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PH4.1-4 | PH4.1-4 | Drugs Affecting Blood and Coagulation — SDL Guide (Part 3)
Clinical Decision-Making: Antithrombotic Therapy and Reversal
Selecting the appropriate antithrombotic strategy requires matching the drug class's pharmacological properties to the specific clinical indication, patient characteristics, and risk of bleeding.
Indication-anticoagulant matching:
- AF — stroke prevention: DOACs are now first-line over warfarin in non-valvular AF — fixed dosing, fewer interactions, no monitoring, favourable bleeding profile. Apixaban has the best evidence (ARISTOTLE: superior to warfarin for both efficacy and safety). Warfarin is still indicated in AF with rheumatic mitral stenosis or mechanical heart valves (DOACs inadequate in these populations — RE-ALIGN trial: dabigatran inferior to warfarin in mechanical valves).
- Venous thromboembolism (DVT/PE): DOACs are first-line (rivaroxaban or apixaban for initial treatment, then extended therapy). LMWH preferred in cancer-associated VTE (LMWH outperformed warfarin in CLOT trial; DOACs now also have evidence in cancer VTE — HOKUSAI-VTE Cancer).
- ACS: UFH or enoxaparin (preferred for predictability) as the anticoagulant bridge during PCI; fondaparinux for NSTEMI (OASIS-5 data). DOACs have no role in the acute ACS anticoagulant phase.
- Pregnancy: LMWH throughout (never warfarin, never DOACs); switch to UFH at 36 weeks for delivery management.
- Mechanical prosthetic heart valves: Warfarin ONLY (DOACs contraindicated based on RE-ALIGN trial).
Warfarin drug interactions — most important:
- ↑INR (bleeding risk): amiodarone (CYP2C9 inhibitor — most common/potent), metronidazole (CYP2C9), fluconazole, clarithromycin, omeprazole, aspirin (additive antihaemostatic effect), NSAIDs.
- ↓INR (thrombosis risk): rifampicin (most potent CYP inducer), carbamazepine, phenytoin, St. John's Wort, high vitamin K foods.
Reversal strategies by drug class:
| Drug | Reversal agent | Onset of reversal |
|---|---|---|
| UFH | Protamine sulphate (1 mg per 100 U UFH) | Immediate |
| LMWH | Protamine (partial — ~60% anti-Xa) | Immediate |
| Warfarin (minor bleeding) | Vitamin K oral 1–2 mg | 12–24h |
| Warfarin (major/life-threatening) | 4-factor PCC (Beriplex) + Vitamin K IV | Immediate + 6–24h |
| Dabigatran | Idarucizumab (Praxbind) specific Ab | Immediate |
| Rivaroxaban/apixaban/edoxaban | Andexanet alfa or 4-factor PCC | Immediate |
Tranexamic acid in clinical practice: Give TXA within 3 hours of trauma (CRASH-2: 15% reduction in relative risk of death from bleeding); standard for major elective surgery (cardiac, orthopaedic — reduces transfusion requirement). DO NOT give TXA to patients with active disseminated intravascular coagulation (DIC) — inhibiting fibrinolysis in DIC worsens microvascular thrombosis.
SELF-CHECK
A patient on apixaban 5 mg BD for AF presents with life-threatening gastrointestinal bleeding. The gastroenterology team needs to perform emergency endoscopy. The most appropriate reversal agent is:
A. Vitamin K 10 mg IV
B. Protamine sulphate 50 mg IV
C. Andexanet alfa (or 4-factor PCC if unavailable)
D. Idarucizumab (Praxbind)
Reveal Answer
Answer: C. Andexanet alfa (or 4-factor PCC if unavailable)
Apixaban is a direct factor Xa inhibitor (DOAC). Its specific reversal agent is andexanet alfa (a modified recombinant Xa mimic that sequesters apixaban and other Xa inhibitors). Where andexanet alfa is unavailable, 4-factor prothrombin complex concentrate (PCC) is used as a non-specific alternative. Vitamin K is the reversal agent for warfarin (vitamin K antagonist) — it has no effect on DOACs. Protamine reverses heparin (potentiates antithrombin III). Idarucizumab (Praxbind) is the specific antidote for dabigatran (direct thrombin inhibitor) — not for Xa inhibitors.
Self-Assessment: Blood Pharmacology Review
Consolidate the four competency families with the following reference summaries.
Anticoagulant monitoring and reversal quick-reference:
| Anticoagulant | Target | Monitor | Reversal |
|---|---|---|---|
| UFH | Thrombin (IIa) + Xa | aPTT 60–100 s | Protamine sulphate |
| LMWH (enoxaparin) | Xa >> IIa | Anti-Xa (if needed) | Protamine (partial) |
| Fondaparinux | Xa only | None routine | No specific antidote; rFVIIa in extremis |
| Warfarin | Vit K factors (II,VII,IX,X) | INR (target 2–3 or 2.5–3.5) | Vit K + PCC/FFP |
| Dabigatran | IIa (thrombin) | None routine (check renal function) | Idarucizumab |
| Rivaroxaban/Apixaban | Xa | None routine | Andexanet alfa / 4F-PCC |
Haematinic and B12/folate key distinctions:
- Iron deficiency anaemia: ferrous sulphate oral; IV iron for intolerance/malabsorption/CKD
- B12 deficiency (pernicious anaemia): IM hydroxocobalamin ONLY (oral ineffective due to absent intrinsic factor)
- Folate deficiency: oral folic acid 5 mg; NEVER give folate alone in suspected mixed B12+folate deficiency (masks neurological damage)
Antiplatelet summary:
- Aspirin: COX-1 inhibitor, irreversible, lifelong in established ASCVD
- Clopidogrel: prodrug (CYP2C19), irreversible — resistance in ~15% Asian patients
- Ticagrelor: NOT a prodrug, reversible, no CYP2C19 issue — PLATO trial preferred in ACS
- Prasugrel: prodrug, potent — contraindicated in prior stroke/TIA/age>75/wt<60kg