Anticoagulant and antithrombotic drugs

• Antithrombotic medicines divide into two groups: anticoagulants, which act on the clotting cascade, and antiplatelet drugs, which stop platelets from sticking together. Thrombolytics dissolve clot that has already formed.
• For most clots in veins and for atrial fibrillation (AF, an irregular heartbeat that allows blood to pool in the atria), a direct oral anticoagulant (DOAC) is now first line; it is taken at a fixed dose and needs little routine monitoring ^[3].
• Older and parenteral agents are still needed: unfractionated heparin (UFH) and low molecular weight heparin (LMWH) for acute or bridging treatment, warfarin when a vitamin K antagonist is required (mechanical valves, triple-positive antiphospholipid syndrome), and specific agents in kidney failure or severe bleeding.
• Every anticoagulant can be monitored, and most can be reversed: UFH with protamine, warfarin with vitamin K and prothrombin complex concentrate (PCC), dabigatran with idarucizumab, the factor Xa inhibitors with andexanet alfa or PCC.
• Choosing and timing treatment depend on the indication, kidney and liver function, pregnancy, age, weight, other medicines and the bleeding risk, which is what this page sets out.

By the end of this page you should be able to:

1. Name the members of each major anticoagulant and antithrombotic class and state their mechanism, where they act in the clotting process and how they are cleared.
2. Select an anticoagulant for venous thromboembolism (VTE), atrial fibrillation, mechanical valves, antiphospholipid syndrome, cancer and pregnancy, and name the ones that must be avoided in each.
3. Plan monitoring with activated partial thromboplastin time (aPTT), anti-Xa assays, the International Normalised Ratio (INR), renal function and calibrated drug assays.
4. Reverse anticoagulation in major bleeding, including the order and timing of agents, and know which drugs have no specific antidote.
5. Manage anticoagulation around a planned procedure, and manage a bleeding patient, including when not to stop the drug.
6. Prescribe safely in low-resource settings with limited tests.

Anticoagulants and antiplatelet drugs are not curative: they stop a clot from growing or forming, while the body's own fibrinolytic system removes it. A venous thrombus is mainly fibrin and red cells, which is why the clotting cascade is the target; an arterial thrombus starts with platelets, which is why antiplatelet drugs are the mainstay of arterial disease. Getting this distinction right is the first clinical decision: venous clotting and atrial stasis call for anticoagulation, platelet-rich arterial disease calls for antiplatelet therapy, and established occlusion of a major vessel calls for thrombolysis.

The common final pathway is the conversion of fibrinogen to fibrin by thrombin. Heparins disable this mainly by accelerating antithrombin: UFH hits both thrombin and factor Xa (and the contact factors), while fondaparinux and LMWH are more selective against factor Xa. Warfarin works upstream, blocking the recycling of vitamin K so the liver makes inactive vitamin K-dependent factors; because the circulating factors already made must be consumed first, warfarin takes several days to work. The DOACs plug one step directly: the factor Xa inhibitors stop the tenase/prothrombinase complex at the common pathway, and dabigatran stops thrombin itself. Platelet inhibitors work on primary haemostasis, which is why they prevent arterial, platelet-driven thrombi but do not treat a deep vein thrombus well.

• Absorption and route. UFH is given intravenously or subcutaneously and is not absorbed orally; LMWH and fondaparinux are subcutaneous; warfarin, the DOACs and the antiplatelet drugs are oral.
• Metabolism and clearance. Warfarin is metabolised by the liver; doses change with age, illness, drugs and diet. Argatroban is hepatically cleared. Renal clearance is the Achilles heel of the others: about 80% of dabigatran, 50% of edoxaban, 35% of rivaroxaban and 27% of apixaban, and LMWH is excreted by the kidneys ^[3]. This is why kidney function, not liver function, drives most DOAC and LMWH dose decisions.
• Half-lives. UFH's effect wears off within hours (protamine's half-life is about 5 minutes ^[3]), LMWH lasts longer than UFH, and warfarin takes days to build up and wear off. DOACs act within hours and clear within a day or two in normal kidney function, which is what makes them quick to start and to reverse around procedures.
• Monitoring intervals. Once a warfarin patient is stable, the INR is usually rechecked about every 4 weeks, and recent data suggest this can be extended to up to 12 weeks with good control ^[3]. DOAC patients do not need routine coagulation testing but need renal function checked regularly and whenever they are ill or dehydrated.

For confirmed proximal DVT or PE, offer apixaban or rivaroxaban first; if neither is suitable, give LMWH for at least 5 days followed by dabigatran or edoxaban, or LMWH overlapped with a VKA until the INR is at least 2.0 on two consecutive readings ^[2]. Treat for at least 3 months; beyond that, weigh the risk of recurrence against bleeding risk ^[2]. UFH with a VKA is reserved for people with renal impairment or an increased bleeding risk ^[2].

Offer a DOAC to people with AF and a CHA2DS2-VASc score of 2 or more, and consider one for men with a score of 1, taking bleeding risk into account ^[1]. Do not offer anticoagulation for stroke prevention to men under 65 with AF and no other risk factors (CHA2DS2-VASc score 0), or to women under 65 with a score of 0 excluding sex (score 1) ^[1]. If DOACs are contraindicated, use a VKA, and reassure stable patients that they need not switch routinely ^[1]. Aspirin alone is not enough for stroke prevention in AF ^[1].

Mechanical valves are thrombogenic and need lifelong warfarin; the DOACs are contraindicated with prosthetic valves ^[4]. Targets are set by valve position and type rather than by a single number (in one thrombosis cohort, targets of 2.0 to 3.0 were used in 35.4% of patients and 2.5 to 3.5 in 58.2%) ^[5], and older or mitral valves are higher risk than a modern bileaflet aortic valve ^[5]. Bridging warfarin with heparin carries bleeding risk without clear benefit in lower-risk patients, and decisions belong to the valve or thrombosis service ^[5].

In antiphospholipid syndrome (APS), warfarin at standard intensity remains the usual long-term treatment, with heparin overlap at the start and indefinite continuation because recurrence is common ^[7]. DOACs are not recommended in APS ^[4], and triple-positive APS should be treated with LMWH overlapped with a VKA ^[2]. ^[6]

Pregnancy is highly thrombogenic, and the choice here is heparin, not a pill. LMWH is the main anticoagulant recommended in pregnancy, while warfarin (which crosses the placenta and can cause embryopathy and fetal bleeding) and the NOACs are avoided or contraindicated ^[6]. Warfarin is teratogenic and contraindicated in pregnancy ^[3]. For lactating women, LMWH and VKAs are the usual choices ^[6]. Obstetric APS is managed with aspirin plus heparin ^[7]. DOACs should be stopped before conception or as soon as pregnancy is diagnosed, and a planned switch to LMWH made under specialist care.

Active cancer predisposes to VTE, and treatment is for 3 to 6 months with review, using a DOAC or (if a DOAC is unsuitable) LMWH, with attention to drug interactions with chemotherapy and bleeding risk (gut or brain tumours bleed more easily) ^[2]. Cancer in remission is treated like other VTE ^[2].

Use licensed adult doses and the patient's weight, renal function and bleed risk; adjust as the product information and local protocol require.

• UFH: intravenous bolus followed by an infusion adjusted to the aPTT or anti-Xa result, or subcutaneous prophylactic doses. Recheck the platelet count to catch HIT.
• LMWH: subcutaneous, usually once daily or twice daily by weight; reduce when the estimated creatinine clearance is reduced, following the specific product's table.
• Fondaparinux: subcutaneous, weight-banded for treatment and prevention; avoid in severe renal impairment.
• Warfarin: start with a low dose and titrate to the INR target; in pregnancy use heparin instead.
• DOACs (adults with adequate kidneys): follow the licence. As examples from the UK safety advice, apixaban is reduced when serum creatinine reaches 1.5 mg per dL together with age 80 years or more or weight 60 kg or less; dabigatran is contraindicated under 30 mL per minute creatinine clearance; edoxaban is reduced in moderate renal impairment in all indications; rivaroxaban requires adjustment in moderate to severe renal impairment ^[4].
• Antiplatelets: daily low-dose aspirin with a P2Y12 inhibitor for the prescribed duration after an acute coronary syndrome or stent, following the local formulary and cardiology advice.
• Thrombolytics: intravenous weight-based dosing for acute ischaemic stroke or myocardial infarction and catheter-directed dosing for iliofemoral DVT or unstable PE, following the indication-specific protocol ^[2].

Bleeding is the universal risk, and its severity ranges from bruising to fatal haemorrhage. Specific harms:

• Heparin: bleeding, HIT in up to 5% (more common with UFH), osteoporosis with prolonged use, hyperkalaemia from aldosterone suppression.
• Warfarin: bleeding; skin necrosis in 0.01 to 0.1%, usually in the first 3 to 10 days; calcification of vessels and valves with long-term use.
• DOACs: bleeding, especially gastrointestinal with the factor Xa inhibitors in older adults; dyspepsia with dabigatran.
• Antiplatelets: gastrointestinal bleeding, bruising, intracranial haemorrhage rarely; ticagrelor can cause dyspnoea.
• Thrombolytics: major bleeding, intracranial haemorrhage; reperfusion arrhythmias after myocardial infarction.

The risk of bleeding is not a reason to deny anticoagulation in AF, where the stroke risk usually outweighs it ^[1].

• Active, serious bleeding or an untreatable bleeding lesion.
• Severe kidney or liver impairment, depending on the drug and its clearance (see the pharmacokinetics above).
• Mechanical prosthetic heart valves and antiphospholipid syndrome: use warfarin, not a DOAC ^[4].
• Pregnancy: avoid warfarin and the DOACs; use LMWH.
• Children: most drugs have paediatric data; follow specialist protocols.
• Frailty, falls, older age, uncontrolled hypertension, recent surgery, alcohol misuse and thrombocytopenia all raise bleeding risk and need dose review rather than automatic refusal.
• NSAIDs, SSRIs and alcohol add bleeding risk in AF patients, a point worth addressing at every review ^[1].

• Warfarin interacts with many drugs and with vitamin K in food (green vegetables, supplements). Enzyme inducers and inhibitors (rifampicin, carbamazepine, amiodarone, azole antifungals, macrolides) change the INR.
• DOACs are substrates of P-glycoprotein and, for apixaban and rivaroxaban, of CYP3A4. Strong inhibitors or inducers of these systems require avoidance or dose change ^[4]. Combining a DOAC with another anticoagulant, aspirin or NSAIDs multiplies bleeding risk.
• Heparins are not affected by CYP3A4 but are contraindicated with therapeutic doses of other anticoagulants.
• Antiplatelets add bleeding risk when used with anticoagulants, and aspirin plus a P2Y12 inhibitor (dual antiplatelet therapy) compounds it further.

• UFH: aPTT or anti-Xa (therapeutic 0.3 to 0.7 U per mL), with platelet count monitoring ^[3]. The anti-Xa assay is more stable than the aPTT and reaches a stable therapeutic range earlier ^[3]. ACT is used for high-dose heparin in bypass or PCI.
• LMWH: anti-Xa in pregnancy, obesity, extremes of weight, children, renal impairment and unexpected bleeding or thrombosis ^[3].
• Warfarin: INR against the agreed target, usually every 4 weeks once stable, more often after any change in health, medicines or diet ^[3].
• DOACs: no routine clotting test, but check renal and hepatic function before starting and regularly thereafter, and after any illness. A calibrated chromogenic anti-Xa assay can quantify a factor Xa inhibitor in bleeding or urgent surgery ^[3][4].
• Antiplatelets: no routine coagulation testing; full blood count and stool or urine testing if bleeding is suspected.

Do not stop anticoagulation for a trivial or already-controlled bleed, but act at once for major bleeding.

Notes:

• Argatroban and bivalirudin have no specific FDA-approved antidote, so stopping the infusion and supporting the patient is the mainstay ^[3].
• Andexanet alfa begins to act within 2 to 5 minutes; its anti-Xa assay results are unreliable for monitoring ^[3][4].
• A mild overdose of warfarin without bleeding is managed with vitamin K and dose reduction rather than emergency reversal.
• Do not use anti-Xa assays to judge andexanet alfa response, because the results may not be reliable; judge by haemostasis instead ^[4].

• Pregnancy: use LMWH; avoid warfarin because it crosses the placenta and can cause embryopathy and fetal bleeding, and avoid DOACs ^[3][6]. Obstetric APS is treated with aspirin plus heparin ^[7].
• Planning pregnancy on a DOAC or warfarin: switch to LMWH before conception when possible, or as soon as pregnancy is recognised, under specialist care.
• Breastfeeding: LMWH and warfarin are generally compatible with breastfeeding; DOACs have limited data and case-by-case decisions should be made with paediatrics and haematology. LMWH and VKAs are the usual choices in the postpartum period ^[6].
• Mechanical valves in pregnancy need specialist input: warfarin may be used after the first trimester with a switch to heparin near term, balancing valve thrombosis against fetal risk.

The table in the classification section above already compares the anticoagulants. In practice they are chosen alongside:

• Antiplatelet drugs, which target platelets and are the right class for arterial thrombosis.
• Thrombolytics, which are the rescue treatment for life-threatening clot, not for prophylaxis.
• Reversal and haemostatic agents (protamine, vitamin K, PCC, FFP, idarucizumab, andexanet alfa), which are medicines of the same pathway but used to undo anticoagulation.

• Mechanical heart valves: warfarin lifelong; the DOACs are not recommended in prosthetic valves ^[4]. Targets depend on valve type and position ^[5].
• Antiphospholipid syndrome: warfarin long-term; DOACs not recommended ^[4][7]; triple-positive APS gets LMWH plus a VKA ^[2].
• Pregnancy: LMWH; no warfarin and no DOACs ^[6].
• Active cancer VTE: a DOAC is often used, or LMWH; treatment for 3 to 6 months ^[2].
• Renal impairment: DOAC dose by clearance, with dabigatran contraindicated under 30 mL per minute and the others used with caution (see the MHRA renal table) ^[4].

• Plan ahead: a planned procedure is far safer than an emergency.
• Warfarin: stop 5 to 6 days before the procedure and check the INR beforehand; it can take about 2 weeks to re-establish therapeutic anticoagulation afterwards ^[5].
• Bridging high-risk warfarin patients (recent VTE, older mitral or dual valves) with LMWH is common but controversial: bridging raises bleeding, and the evidence that it prevents thromboembolism is limited. Decisions are taken with the thrombosis and surgical teams ^[5].
• DOACs: interrupt according to the drug, renal function and the bleeding risk of the procedure, using a standardised protocol (for example the PAUSE/ASRA approach). Recheck that kidney function has not worsened since the last dose was calculated ^[4].
• Mechanical valves and perioperative thrombosis: in a retrospective cohort of left-sided mechanical valve patients needing interruption, the estimated 30-day risks were 1.5% arterial thromboembolism and 2.1% major bleeding ^[5].
• LMWH and fondaparinux: stop the treatment dose ahead of a high-bleed procedure in line with its last dosing interval; prophylactic doses often continue.
• Antiplatelet drugs: aspirin is often continued through surgery because the thrombosis risk exceeds the bleeding risk; dual antiplatelet therapy decisions are timed with cardiology.
• Restart when haemostasis is secure, with prophylactic or therapeutic dosing in hospital, and make sure contraception, infection and hydration are reviewed.

• UFH and warfarin are cheap and effective when tests are scarce: UFH is short-acting and reversible with protamine; warfarin is monitored by the one test most laboratories can do, the INR.
• If anti-Xa assays are unavailable, use aPTT for UFH and clinical judgement; do not guess heparin levels in renal impairment, because accumulation is real.
• LMWH is convenient (once daily, no aPTT) but costs more and persists in renal impairment; adjust the dose or choose UFH when the kidneys are failing.
• INR target achievement is the hard part. Poverty, distance, drug shortages, dietary change and interactive medicines all lower the time in the therapeutic range; keep doses simple, provide printed dose cards, and recheck after any acute illness or new medication.
• DOACs are attractive (no monitoring) but may be unavailable, unaffordable, or not on local essential medicines lists, and renal function monitoring must still happen.
• Standardised protocols matter more, not less: a single printed card for warfarin dose adjustment, vitamin K availability for over-anticoagulation, and a clear major haemorrhage pathway save lives.
• For thrombolysis, if a catheter service or ICU is unavailable, refer early; anticoagulation alone is the fallback while transport is arranged.
• Close the loop with patients: they should carry an anticoagulation card, know the warning signs of bleeding and clotting, and know where to seek help.

• Anticoagulants act on the clotting cascade; antiplatelet drugs act on platelets. Choose the class for the type of clot.
• DOACs are first line for most atrial fibrillation and for most venous thromboembolism; they do not need routine coagulation testing but do need renal function checks ^[3].
• UFH is the parenteral drug of acute situations and the only heparin that protamine fully reverses; LMWH is simpler but accumulates in renal failure.
• Warfarin is a vitamin K antagonist with many interactions; it is required for mechanical valves and most antiphospholipid syndrome, and is contraindicated in pregnancy.
• Fondaparinux and the parenteral direct thrombin inhibitors have no specific antidote.
• Reversal is now practical: protamine for UFH, vitamin K plus PCC for warfarin, idarucizumab for dabigatran, andexanet alfa or PCC for the factor Xa inhibitors.
• Monitor UFH by aPTT or anti-Xa, warfarin by INR against the agreed target, LMWH by anti-Xa when at extremes or in renal impairment, DOACs by renal function and (when needed) calibrated drug assays.
• Around surgery, stop warfarin 5 to 6 days ahead; use standardised, kidney-aware interruption for DOACs; bridge only when the thrombosis risk justifies the bleeding risk.
• Bleeding is the main harm of every agent; treat major bleeding with targeted reversal and support, not with panic.
• In low-resource settings the basics (UFH, warfarin, the INR, protamine, vitamin K) are life-saving when applied with simple protocols and patient education.