Pediatric Thromboembolism Medication
- Author: Scott C Howard, MD; Chief Editor: Robert J Arceci, MD, PhD more...
Information continues to emerge on the use of antithrombotic agents in neonates and children. Unfractionated heparin (UFH) has for years been the mainstay of initial therapy for thromboembolism in adults and children. However, low-molecular-weight heparin (LMWH) has similar efficacy, is easier to administer and monitor, and has a lower risk of heparin-induced thrombocytopenia.
In the Reviparin in Childhood Venous Thromboembolism (REVIVE) trial, researchers compared subcutaneous reviparin with UFH, followed by oral warfarin. The study was limited by the small number of patients but did show equivalence with respect to risk of bleeding and recurrent venous thromboembolism.
Medical therapy for venous thromboembolism in children is not evidence-based, because few randomized studies address important questions, such as duration of therapy for each type of venous thromboembolism. When one considers the subset of children with central venous catheter–associated thrombosis and cancer, clinical practice widely varies.
If thrombosis or PE is not extensive, oral anticoagulation with warfarin may be started on the second or third day and continued for 3-6 months unless risk factors for recurrent thrombosis persist. Pediatric studies have not yet been performed to identify the optimal length of therapy for each type of thrombosis.
Adults with cancer should be treated with LMWH for 6-12 months because the rate of recurrent thrombosis with warfarin therapy is unacceptably high. Similarly, children with thromboembolism and cancer should be treated with LMWH rather than warfarin because safe therapeutic levels of anticoagulation with warfarin can rarely be achieved in children undergoing cancer therapy, and the risk of bleeding and recurrent thrombosis are therefore unacceptably high.
Patients with thrombosis associated with a central venous catheter should receive anticoagulation therapy for 3-6 months if the catheter is removed and thrombotic risk factors have resolved. However, if the central line must remain in place once the period of anticoagulation has been completed, some advocate administration of prophylactic doses of LMWH (eg, enoxaparin at 0.5 mg/kg/day) until the central venous catheter is removed.
Values from the chapter “Antithrombotic and Thrombolytic Therapy,” in American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed, 2008), were used in the medication subsections below.
Inhibition of thrombin prevents the formation and/or extension of thrombus and thus allows for recanalization of the blood vessel over time.
Oral anticoagulants are used to prevent recurrent or ongoing thromboembolism-related occlusion. They are the mainstays of long-term outpatient therapy in patients who do not have cancer. Oral anticoagulants competitively interfere with vitamin K metabolism, decreasing plasma concentrations of the active forms of factors II, VII, IX, and X. Compared with adults, infants and children tend to require high maintenance doses and frequent dosage adjustments. Besides warfarin, acenocoumarol has also been used.
Warfarin interferes with the hepatic synthesis of vitamin K-dependent coagulation factors. It is used for the prophylaxis and treatment of venous thromboembolism, PE, and embolic complications. The drug is used for long-term anticoagulation.
Warfarin has a half-life of 36-42 hours. PT and INR can be difficult to monitor in children because of variability in dietary vitamin K intake, effects of other drugs, and age.
Unfractionated heparin sodium
Unfractionated heparin (UFH) sodium augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse clots but it can inhibit further thrombogenesis. UFH prevents reaccumulation of clot after spontaneous fibrinolysis. This agent is usually started as the initial treatment for thromboembolism.
Monitor the patient's CBC count, PT, and aPTT daily after aPTT is therapeutic. For reversal, stopping infusion usually sufficient. If rapid reversal is needed, give protamine. The dose is based on the heparin received in previous 2 hours. If less than 30 minutes have passed since last dose of heparin, give 1 mg per 100 U of heparin received, not to exceed 50 mg, administered intravenously, over 10 minutes.
Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. It also preferentially increases the inhibition of factor Xa.
The goal is to maintain an anti-Xa level of 0.5-1 U/mL (measured peak level 4 h postinjection). Enoxaparin may be used like UFH for 5-7 days, until oral anticoagulation yields an INR of greater than 2. As an alternative, LMWH may be continued for the entire 3-6 months of treatment.
For reversal, stopping the drug usually sufficient. If rapid reversal is needed, administer protamine. If less than 3-4 hours have passed since the last dose of LMWH, give 1 mg per 1 mg (or 100 U) of LMWH received, not to exceed 50 mg, administered intravenously, over 10 minutes.
Potential advantages to enoxaparin use include less osteoporosis, equivalent or less bleeding, and less heparin-induced thrombocytopenia. Enoxaparin is useful in infants and children with poor venous access.
Thrombolytic agents convert plasminogen to plasmin, leading to clot lysis. Pediatric indications are not established. Because of developmental differences in the hemostatic system, infants require doses higher than those used in adults to generate the same amount of plasmin.
Thrombolytic agents are most frequently used to manage blocked central catheters and are less often used to treat PE and stroke.
Alteplase is a recombinant tissue plasminogen activator (rt-PA). It is the drug of choice for thrombolysis, given that urokinase is unavailable in the United States. Alteplase is a specific, fibrin-bound plasminogen activator. Pediatric data on this drug is limited.
However, in research using a small number of infants and neonates with large-vessel thromboses, dosages were 0.01-0.5 mg/kg/h intravenous. Intracranial hemorrhage has been observed at dosages of 0.4 mg/kg or higher.
Antiplatelet Agents, Cardiovascular
Antiplatelet agents are used as prophylaxis for arterial thrombosis (stroke) and after Blalock-Taussig or endovascular shunt placement. They have no role in the prevention or treatment of venous thrombosis.
Aspirin can be used in low doses to inhibit platelet aggregation and to treat the complications of venous stases and thrombosis. It irreversibly inactivates cyclo-oxygenase and ultimately prevents thromboxane A2 production in platelets. Platelet function does not fully recover until new platelets are made in 7-10 days.
Protein C concentrate is now available for replacement therapy and to treat and prevent severe sequelae caused by hereditary protein C deficiency.
This agent is an orphan drug that is indicated for the prevention and treatment of life-threatening venous thromboembolism and purpura fulminans caused by severe congenital protein C deficiency. It is also indicated as replacement therapy for inherited protein C deficiency.
Protein C is an essential component of hemostasis. Thrombomodulin is necessary to convert protein C to its activated form.
The dosage and duration of protein C therapy depend on the severity of the patient's protein C deficiency and are adjusted to an individual pharmacokinetic profile.
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