In Kawasaki disease, when is anticoagulation indicated (e.g., giant coronary artery aneurysm ≥8 mm or Z‑score ≥10, intraluminal thrombus, rapidly enlarging aneurysm, coronary occlusion or severe stenosis)?

Anticoagulation Indications in Kawasaki Disease

Systemic anticoagulation with warfarin (INR 2.0-3.0) or low-molecular-weight heparin plus low-dose aspirin is indicated for patients with giant coronary artery aneurysms (≥8 mm absolute diameter or Z-score ≥10) or rapidly expanding aneurysms approaching this threshold. 1

Primary Indications for Anticoagulation

Giant Coronary Artery Aneurysms

• Patients with coronary artery aneurysms ≥8 mm in absolute diameter OR Z-score ≥10 require dual therapy with low-dose aspirin (3-5 mg/kg/day) plus systemic anticoagulation. 1, 2
• The anticoagulation options include warfarin (target INR 2.0-3.0) or LMWH (target anti-factor Xa 0.5-1.0 U/mL). 1
• Giant aneurysms create markedly abnormal flow conditions with low wall shear stress, stasis, and turbulence that powerfully stimulate thrombus formation through both platelet activation and endothelial dysfunction. 1

Rapidly Expanding Aneurysms

• For patients with rapidly expanding coronary artery aneurysms approaching Z-score ≥10, systemic anticoagulation with LMWH or warfarin plus low-dose aspirin is reasonable even before reaching the giant aneurysm threshold. 1
• These patients require echocardiography at least twice weekly during the rapid expansion phase to monitor progression. 3

High-Risk Scenarios Requiring Triple Therapy

Triple therapy (aspirin + second antiplatelet agent + anticoagulation) may be considered for patients at exceptionally high thrombotic risk: 1

• Giant aneurysms (≥8 mm or Z-score ≥10) with recent history of coronary artery thrombosis 1, 2
• Patients who recently required thrombolysis for coronary thrombosis 1
• The second antiplatelet agent is typically clopidogrel (1 mg/kg/day, maximum 75 mg/day). 1
• This regimen carries greater bleeding risk and must be weighed carefully against thrombotic risk on an individual basis. 1

Anticoagulation NOT Routinely Indicated

Medium Aneurysms

• Patients with medium aneurysms (Z-score ≥5 to <10, absolute dimension <8 mm) typically receive dual antiplatelet therapy (aspirin plus clopidogrel) without anticoagulation unless additional risk factors are present. 3, 2

Small Aneurysms

• Patients with small aneurysms (Z-score ≥2.5 to <5) receive low-dose aspirin alone without anticoagulation. 3, 2

No Coronary Involvement

• Patients without coronary artery changes receive low-dose aspirin until 4-6 weeks after illness onset, then discontinue. 1, 2

Choice of Anticoagulant Agent

LMWH vs Warfarin

• Both LMWH and warfarin demonstrate equivalent effectiveness for preventing thrombosis in giant aneurysms, with no significant difference in thrombotic events. 4
• LMWH is generally preferred for infants and young children, particularly during the acute phase when aneurysms are still expanding. 1
• LMWH offers potential anti-inflammatory benefits during the acute illness and may be associated with better aneurysm regression compared to warfarin. 5
• Warfarin is typically used for long-term management once aneurysms have stabilized, though maintaining therapeutic INR is challenging with only 59-68% of time in therapeutic range. 6
• Transition from LMWH to warfarin may be considered once aneurysms have stopped expanding and the patient is clinically stable. 1

Dosing Specifics

LMWH (Enoxaparin): 1

• <2 months of age: 1.5 mg/kg subcutaneously every 12 hours
• ≥2 months of age: 1.0 mg/kg subcutaneously every 12 hours
• Target anti-factor Xa level: 0.5-1.0 U/mL, checked 4-6 hours after dose

Warfarin: 1

• Initial dose: 0.1 mg/kg/day orally
• Target INR: 2.0-3.0
• Requires frequent monitoring, initially daily until stable, then at minimum monthly

Critical Period and Monitoring

• The highest risk of thrombosis occurs in the first 3 months after illness onset, with peak risk between 15-45 days. 3
• Patients with giant aneurysms require echocardiography at least twice weekly during rapid expansion, then weekly for the first 45 days, then monthly until 3 months. 3
• After 3 months, echocardiography should be performed every 3 months until the end of the first year. 3

Important Caveats and Pitfalls

Antithrombin Deficiency

• More than half of KD patients develop transient antithrombin deficiency during acute illness, which can impair LMWH effectiveness. 1
• If patients fail to achieve target anti-factor Xa levels on appropriate LMWH dosing, measure antithrombin levels. 1
• If deficient, administer fresh-frozen plasma or antithrombin supplementation. 1

Drug Interactions

• Ibuprofen and other NSAIDs that affect the cyclooxygenase pathway should be avoided in patients taking aspirin for antiplatelet effects. 1

Reye's Syndrome Risk

• During influenza or varicella infections, aspirin must be temporarily replaced with clopidogrel or LMWH to avoid Reye's syndrome risk. 3

Bleeding Complications

• Severe bleeding occurs at a rate of approximately 1.6 events per 100 patient-years with anticoagulation, with similar rates for LMWH and warfarin. 4
• Major bleeding events occur at 4.3 per 100 patient-years in patients on warfarin plus aspirin. 6

Treatment of Acute Coronary Thrombosis

When acute coronary thrombosis with actual or impending occlusion occurs, immediate thrombolytic therapy or mechanical intervention is required: 1

• Tissue plasminogen activator (tPA) is the most commonly used thrombolytic agent at 0.5 mg/kg/hour IV over 6 hours. 1
• Administer concurrently with aspirin and unfractionated heparin. 3
• Maintain fibrinogen >100 mg/dL to minimize bleeding risk. 3
• Monitor coagulation parameters at least daily. 3
• Alternative mechanical restoration of coronary blood flow via cardiac catheterization may be performed in patients of sufficient size. 1