Pediatric Thromboembolism Medication

  • Author: Scott C Howard, MD; Chief Editor: Robert J Arceci, MD, PhD   more...
 
Updated: Nov 2, 2011
 

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]

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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.

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Enoxaparin (Lovenox)

 

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.

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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.

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Warfarin (Coumadin)

 

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.

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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.

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Alteplase (Activase)

 

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.

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Urokinase (Abbokinase)

 

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.

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Streptokinase (Streptase, Kabikinase)

 

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.

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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.

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

 

Used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Irreversibly inactivates cyclooxygenase; ultimately prevents thromboxane A2 production in platelets. Platelet function does not fully recover until new platelets are made in 7-10 d.

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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.

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Protein C concentrate, human (Ceprotin)

 

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.

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Contributor Information and Disclosures
Author

Scott C Howard, MD  Associate Member, Department of Oncology, Director of Clinical Trials, International Outreach Program, St Jude Children's Research Hospital; Associate Professor, University of Tennessee Health Science Center College of Medicine

Scott C Howard, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, and International Society of Paediatric Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

J Martin Johnston, MD  Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Hematology/Oncology, The Children's Hospital at Memorial University Medical Center; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

J Martin Johnston, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD  Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Samuel Gross, MD  Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University

Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD  King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Philip M Monteleone, MD, to the development and writing of this article.

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Virchow triad for the pathophysiology of thrombus formation.
Coagulation cascade. Solid arrows represent activation events, dashed arrows represent inhibition events, and dotted lines with circles represent inactivation events. a = active; APC = activated protein C; F = factor; FDP= fibrin degradation products; HMW = high molecular weight; PAI-1 = plasminogen activator inhibitor-1; PL = phospholipid; TM = thrombomodulin; t-PA = tissue type plasminogen activator; u-PA = urokinase plasminogen activator; XL= crosslinked.
Nomogram for adjusting the dosage of heparin. Reproduced with permission from Michelson et al (1998). APTT = activated partial thromboplastin time.
Dosing of low-molecular-weight heparins (LMWHs) in children. Reproduced with permission from Michelson et al (1998).
Warfarin dosing in children. INR = international normalized ratio. Reproduced with permission from Michelson et al (1998).
 
 
 
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