Makindo Medical Notes

Related Subjects:Warfarin | Warfarin and Bleeding | Vitamin K (Phytomenadione) |

Important: Warfarin inhibits vitamin K–dependent clotting factors (II, VII, IX, and X) as well as protein C.
Because protein C (an anticoagulant) is depleted first, patients may paradoxically be at increased risk of clotting early in therapy, potentially leading to skin necrosis.
Hence, concurrent heparin therapy (e.g., LMWH) is often required when initiating warfarin.

About: Always check the BNF or equivalent for prescribing advice.

• Used for the treatment and prevention of thrombotic disorders (DVT, PE, AF-related stroke prevention, mechanical heart valves, etc.).
• The name “Warfarin” derives from the Wisconsin Alumni Research Foundation + “-arin.”

Pathophysiology & Mode of Action

• Vitamin K–dependent factors include II (prothrombin), VII, IX, X and the anticoagulant proteins C and S.
• These factors require γ-carboxylation of glutamic acid residues for proper function.
• This carboxylation is enabled by Vitamin K in its reduced form; after the reaction, Vitamin K is converted to Vitamin K epoxide, which must be recycled by Vitamin K epoxide reductase (VKOR).
• Warfarin inhibits VKOR, thereby depleting functional vitamin K and reducing production of the above clotting factors.

Indications

• Mechanical (prosthetic) heart valves (especially mitral position).
• Venous thromboembolism (DVT, PE).
• Atrial fibrillation (particularly with additional stroke risk factors).
• Antiphospholipid syndrome (in some cases).
• Certain cases of rheumatic heart disease.

Warfarin Tablets (UK)

• Brown: 1 mg
• Blue: 3 mg
• Pink: 5 mg

Investigations

• INR (International Normalized Ratio): Calculated from prothrombin time (extrinsic pathway), standardizing results across different labs. Therapeutic ranges vary (e.g., target INR 2.0–3.0 or 2.5–3.5), depending on indication.

Reversal of Warfarin

• Vitamin K: Oral or IV, depending on urgency.
• Prothrombin Complex Concentrate (e.g., Octaplex/Beriplex): Contains concentrated clotting factors II, VII, IX, X for rapid reversal (e.g., in life-threatening bleeding).

Interactions (Drugs that may Raise INR)

• Cranberry juice: Contains flavonoids that may inhibit CYP2C9, reducing warfarin metabolism.
• NSAIDs: Displace warfarin from protein-binding sites and increase bleeding risk (via platelet dysfunction).
• Ciprofloxacin, amiodarone: Can increase warfarin levels (often through CYP450 interactions).
• Liver disease: Impaired synthesis of clotting factors, reduced vitamin K absorption if cholestatic.
• Herbals: Ginkgo biloba, ginseng, cranberry products may increase warfarin effect; Coenzyme Q10, St. John’s wort may decrease its effect.

BCSH Warfarin Guidelines (Key Points)

• First episode VTE: Target INR 2.5. Start warfarin alongside parenteral anticoagulation for at least 5 days and until INR ≥2 for ≥24 hours.
• Recurrent VTE on therapeutic INR: Consider increasing target INR to 3.5.
• Atrial Fibrillation & Stroke Prevention: Target INR 2.5.
• Bioprosthetic valves: Generally INR target 2.5 for at least 3 months post-implantation, or longer if additional risk factors (e.g., AF, low EF).
• Mechanical valves: Higher targets in mitral position. Consult guidelines for specific recommended range (often 2.5–3.5).
• Duration of Therapy:
  • Provoked DVT/PE: At least 3 months.
  • Unprovoked (idiopathic) DVT/PE: Consider indefinite therapy depending on bleeding risk.
  • Cancer-associated VTE: LMWH for ≥6 months preferred over warfarin.

Bridging Therapy

• Pre-op bridging: May be considered low risk for bleeding, but post-op bridging can significantly increase bleeding risk.
  • Wait ≥48 hours after high-bleeding-risk surgery before starting bridging LMWH.
• Low-risk scenarios (e.g., stable AF with no prior stroke/TIA) may not require bridging if warfarin is stopped a few days pre-op.
• High-risk scenarios (recent VTE, certain mechanical valves, prior stroke/TIA) may need bridging therapy.

Side Effects

• Bleeding: The most significant risk (e.g., intracranial haemorrhage, GI bleed).
• Pregnancy: Warfarin crosses the placenta and is generally contraindicated (especially in first trimester) due to teratogenicity and fetal anticoagulation.
• Skin Necrosis: Rare, often in patients with protein C deficiency, usually early in therapy.

Cautions & Contraindications

• Generally avoid in pregnancy, except in highly specific scenarios (e.g., mechanical valve with specialist input).
• Homozygous protein C deficiency: Risk of skin necrosis.
• Unreliable patients who may not adhere to monitoring or dosing instructions.
• Severe hypertension (systolic >200 mmHg or diastolic >120 mmHg), active peptic ulcer disease, recent CNS surgery or bleed.

Management

• Initiation (Slow Loading): 3–5 mg/day, bridging with LMWH/UFH if immediate anticoagulation is needed. Continue bridging at least 5 days or until INR ≥2 for ≥24 hours.
• Monitoring: Outpatient anticoagulation clinics often provide dose adjustments. Ensure patients carry a warfarin monitoring booklet.
• Patient Education: Rationale, risks (bleeding, interactions), signs to watch for, and need for regular INR checks.

Guidance on Dosing & Monitoring

• Computer-assisted dosing often outperforms manual dosing in maintaining stable INR.
• Self-testing and self-management can improve time in therapeutic range for motivated patients, but not all are suitable.
• All patients need a written record of their INR results and warfarin dose changes.
• In patients with unstable INR, supplementing with 100–150 mcg of vitamin K daily (diet or tablet) may help.
• Any newly prescribed interacting drug warrants an INR check after 3–5 days.

References

• Guidelines on oral anticoagulation with Warfarin (BCSH, 2011)