What are the side effects of Coumadin (warfarin)?

Coumadin (Warfarin) Side Effects

The most critical side effect of Coumadin is hemorrhage (bleeding), which can be fatal and occur from any tissue or organ, followed by the rare but serious complication of skin necrosis, typically appearing 3-8 days after starting therapy. 1

Major Side Effects

Hemorrhagic Complications (Most Common and Serious)

Bleeding is the primary adverse effect and the leading cause of warfarin-related mortality and morbidity. 1, 2

• Fatal or nonfatal hemorrhage can occur from any tissue or organ as a direct consequence of warfarin's anticoagulant mechanism 1
• Warfarin causes approximately 29,000 emergency department visits annually for bleeding complications in the United States 2
• Major bleeding frequencies range from 10% to 16% in clinical practice 2
• Anticoagulants, primarily warfarin, ranked first in 2003-2004 for total mentions of deaths from drugs causing "adverse effects in therapeutic use" 2

Clinical presentations of bleeding include:

• Paralysis, paresthesia, headache 1
• Chest, abdominal, joint, or muscle pain 1
• Dizziness, shortness of breath, difficult breathing or swallowing 1
• Unexplained swelling, weakness, hypotension, or shock 1

Critical caveat: Bleeding during anticoagulant therapy does not always correlate with PT/INR levels 1. When bleeding occurs within the therapeutic INR range (2.0-3.0), it warrants diagnostic investigation as it may unmask previously unsuspected lesions such as tumors or ulcers 1.

Skin Necrosis (Most Important Non-Hemorrhagic Complication)

Warfarin-induced skin necrosis is the most important non-hemorrhagic side effect, occurring in 0.01% to 0.1% of patients. 3, 4

• Typically appears on the third to eighth day of therapy 3, 4
• Caused by extensive thrombosis of venules and capillaries within subcutaneous fat 3
• Most commonly affects fatty areas: breasts, thighs, and buttocks 4
• Strongly associated with protein C deficiency and, less commonly, protein S deficiency, though it can occur without these deficiencies 3, 4
• Middle-aged, perimenopausal women with venous thromboembolism are at increased risk 4
• Large loading doses of warfarin increase risk 4

Management approach if skin necrosis occurs:

• Immediately discontinue warfarin 4
• Administer vitamin K and replenish vitamin K-dependent factors (fresh frozen plasma or 4-factor prothrombin complex concentrates) 4
• Switch to heparin for ongoing anticoagulation 4
• Perform surgical debridement of necrotic tissue as needed 4
• If warfarin must be restarted, begin with a low dose (2 mg daily) while administering concurrent therapeutic heparin, gradually increasing over several weeks 3, 4

Other Adverse Reactions

Hypersensitivity and Allergic Reactions

• Anaphylactic reactions (rare) 1
• Rash, dermatitis, including bullous eruptions 1
• Urticaria, pruritus 1

Vascular Complications

• Purple toes syndrome 1
• Systemic cholesterol microembolization 1
• Vasculitis, hypotension 1

Hepatic Effects

• Hepatitis, cholestatic hepatic injury 1
• Jaundice, elevated liver enzymes 1

Gastrointestinal Effects

• Abdominal pain including cramping 1
• Flatulence/bloating 1
• Nausea, vomiting, diarrhea 1

Neurological Effects

• Headache, dizziness 1
• Loss of consciousness, syncope, coma 1
• Paresthesia including feeling cold and chills 1

Other Effects

• Anemia, pallor 1
• Fever, edema 1
• Fatigue, lethargy, malaise, asthenia 1
• Alopecia, cold intolerance 1
• Taste perversion 1
• Rare tracheal or tracheobronchial calcification with long-term therapy (clinical significance unknown) 1
• Priapism (causal relationship not established) 1

Special Considerations

Pregnancy-Related Effects

• Warfarin interferes with carboxylation of Gla proteins synthesized in bone, contributing to fetal bone abnormalities when mothers are treated during pregnancy 3
• However, there is no evidence that warfarin directly affects bone metabolism when administered to children or adults 3

Cancer Patients

• Cancer patients have a six-fold higher risk of major bleeding compared to non-cancer patients 3
• Bleeding complications in cancer patients often occur at the lowest INR category (INR ≤ 2.0) 3
• Interactions with chemotherapeutic agents, particularly 5-fluorouracil-based regimens and capecitabine, can exaggerate anticoagulant activity and increase bleeding risk 3

Critical Drug and Dietary Interactions Affecting Side Effects

Medications That Increase Bleeding Risk

• Antibiotics and amiodarone potentiate warfarin's effect 5
• Aspirin and NSAIDs affect platelet function, increasing bleeding complications 6
• Miconazole, phenylbutazone, and sulfinpyrazone inhibit warfarin elimination 6

Medications That Decrease Warfarin Effect

• Barbiturates, rifampin, and carbamazepine increase hepatic clearance 5, 6
• Cholestyramine impairs warfarin absorption 3

Dietary Considerations

• Vitamin K directly counteracts warfarin and can significantly reduce INR 5
• Maintaining consistent vitamin K intake is crucial for stable anticoagulation 5
• Important distinction: Vitamin D does not interfere with warfarin's mechanism and does not require dietary restriction 5

Key Clinical Pitfalls to Avoid

• Never assume bleeding correlates with INR levels—investigate all bleeding episodes even when INR is therapeutic 1
• Do not confuse vitamin D with vitamin K when counseling patients on dietary restrictions 5
• Avoid large loading doses of warfarin, which increase skin necrosis risk 4
• Monitor for protein C and S deficiencies in patients who develop skin necrosis 4
• Ensure adequate wound care if skin necrosis occurs to prevent secondary infections 4
• Do not restart warfarin without appropriate precautions (low dose with concurrent heparin) in patients who experienced skin necrosis 3, 4