio (INR), the prothrombin time of the patient's plasma compared to a standardised control. Targets:

• INR 2.5 (range 2-3): AF, first VTE.
• INR 3.5 (range 3-4): mechanical mitral valve, recurrent VTE on warfarin.

Side effects:

• Bleeding: the principal ADR, ranging from minor bruising to fatal intracranial haemorrhage.
• Skin necrosis: rare, in protein C deficiency, in the first days of treatment.
• Purple toe syndrome: rare, from cholesterol microemboli.

Drug interactions are vast and central to safe prescribing. The two most useful mnemonics for the directions:

• Drugs that increase INR (potentiate warfarin): CYP2C9 inhibitors (amiodarone, fluconazole, metronidazole, ciprofloxacin, sulphonamides), antibiotics that reduce gut bacterial vitamin K production (cephalosporins), drugs that displace warfarin from albumin (NSAIDs), and aspirin (additive bleeding via platelets).
• Drugs that decrease INR: CYP inducers ("PC BRAS": phenytoin, carbamazepine, barbiturates, rifampicin, alcohol [chronic], St John's wort).

Heparins

Heparins are negatively charged glycosaminoglycans that bind antithrombin (ATIII), increasing its activity 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). 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 inpatient and prophylactic agent.

Indications:

• VTE prophylaxis in hospital inpatients (every UK trust uses LMWH for this).
• Treatment of DVT and PE: LMWH for several days, often as a bridge to warfarin or as an alternative to DOACs.
• Acute coronary syndromes as part of MONA-BASH.
• 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 (heparin reduces aldosterone secretion).

Reversal: protamine sulfate reverses UFH almost completely and partially reverses LMWH. It 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 (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, particularly triple-positive disease, where MHRA advice is to avoid DOACs because of an increased thrombotic risk.

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.
• Prothrombin complex concentrate (PCC): non-specific reversal where the specific antidote is unavailable.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa via antithrombin. Given subcutaneously, no monitoring required, no risk of HIT. Used in acute coronary syndromes as an alternative to LMWH and in patients with a history of HIT.

Thrombolysis

Thrombolytic agents convert plasminogen to plasmin, which dissolves the fibrin meshwork of an established thrombus. They are sometimes called "clot busters". The three drugs in UK use are:

• Alteplase: recombinant tissue plasminogen activator (tPA). The standard agent in the UK.
• Tenecteplase: a modified form of alteplase, given as a single bolus, increasingly the preferred agent in stroke and STEMI.
• Streptokinase: older, derived from streptococci, antigenic (cannot be re-administered after the first dose because of antibody formation). Largely superseded.

Indications:

• Acute ischaemic stroke: within 4.5 hours of symptom onset, after exclusion of haemorrhage on CT, in eligible patients.
• STEMI: when primary PCI is not available within 120 minutes of diagnosis.
• Massive (haemodynamically unstable) pulmonary embolism.

The principal complication is major bleeding, particularly intracranial haemorrhage in stroke (around 6%). Strict exclusion criteria apply: recent surgery, recent stroke, uncontrolled hypertension, active bleeding, recent head trauma.

Tranexamic acid works in the opposite direction: it inhibits plasminogen activation and reduces fibrinolysis. It is used to reduce bleeding in trauma (the CRASH-2 trial), surgery and menorrhagia.

Reversal of Anticoagulation

A short reference table worth committing to memory:

• Warfarin (minor bleeding, INR 5-8): omit a dose; resume at lower dose when in range.
• Warfarin (major bleeding): vitamin K (phytomenadione) intravenously plus prothrombin complex concentrate (PCC, e.g. Beriplex); fresh frozen plasma if PCC unavailable.
• UFH: stop infusion (short half-life); protamine sulfate if needed.
• LMWH: protamine sulfate partially reverses (around 60%).
• Dabigatran: idarucizumab.
• Apixaban, rivaroxaban: andexanet alfa; PCC if unavailable.
• Aspirin / P2Y₁₂ inhibitors: no specific antidote; platelet transfusion in severe bleeding.
• Thrombolytic-induced bleeding: stop infusion; cryoprecipitate or fresh frozen plasma; tranexamic acid.

Risk Stratification: CHA₂DS₂-VASc and HAS-BLED

Two scoring systems frame the decision to anticoagulate in atrial fibrillation. They are routinely tested at pre-clinical level.

CHA₂DS₂-VASc: stroke risk in non-valvular AF:

C: Congestive heart failure (1)
H: Hypertension (1)
A₂: Age ≥ 75 (2)
D: Diabetes (1)
S₂: previous Stroke / TIA / thromboembolism (2)
V: Vascular disease (1)
A: Age 65-74 (1)
Sc: Sex category: female (1, only counted if any other risk factor is also present)

NICE NG196 recommends offering anticoagulation when CHA₂DS₂-VASc is ≥ 2 in either sex; consider anticoagulation in men with a score of 1; and not anticoagulating women with a score of 1 driven by sex category alone.

NICE NG196 now recommends the ORBIT bleeding-risk score for risk stratification (the older HAS-BLED score remains widely taught and is the version most often tested at pre-clinical level):

H: Hypertension (uncontrolled, > 160 systolic)
A: Abnormal renal or liver function (1 each)
S: Stroke history
B: Bleeding history or predisposition
L: Labile INRs
E: Elderly (> 65)
D: Drugs (e.g. NSAIDs, antiplatelets) or alcohol excess (1 each)

A HAS-BLED score ≥ 3 indicates a high bleeding risk, prompting more frequent review rather than withholding anticoagulation outright.

Summary

• "White arterial thrombi → antiplatelets; red venous thrombi → anticoagulants."
• Aspirin irreversibly inhibits platelet COX-1 (effect lasts 7-10 days, the lifespan of the platelet). P2Y₁₂ inhibitors (clopidogrel, ticagrelor, prasugrel) are added in dual antiplatelet therapy.
• Warfarin blocks vitamin K-dependent clotting factors (the "1972" factors: II, VII, IX, X). Monitored by INR. Slow onset (3-5 days) requires heparin bridging. Many drug interactions, especially via CYP2C9.
• Heparins (UFH, LMWH) work via antithrombin. LMWH is the standard for most inpatient indications. Watch for HIT (5-14 days into treatment).
• DOACs: -xaban drugs inhibit Xa, dabigatran inhibits IIa. First-line for non-valvular AF and most VTE.
• Thrombolytics (alteplase, tenecteplase) dissolve clot in acute ischaemic stroke (< 4.5 hours), STEMI when PCI unavailable, and massive PE.
• Reversal: vitamin K + PCC for warfarin; protamine for heparin; idarucizumab for dabigatran; andexanet alfa for the -xabans.
• CHA₂DS₂-VASc stratifies stroke risk in AF; HAS-BLED stratifies bleeding risk on anticoagulation.

Drug Summary Table

Antiplatelets, anticoagulants, thrombolytics, and the antidotes for each.

Reviewed by: Dr. Marcus Judge

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