Warfarin

Warfarin inhibits the hepatic synthesis of functional vitamin K–dependent clotting factors (II, VII, IX, X) as well as the natural anticoagulant proteins C and S. Because circulating clotting factors must degrade before anticoagulation is achieved, there is a delay of several days in reaching therapeutic effect.

Importantly, the rapid fall in protein C and S relative to procoagulant factors produces an initial transient prothrombotic state.

Indications for Warfarin

Unlike DOACs, warfarin dosing is not indication-dependent, but rather tailored to a target INR. Common clinical uses include:

• Stroke prevention in atrial fibrillation (moderate–high risk of stroke/systemic embolism).
• Thromboembolism prophylaxis in rheumatic mitral stenosis and/or mechanical heart valves.
• Secondary prophylaxis of venous thromboembolism.
• Treatment of venous thromboembolism.
• Prevention of embolic events after myocardial infarction in selected high-risk patients.
• Idiopathic arterial thrombosis (specialist input advised).
• Adjunctive therapy in coronary artery occlusion (specialist input advised).

For peri-procedural interruption, see Periprocedural use of warfarin.

Contraindications to Warfarin

• Bleeding diathesis
• Previous GI bleeding
• Intracranial hemorrhage/aneurysm/retinopathy
• Severe hypertension
• Bacterial endocarditis
• Alcoholism
• Unsupervised dementia
• Frequent falls
• First trimester of pregnancy

Other Risk Factors for Adverse Events on Warfarin

• Elderly
• Polypharmacy
• Renal impairment
• Hepatic impairment
• Pregnancy
• Recent surgery/trauma/heart failure/thyrotoxicosis

Advice on Warfarin

Nature of Warfarin

• Warfarin is an oral anticoagulant that thins the blood to prevent clot formation in the legs and other parts of the body.

Benefits

• Recommended for the prevention of recurrent DVT due to the risk of potentially life-threatening pulmonary embolism (PE).

Risks

1. Bleeding
   • Major bleeding < 2% per year.
   • INR is a major determinant, especially if > 3.
   • Bleeding is most likely in the first 3 months of therapy.
2. Risk in Pregnancy (Teratogenicity)
   • Recognized teratogen (Category D) – crosses placenta.
   • Contraindicated in pregnancy.
   • First trimester: Fetal warfarin syndrome (FWS)/warfarin embryopathy (bone stippling & nasal hypoplasia).
   • Third trimester: Perinatal fetal or placental hemorrhage.
3. Infrequent Idiosyncratic Reactions (Type B)
   • Rashes
   • Purple discoloration of toes
   • Skin necrosis
   • Fever
   • Cholesterol embolism
   • Allergic reactions
   • Alopecia
   • Nausea & vomiting
   • Hepatic dysfunction
   • Diarrhea

Interactions

• Warfarin is metabolized by liver enzymes (cytochrome P450). Many medications and herbal preparations can affect its absorption, binding, and metabolism.

1. Drugs that Inhibit Cytochrome P450 Enzymes (Increased Effect)
   • Antibiotics: erythromycin, ciprofloxacin, co-trimoxazole, metronidazole, fluconazole.
2. Drugs that Induce Hepatic Enzymes (Reduced Effect)
   • Antibiotics: rifampicin.
   • Antiepileptics: carbamazepine, phenytoin.
   • St. John’s Wort
   • Alcohol
3. Antiplatelet Drugs (Additive Effect – Avoid)
   • Aspirin
   • Clopidogrel
   • Dipyridamole

Dosing Principles

• Individualised dosing: Adjust to achieve target INR.
• Starting dose: Follow local protocol; if none, validated age-adjusted dosing schedules (see Table below – eTG) may be used.
• Start with warfarin on the same day as therapeutic heparin or LMWH and overlap for a minimum of five days.
• Consider overlapping for at least two consecutive days after target INR reached or as clinically indicated according to assessment of patient bleeding risks.
• Lower maintenance dose likely in: advanced age, severe liver disease, malnutrition, Asian ethnicity, increased sensitivity, or interacting medications.
• Pharmacogenetics: Variability partly explained by polymorphisms, but routine pharmacogenetic testing is not validated.
• Brands: Coumadin and Marevan are not bioequivalent; avoid interchange.

Monitoring

1. INR measurement:
   • Daily or alternate-day testing at initiation.
   • Every 4–6 weeks during stable therapy.
2. Frequency varies depending on INR stability, comorbidities, concurrent therapy, and planned procedures.
3. High or unstable INR: Reassess suitability for ongoing warfarin and consider alternatives.
4. Self-monitoring: Suitable for selected long-term patients with stable INR, using validated point-of-care devices under clinician oversight.
   • Benefits: ↑ time in therapeutic range, ↓ clinic visits, and in some studies ↓ thromboembolic events without ↑ bleeding.

Patient Education (Anticoagulant Book)

• Dosing
  • Same brand of tablets.
  • Same time every day.
  • Emphasize adherence.
• Lifestyle
  • Dietary Consistency:
    • Maintain a consistent intake of vitamin K, which is found in green leafy vegetables (e.g., spinach, broccoli, kale).
    • Avoid sudden changes in the amount of vitamin K in your diet, as this can affect your INR.
  • Alcohol:
    • Limit alcohol intake to no more than 1-2 standard drinks per day, as excessive alcohol can increase bleeding risk.
  • Exercise:
    • Engage in regular physical activity
    • avoid contact sports or activities that increase the risk of injury
  • Side Effects
    • Heightened awareness of signs of bleeding: headache, abdominal pain, melena, hematuria, nosebleeds.
  • Pregnancy
    • Use barrier contraception.
    • Inform doctor if pregnant.
  • Interactions
    • Avoid aspirin.
    • Inform pharmacist and doctor about any new medications (prescription, herbal, vitamin supplements).
    • INR tested after 4 days of new drug and at the end of the course.
  • Inform Healthcare Providers
    • Inform physiotherapist, podiatrist, chiropractor, dentist.
  • Surgery
    • Stop warfarin 4-5 days prior. Substitute with unfractionated or low-molecular-weight heparin subcutaneously.
  • Medical Alert:
    • Consider wearing a medical alert bracelet indicating you are on warfarin.
  • Travel:
    • If traveling, ensure you have enough medication and arrange for INR testing if you will be away for an extended period.

Complications to Watch Out For

• Signs of Bleeding:
  • Unusual bruising or bleeding (e.g., gums, nosebleeds, heavier menstrual periods).
  • Dark, tarry stools or blood in your urine.
  • Severe headaches, dizziness, or weakness (potential signs of internal bleeding).
  • Prolonged bleeding from cuts or injuries.
• Signs of Blood Clots:
  • Swelling, pain, or tenderness in your legs (potential DVT).
  • Sudden shortness of breath, chest pain, or coughing up blood (potential PE).

---

from etg 2025

Management of Bleeding and Overanticoagulation

Key Principles

1. Assessment Factors:
   • Presence and severity of bleeding (none, minor, clinically significant, or life-threatening).
   • INR value.
   • Risk of serious bleeding from warfarin poisoning based on INR:
     • INR less than 5 – low
     • INR 5 to 9 – moderate
     • INR 9 or more – high
   • Risk factors for bleeding, including:
     • Age > 65 years
     • Hypertension
     • History of gastrointestinal bleed
     • a major bleed within the preceding 4 weeks
     • surgery within the preceding 2 weeks
     • platelet count of less than 50 × 10⁹/L
     • Concomitant antiplatelet/NSAID use
       • aspirin
       • clopidogrel
       • prasugrel
       • ticagrelor
     • Renal impairment
     • Hepatic impairment
     • High fall risk
2. Bleeding can occur even at therapeutic INR.
   • Always evaluate bleeding risk independently of INR.
3. Identify and address precipitating factors:
   • Drug interactions (e.g., antibiotics, amiodarone, antifungals).
   • Acute illness (fever, diarrhoea, heart failure, hepatic dysfunction).
   • Dietary vitamin K fluctuation.
4. bleeding complications:
   • intracranial haemorrhage—altered conscious state, focal neurological signs and symptoms
   • gastrointestinal haemorrhage—haematemesis, melaena, rectal bleeding, retroperitoneal bleeding (may present as abdominal pain)
   • genitourinary haemorrhage—haematuria
   • pulmonary haemorrhage—haemoptysis, dyspnoea
   • haemorrhagic shock secondary to massive haemorrhage
   • external signs of bleeding—bruising, epistaxis, bleeding gums.

2. Reversal of Anticoagulant Effect

Therapeutic options

• Vitamin K1 (phytomenadione):
  • Restores synthesis of vitamin K–dependent clotting factors (II, VII, IX, X).
  • Onset:
    • IV: 1–3 hours
    • PO: 6–8 hours
  • Similar INR effect by 24 hours (PO ≈ IV).
  • Caution: Large doses delay re-establishment of anticoagulation. Always use lowest effective dose if warfarin will be restarted.
• Prothrombinex-VF (PCC = Prothrombin Complex Concentrate):
  • Provides immediate replacement of clotting factors II, IX, X (and small amounts of VII).
  • Onset: Minutes.
  • Short half-life → always co-administer vitamin K1.
• Fresh Frozen Plasma (FFP):
  • Used if PCC unavailable.
  • Slower to administer, large volumes required (15 mL/kg).
  • Risk: Volume overload, transfusion reactions.

3. Restarting Warfarin

• Restarting therapy is individualised. Consider:
  • Site and severity of bleeding.
  • Control of haemorrhage.
  • Ongoing thromboembolic risk (e.g., atrial fibrillation, prosthetic valve, VTE).
  • Whether bleed occurred at therapeutic INR.
• Decision should be made in consultation with a haematologist or relevant specialist.

4. Management by Clinical Scenario

4.1 No bleeding

INR < 4.5 but above therapeutic range

• Withhold or lower next dose of warfarin.
• Do not administer vitamin K1.
• Resume at reduced dose when INR approaches therapeutic range.
• If INR only slightly raised (<10% above target), dose adjustment may not be necessary.

INR 4.5–10

• Withhold warfarin.
• Vitamin K1 usually unnecessary.
• If high bleeding risk, give vitamin K₁:
  • 1–2 mg PO OR
  • 0.5–1 mg IV.
• Measure INR within 24 hours.
• Resume warfarin at reduced dose once INR is therapeutic.

INR ≥ 10

• Withhold warfarin.
• Administer 3–5 mg vitamin K₁ PO or IV.
• Monitor INR at 12–24 hours, then daily to every second day for one week.
• Resume at reduced dose when INR therapeutic.
• If bleeding risk high → consider adding Prothrombinex-VF 15–30 u/kg IV.

4.2 Bleeding present

Life-threatening bleeding (critical organ, e.g. intracranial) with INR ≥ 1.5

• Withhold warfarin.
• Administer:
  • Vitamin K1 (5–10 mg IV) PLUS
  • Prothrombinex-VF 50 u/kg IV (consider <50 if INR 1.5–1.9) PLUS
  • FFP 150–300 mL.
• If PCC unavailable: Vitamin K1 5–10 mg IV + FFP 15 mL/kg.

Clinically significant (non-life-threatening) bleeding with INR ≥ 2

• Withhold warfarin.
• Administer:
  • Vitamin K1 (5–10 mg IV) PLUS
  • Prothrombinex-VF (dose per INR – see Table below).
• If PCC unavailable: substitute FFP 15 mL/kg.

Table: Suggested PCC dosing (Prothrombinex-VF) for clinically significant bleeding

Initial INR	Target INR 0.9–1.3	Target INR 1.4–2.0
1.5–2.5	30 u/kg	15 u/kg
2.6–3.5	35 u/kg	25 u/kg
3.6–10	50 u/kg	30 u/kg
> 10	50 u/kg	40 u/kg

Note: Choose target INR depending on balance between bleeding control and thromboembolic risk (e.g., mechanical valves may benefit from partial reversal).

Minor bleeding (any INR)

• Withhold warfarin.
• Check INR and repeat next day.
• Resume at adjusted dose when INR therapeutic.
• If INR > 4.5 or bleeding risk high, give:
  • Vitamin K1 1–2 mg PO OR
  • 0.5–1 mg IV.

5. Monitoring After Reversal

• Measure INR:
  • 12–24 hrs after vitamin K1 or PCC/FFP administration.
  • Repeat daily or every second day until stable.
• Clinical monitoring:
  • Observe for rebleeding.
  • Monitor haemoglobin and haematocrit if bleeding was significant.

6. Key Safety Notes

• Always give the lowest effective dose of vitamin K1 if warfarin is likely to be restarted.
• PCC must always be co-administered with vitamin K1 to maintain reversal.
• FFP alone is inadequate unless PCC is unavailable.
• Restarting anticoagulation after major bleed requires careful multidisciplinary decision-making.

Summary (Practical Points)

• No bleed, INR < 4.5: Adjust/withhold dose. No Vit K.
• No bleed, INR 4.5–10: Withhold. Vit K if high risk.
• No bleed, INR ≥ 10: Withhold. Vit K (3–5 mg PO/IV). ± PCC if high risk.
• Minor bleed: Withhold. ± low-dose Vit K.
• Clinically significant bleed: Withhold. IV Vit K + PCC (± FFP).
• Life-threatening bleed: Withhold. IV Vit K + PCC + FFP.