Pediatric Thromboembolism Medication

Medication Summary
For years, unfractionated heparin (UFH) has 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,[14]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 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 (CVC)-associated thrombosis and cancer, clinical practice widely varies.[15] If thrombosis or pulmonary embolism (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, thus the risk of bleeding and recurrent thrombosis are unacceptably high. Those with thrombosis associated with a CVC 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/d) until the CVC is removed. [13] Information continues to emerge on use of antithrombotic agents in neonates and children. The 2008 guidelines by Monagle et al were used to provide the following suggested dosages. [16]

Heparin anticoagulants
Class Summary
Inhibition of thrombin prevents the formation and/or extension of thrombus and thus allows for recanalization of the blood vessel over time.

Unfractionated heparin sodium

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse clots but can inhibit further thrombogenesis. Prevents re-accumulation of clot after spontaneous fibrinolysis. Usually started as initial treatment of thromboembolism. Dosage titrated to maintain aPTT of 60-85 s (assuming this reflects an antifactor Xa level of 0.3-0.7 U/mL). Monitor CBC count, PT, and aPTT daily after aPTT is therapeutic. For reversal, stopping infusion usually sufficient. If rapid reversal needed, give protamine. Dose based on heparin received in previous 2 h. If < 30 min since last dose of heparin, give 1 mg per 100 mg of heparin received; not to exceed 50 mg IV over 10 min.

Enoxaparin (Lovenox)

Pediatric Dosing & Uses

Dosing Forms & Strengths
multidose vial 100mg/3mL prefilled syringe 30mg/0.3mL 40mg/0.4mL 60mg/0.6mL 80mg/0.8mL 100mg/mL 120mg/0.8mL 150mg/mL

Deep Vein Thrombosis (Off-label)

Note: Multidose vial contains benzyl alcohol (associated with gasping syndrome in premature infants) Prophylaxis <2 months: 0.75 mg/kg SC q12hr >2 months: 0.5 mg/kg SC q12hr Treatment <2 months: 1.5 mg/kg SC q12hr >2 months: 1 mg/kg SC q12hr Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. Also preferentially increases inhibition of factor Xa. Goal is to maintain anti-Xa level of 0.5-1 U/mL (measured peak levels 4 h post injection). May be used like UFH for 5-7 d until PO anticoagulation yields INR >2. As an alternative, LMWH may be continued for entire 3-6 mo of treatment. For reversal, stopping drug usually sufficient. If rapid reversal needed, administer protamine. If < 3-4 h since last dose of LMWH, give 1 mg per 1 mg (or 100 U) of LMWH received; not to exceed 50 mg IV over 10 min. Potential advantages include less osteoporosis, equivalent or less bleeding, and less HIT. Useful in infants and children with poor venous access.

Reviparin (Clivarine)
Goal of therapy is to maintain an anti-Xa level of 0.5-1 U/mL (measure peak level 4 h after dose). Potential advantages similar to those of enoxaparin. Not available in United States.

Oral anticoagulants
Class Summary
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, phenprocoumon and acenocoumarol have also been used.

Warfarin (Coumadin)

Pediatric Dosing & Uses

Dosing Forms & Strengths
powder for injection 5mg/vial tablets 1mg 2mg 2.5mg 3mg 4mg 5mg 6mg 7.5mg 10mg

Thrombosis
Prevention/treatment: If baseline INR is 1.0-1.3, administer loading dose of 0.1-0.2 mg/kg PO qDay x1 day; check INR on days 2-4 and adjust daily dose adjustment to maintain INR between 2.0-3.0 (unless valve replacement indicates a higher range) Use 0.1 mg/kg to initiate therapy with liver impairment or in patients who have had a Fontan procedure Typical maintainance dose: 0.09-0.33 mg/kg/day, with infants <12 months old often requiring doses at high end of range Consistent anticoagulation in children is difficult and requires close supervision and frequent dose adjustments Refer to ACCP recommendations or institutional protocol for treatment duration dependent on indication

Hepatic Impairment
Hepatic impairment may potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors Load: 0.1 mg/kg PO qDay x2 days Typical maintenance dose: 0.1 mg/kg PO qDay; adjust dose to achieve desired INR Common maintenance dose range: 0.05-0.34 mg/kg PO qDay

Other Information
Infants and children receiving vitamin K-supplemented nutrition (including infant formulas): May be resistant to warfarin therapy Human milk-fed infants: May be sensitive to warfarin therapy

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for prophylaxis and treatment of venous thromboembolism, PE, and thromboembolism. Used for long-term anticoagulation. Half-life of 36-42 h. PT and INR can be difficult to monitor in children because of variability in dietary vitamin K intake, effects of other drugs, and age.

Thrombolytic agents
Class Summary
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. These agents are most frequently used to manage blocked central catheters and are less often used to treat PE and stroke.

Alteplase (Activase)

Pediatric Dosing & Uses

Dosing Forms & Strengths
powder for injection 2mg 50mg 100mg

Central Venous Catheter Occlusion

<30 kg Cathflo Activase: instill 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL 30 kg Cathflo Activase: 2 mg instilled into occluded catheter Assess catheter function after 30 minutes of dwell time by attempting to aspirate blood; if unable to aspirate after 120 minutes dwell time, a 2nd dose may be administered and the process repeated If catheter function restored, aspirate 4-5 mL blood in patients 10 kg or more (aspirate 3 mL if <10 kg) to remove Cathflo Activase and residual clot Gently irrigate with 0.9% NaCl Recombinant tissue plasminogen activator. DOC for thrombolysis, given current shortage of urokinase. Specific fibrin-bound plasminogen activator. Pediatric data limited. In small series of infants and neonates with large-vessel thromboses, dosages were 0.01-0.5 mg/kg/h IV. Intracranial hemorrhage observed at dosages of 0.4 mg/kg or higher.

Urokinase (Abbokinase)

Pediatric Dosing & Uses

Safety & efficacy not established

Direct plasminogen activator. Acts on endogenous fibrinolytic system and converts plasminogen to plasmin, which degrades fibrin clots, fibrinogen, and other plasma proteins. Until recent shortage, was drug most often used to clear blocked central venous lines. Low-dose infusions of 200 U/kg/h do not cause systemic fibrinolysis.

Streptokinase (Streptase, Kabikinase)

Pediatric Dosing & Uses

Safety & efficacy not established

DVT (Limited Data)

Step 1: 3500-4000 international unit/kg over 30 minutes IV infusion Step 2: 1000-1500 international unit/kg/hr

Arterial Occlusions (Anecdotal Data)

Load: 1000 international unit/kg IV over 5-30 minutes, THEN 1000-1500 international unit/kg/hr continuous infusion

Converts plasminogen to plasmin, which degrades fibrin clots, fibrinogen, and other plasma proteins. IV infusion increases fibrinolytic activity, which degrades fibrinogen levels for 24-36 h. First thrombolytic agent used in children. Also least expensive. Potential for allergic reactions limits use.

Antiplatelet agents
Class Summary
Antiplatelet agents are used as prophylaxis for arterial thrombosis (stroke) and after Blalock-Taussig or endovascular shunt placement. They have no role for prevention or therapy of venous thrombosis.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Pediatric Dosing & Uses

Dosing Forms & Strengths
tablet 81mg 300mg 325mg 500mg 650mg tablet, quick-release 325mg 500mg tablet, chewable 81mg tablet, enteric coated 975mg tablet, continual release 800mg Not indicated with viral illness (risk of Reye's syndrome)

Analgesic/Antipyretic
<12 years old: 10-15 mg/kg/dose PO q4hr, up to 60-80 mg/kg/day 12 years or older: As in adults

Juvenile Rheumatoid Arthritis

<25 kg: 60-100 mg/kg/day PO divided q6-8hr (maintain serum salicylate 150-300 mcg/mL) 25 kg or heavier: 2.4-3.6 g/day

Kawasaki Disease
Febrile phase: 80-100 mg/kg/day PO divided q6hr After defervesces: 3-6 mg/kg PO qDay

Other Information
Toxic dose: 200 mg/kg

Used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Irreversibly inactivates cyclooxygenase; ultimately prevents thromboxane A 2 production in platelets. Platelet function does not fully recover until new platelets are made in 7-10 d.

Blood Product Derivative

Class Summary
Protein C concentrate is now available for replacement therapy and to treat and prevent severe sequelae caused by hereditary protein C deficiency.

Protein C concentrate, human (Ceprotin)

Pediatric Dosing & Uses

Dosing Forms & Strengths
lyophilized powder 500 International Units 1000 International Units

Protein C Deficiency
Indicated for prevention and treatment of venous thrombosis & purpura fulminans in patients with congenital Protein C deficiency Acute episode or short term prophylaxis: Initial 100-120 International Units/kg IV, THEN 60-80 International Units/kg IV q6hr for 3 doses; THEREAFTER 45-60 International Units/kg IV BID/QID Long-term prophylaxis: 45-60 International Units/kg IV q12hr

Orphan drug indicated for prevention and treatment of life-threatening venous thromboembolism and purpura fulminans caused by severe congenital protein C deficiency. Also indicated as replacement therapy for inherited protein C deficiency. Protein C is essential component for hemostasis. Thrombomodulin necessary to convert protein C to its activated form. Dosage and treatment duration depend on severity of protein C deficiency and are adjusted to individual pharmacokinetic profile.