Heparins and direct oral anticoagulants: pharmacology and reversal

At a glance

• Heparins work through antithrombin. Unfractionated heparin (UFH) inactivates thrombin and factor Xa; LMWH mostly Xa; fondaparinux only Xa.
• DOACs inhibit one enzyme directly, with no cofactor: dabigatran blocks thrombin, while rivaroxaban, apixaban and edoxaban block factor Xa.
• Kidney function, P-glycoprotein and CYP3A4 set most of the dosing rules, interactions and reversal choices.
• Paper 1 asks you to explain HIT, interpret a coagulation screen on a DOAC, calculate creatinine clearance for a dose, and pick the reversal agent.

Clinical use is in venous thromboembolism and atrial fibrillation.

Heparins

Mechanism

Heparin's unique pentasaccharide binds antithrombin and accelerates its inhibition of thrombin and Xa about 1,000-fold. For Xa, the conformational change in antithrombin is enough. For thrombin, the heparin chain must bind both proteins at once, which needs at least 18 saccharides.

	UFH	LMWH (enoxaparin)	Fondaparinux
Anti-Xa to anti-IIa ratio	1:1	About 4:1	Xa only
Clearance	Endothelium and macrophages (saturable), then renal	Renal	Renal
Half-life	60 to 90 min, dose-dependent	About 4 to 5 h	About 17 h
Monitoring	aPTT or anti-Xa 0.3 to 0.7 units/mL	Anti-Xa if needed (renal failure, obesity, pregnancy)	Not routine
Protamine	Full reversal	Partial	None
HIT risk	Highest	About 10 times lower	Negligible

UFH binds plasma proteins, endothelium and macrophages, so its response is unpredictable and its clearance is saturable. Larger doses last disproportionately longer. Its short half-life and full reversibility make it the choice when creatinine clearance is under 30 mL/min or a procedure may be needed soon.

LMWH binds proteins less, so subcutaneous dosing by weight works. It accumulates in kidney failure: enoxaparin goes from 1 mg/kg twice daily to 1 mg/kg once daily below 30 mL/min. Check an anti-Xa level 4 hours after the third or fourth dose (BD target about 0.5 to 1.0 units/mL).

Pitfall: heparin resistance (large UFH doses with little aPTT change) suggests antithrombin deficiency, high factor VIII or high heparin-binding proteins in acute illness. An anti-Xa level separates real resistance from a misleading aPTT.

Heparin-induced thrombocytopenia

HIT is immune, not dose-related. Heparin binds platelet factor 4 (PF4), and IgG forms against the complex. The IgG-PF4-heparin complexes bind platelet FcγRIIa, activating platelets, releasing more PF4 and generating thrombin. Platelets fall by over 50%, usually 5 to 10 days after starting heparin (sooner if exposed in the last 100 days), and the risk is thrombosis, both venous and arterial.

• Assess pre-test probability with the 4Ts score. An immunoassay screens; a functional assay (serotonin release or heparin-induced platelet activation) confirms.
• Stop all heparin, including flushes. Start a non-heparin anticoagulant: argatroban, fondaparinux, danaparoid, or a DOAC in stable patients.
• Don't transfuse platelets routinely, and delay warfarin (see cards).

See thrombocytopenia.

Direct oral anticoagulants

	Dabigatran	Rivaroxaban	Apixaban
Target	Thrombin	Xa	Xa
Prodrug	Yes (etexilate)	No	No
Oral bioavailability	About 6.5%	80 to 100% with food (20 mg)	About 50%
Renal excretion unchanged	About 80%	About 33%	About 27%
Protein binding	About 35% (dialysable)	Over 90%	About 87%
Metabolism	Esterases; P-gp substrate	CYP3A4 and P-gp	CYP3A4 and P-gp
Half-life	12 to 17 h	5 to 13 h	About 12 h
Reversal	Idarucizumab 5 g IV	4-factor PCC	4-factor PCC

Mechanism explains several exam facts:

• Dabigatran's low bioavailability depends on its acidic capsule. Opening the capsule raises absorption by about 75%. Dyspepsia is common for the same reason.
• Rivaroxaban 15 and 20 mg must be taken with food: food raises exposure by about 40%, and fasting bioavailability of the 20 mg tablet is only about 66%.
• Strong P-gp and CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort) lower DOAC levels enough to cause treatment failure. Strong dual inhibitors (ketoconazole, ritonavir) raise them. See drug interaction mechanisms.
• Rivaroxaban and apixaban are mostly protein-bound, so haemodialysis removes dabigatran but not the Xa inhibitors.

Worked example: renal dosing

An 82-year-old woman, 55 kg, serum creatinine 140 µmol/L, has non-valvular AF.

Cockcroft-Gault: CrCl = (140 − 82) × 55 × 0.85 / (0.814 × 140) = 2,711.5 / 114 = about 24 mL/min.

• Dabigatran is contraindicated below 30 mL/min in Australia, because 80% depends on the kidney.
• Apixaban is also off the table: Australian product information and the ASTH 2025 guideline advise against it below CrCl 25 mL/min (ARISTOTLE enrolled no one below 25). She meets all three dose-reduction criteria, but that doesn't help.
• Rivaroxaban 15 mg daily (used with caution at CrCl 15 to 29 mL/min) or warfarin are the options left.

Had her CrCl been 27 mL/min, apixaban 2.5 mg twice daily would have been right. Pitfall: the 2.5 mg criteria don't extend apixaban below the 25 mL/min floor.

Use Cockcroft-Gault with actual body weight, not eGFR, because the trials and product information used it. eGFR normalised to 1.73 m² overestimates clearance in small older women.

Coagulation tests on a DOAC

Test	Dabigatran	Xa inhibitors
Thrombin time	Very prolonged even at trace levels	Normal
aPTT	Prolonged, but may be normal at low levels	Variable
PT/INR	Mildly prolonged	Rivaroxaban prolongs more than apixaban; may be normal
Drug-specific test	Dilute thrombin time (calibrated)	Anti-Xa calibrated to the drug

A UFH-calibrated anti-Xa assay detects Xa inhibitors but doesn't quantify them.

Where DOACs fail

• Mechanical valves: dabigatran caused more thrombosis and bleeding than warfarin (RE-ALIGN). Use warfarin.
• Triple-positive antiphospholipid syndrome: rivaroxaban caused more arterial events (TRAPS).
• Rheumatic AF with mitral stenosis: warfarin was superior to rivaroxaban (INVICTUS), relevant to Aboriginal and Torres Strait Islander and Māori and Pacific patients with rheumatic heart disease.
• Pregnancy and breastfeeding: DOACs cross the placenta. Use LMWH.

Reversal

Drug	Agent	How it works
UFH	Protamine	Basic protein binds acidic heparin
LMWH	Protamine (partial)	Binds the longer chains; short chains escape
Dabigatran	Idarucizumab 5 g IV	Humanised Fab binding dabigatran with about 350 times thrombin's affinity
Rivaroxaban, apixaban	4-factor PCC (Beriplex AU), dose by local or Lifeblood protocol (commonly 25 to 50 IU/kg)	Supplies excess factors to overwhelm inhibition

Beriplex AU (factors II, VII, IX, X, proteins C and S) replaced the 3-factor Prothrombinex-VF from 2024, and the two aren't dose-interchangeable. Beriplex contains heparin, so a history of HIT contraindicates it. Andexanet alfa, a decoy Xa, was discontinued in Australia in May 2026. Protamine can cause anaphylaxis, especially after protamine-containing insulin or fish allergy. See intracerebral haemorrhage for reversal in practice.

How it's tested

• A falling platelet count on day 7 of heparin with a new DVT: mechanism and next step.
• Choosing a DOAC and dose from age, weight and creatinine, or recognising when dabigatran is contraindicated.
• A normal PT on apixaban, or a prolonged thrombin time on dabigatran: what the result means.
• A DOAC failing after rifampicin or carbamazepine is added.
• Picking the reversal agent, and knowing when dialysis helps.

Pitfalls

• LMWH needs an anti-Xa level, not an aPTT, to check its effect.
• Protamine only partly reverses enoxaparin and doesn't reverse fondaparinux at all.
• HIT causes clots. Platelet counts rarely fall below 20 × 10⁹/L, and bleeding is unusual.
• A normal INR does not exclude a clinically relevant apixaban level.
• Apixaban is contraindicated below CrCl 25 mL/min in Australia, whatever the dose.
• Dabigatran dose depends on Cockcroft-Gault clearance, not eGFR.