Best Anticoagulant and Thrombolytic Therapy in Children :2024

Anticoagulant and Thrombolytic Therapy in Children

Initial Anticoagulation Options

For children, initial anticoagulation generally involves unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), followed by maintenance therapy with LMWH or warfarin. Direct oral anticoagulants (DOACs), which inhibit factor Xa or thrombin, are approved for adults and currently undergoing phase III clinical trials for pediatric use. These are recommended for both acute and long-term treatment of venous thromboembolism (VTE) in adults.

Duration of Therapy

Guidelines suggest neonates with VTE should receive 6 weeks to 3 months of therapy, while older children should receive 3-6 months. Patients with strong inherited thrombophilia, recurrent thrombosis, or antiphospholipid syndrome (APS) may require indefinite anticoagulation.

Unfractionated Heparin (UFH)

UFH and LMWH work by enhancing antithrombin III (AT III), which inhibits factor Xa and thrombin. UFH is composed of large polysaccharide chains that interact with AT III to inhibit several serine proteases.

• Dosage: A bolus of 75-100 units/kg followed by continuous infusion is typically used. Therapeutic PTT is aimed at 1.5-2.5 times the upper limit of normal. Infants usually require higher doses.
• Monitoring: PTT levels should be closely monitored. In certain cases, such as lupus anticoagulant presence or elevated factor VIII, anti-Xa levels are monitored instead, targeting 0.35-0.7 units/mL.

Complications:

• Bleeding: The primary adverse effect; can be life-threatening.
• Difficulty in dosing: Due to unpredictable bioavailability, frequent monitoring, and dose adjustments are needed.
• Other complications: Osteoporosis and heparin-induced thrombocytopenia (HIT), a rare but serious immune-mediated condition causing thrombosis. HIT requires discontinuation of heparin and alternative anticoagulants like argatroban or bivalirudin.

Low-Molecular-Weight Heparin (LMWH)

LMWH contains smaller polysaccharide chains, primarily inhibiting factor Xa and having a lesser effect on thrombin.

• Dosing: For infants <2 months, 1.5 mg/kg every 12 hours; for older children, 1 mg/kg every 12 hours. Target anti-factor Xa levels are 0.5-1.0 IU/mL, measured 4 hours post-dose.
• Advantages: Easier dosing, less frequent monitoring, and subcutaneous administration make it preferred in pediatric patients. Enoxaparin is the most commonly used LMWH.

Warfarin

Warfarin is an oral anticoagulant that inhibits vitamin K-dependent clotting factors II, VII, IX, and X. It requires concurrent heparin or LMWH during initiation due to the risk of warfarin-induced skin necrosis.

• Dosing: Initiated with a loading dose and adjusted using a nomogram. Heparin or LMWH is continued until the INR is therapeutic for 2 days. The target INR range is generally 2.0-3.0, with higher ranges for high-risk patients.
• Complications: Bleeding is the most common adverse effect, with a significant risk at supratherapeutic INR levels. Diet, medications, and illnesses can affect warfarin metabolism, necessitating frequent monitoring. Warfarin is also teratogenic.

Direct Oral Anticoagulants (DOACs)

DOACs, including dabigatran (a direct thrombin inhibitor) and factor Xa inhibitors like apixaban, rivaroxaban, and edoxaban, offer fixed dosing, no dietary restrictions, and do not require routine lab monitoring. While approved for adults, they are under clinical trials for pediatric use.

Thrombolytic Therapy

For rapid clot resolution in life- or limb-threatening thrombosis, thrombolytic agents like tissue plasminogen activator (TPA) are used. These agents convert plasminogen to plasmin, which degrades fibrin and fibrinogen.

• Dosing: Ranges widely; recent reports favor very low doses (0.01-0.06 mg/kg/hr) over previous higher doses.
• Monitoring: Fibrinogen levels should be maintained above 100 mg/dL and platelet count above 75,000 x 10^9/L. Clinical and radiologic responses should be closely monitored.

Complications:

• Bleeding: The most significant risk, with contraindications including recent major surgery, significant bleeding history, uncontrolled hypertension, and severe thrombocytopenia.

Thromboprophylaxis

No formal trials exist for VTE prevention in children. However, hospitalized adolescents with multiple risk factors and prolonged immobilization might benefit from prophylactic enoxaparin.

Antiplatelet Therapy

Antiplatelet agents like aspirin inhibit platelet function and are more effective against arterial than venous thromboembolism. Aspirin is commonly used in conditions like Kawasaki disease, stroke, and certain cardiac defects, with recommended doses of 1-5 mg/kg/day.