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Principal Developer: M. David Warfarin Therapy in Children Warfarin & Vitamin K Dependent Factors The molecular structures of clotting factors VII, IX, X and II are modified by an enzymatic system in the presence of vitamin K. This is an essential step for the function of these factors. The activation of coagulation factors will ultimately lead to the formation of thrombin - the key enzyme which produces fibrin, an essential component in thrombus formation. Warfarin will inhibit thrombin formation by interfering with vitamin K metabolism. The degree of inhibition will depend on the treatment intensity and the age of the child. At birth, the coagulation system is immature with plasma levels of the vitamin K dependent factors reduced to less than 50% of adult values. For this reason, warfarin therapy is rarely recommended for infants less than 2 months of age. By 6 months of age, the coagulation system is similar to the adult system and warfarin therapy can be used with careful monitoring. Validated Regimen for Infants, Children and Teens Aiming for an INR of 2.0 - 3.0 Initial Dosing (Day 1) If baseline INR is 1.0-1.3, start with 0.2 mg/kg orally (maximum of 5 mg). Reduce the
dose to 0.1 mg/kg Adjusting dosing (Day 2 - 5)
Adjusting dosing (Day 6 onward)
An injectable form of warfarin which facilitates treatment in some children is also available. Monitoring General guidelines for monitoring warfarin therapy in children are similar to adult patients. The prothrombin time (PT) is the most commonly used test to monitor oral anticoagulant therapy. The PT should be reported using the International Normalized Ratio (INR). By using the INR, monitoring of warfarin is simplified and its safety is improved by the standardization of the therapeutic range, irrespective of the thromboplastin reagent used. Many laboratories now report INRs. The INR is calculated from the observed PT using the formula. INR = (Patient's PT in seconds / Mean of PT of normal range in seconds) ISI The ISI is the International Sensitivity Index for a given reagent. The mean of the normal range should be calculated by obtaining the mean of a minimum of 20 subjects' PTs with the PT determined using the laboratory's individual thromboplastin. This calculation is done by the laboratory. Capillary whole blood monitoring is feasible and safe in children. Warfarin Dosing Since the half lives of the vitamin K-dependent coagulation factors vary from 6 to 72 hrs and the half life of warfarin is 2.5 days, changes made to the dosage will not be reflected in the INR value completely until day 3 or 4. Maintenance doses are highly dependent on patient age, vitamin K intake, intercurrent illnesses and concurrent use of other drugs. On average children require weekly INRs with frequent changes precipitated by the introduction of antibiotics, changes in diet, and concurrent illnesses. Warning to Parents
A physician should be consulted for the following:
Teenage Pregnancy Warfarin should not be used. It crosses the placenta and may cause embryopathy, CNS abnormalities and fetal bleeding. Teenagers need to receive appropriate counselling about these potential problems. Teenagers who become pregnant while on warfarin therapy should notify their physician immediately. In teens who require anticoagulants during pregnancy, heparin is the treatment of choice. Adverse Effects The types and frequency of adverse effects in children are similar to adult patients. Bleeding, usually mild, is the most important complication of anticoagulant therapy. The intensity of anticoagulation, the concomitant use of ASA, NSAIDs and the underlying clinical disorder are factors influencing the risk of bleeding. Skin rash and alopecia are uncommon adverse effects and may be managed by changing oral anticoagulants. Skin necrosis is a rare complication and usually appears within a few days of the start of oral anticoagulation therapy. Children presenting with skin necrosis should be investigated for deficiencies in Protein C and S. Osteopenia is a potential complication in children receiving long-term warfarin therapy and periodic monitoring of bone density is suggested. Factors Affecting Warfarin's Effect Children requiring oral anticoagulation therapy frequently have serious underlying disorders that influence their response to therapy. New medications, dosage changes in medications, diet and intercurrent viral infections are the most common factors influencing warfarin's effects. In some instances, the anticoagulant response is unpredictable. For these reasons, it is imperative to closely monitor the child's response. This guideline was developed in collaboration with the Canadian Children's Thrombophilia Society and reviewed by T.I.G.C. members, based on medical literature and on current Canadian medical practice. Canadian Children's Thrombophilia Society: 1-800-NO CLOTS References:
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