eMedicine Specialties > Pediatrics: General Medicine > Hematology
Thromboembolism: Treatment & Medication
Updated: Jan 13, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Initial care and evaluation for thromboembolism should occur in a pediatric inpatient ward or the ICU if severe respiratory distress or neurologic deterioration occurs. Management includes assessment of the extent of the thrombosis and clinical consequences, a search for thrombophilic risk factors, and anticoagulation therapy. The duration of anticoagulation depends on the extent and location of the thrombosis, whether the thrombophilic risk factors have resolved, and, in some cases, the degree of resolution for thrombosis after initial therapy (see Medication).6,7,10,11,12,13
Surgical Care
On occasion, surgical thrombectomy may be necessary, especially after major cardiac surgery or if thrombolytic agents fail or are contraindicated.
Consultations
A pediatric hematologist should be involved in the care of all neonates, infants, and children with thromboembolism, and a pediatric neurologist should be involved in the care of children with suspected or proven CNS thrombosis.
Diet
Vitamin K directly interferes with the effectiveness of warfarin and potentially increases the risk for recurrent thrombosis. Daily intake of foods high in vitamin K, such as green leafy vegetables, should be kept at a consistent level. For example, patients should eat similar amounts of vitamin-K rich foods each day.
Maternal intake of vitamin K can also affect levels in breast milk and cause similar problems in neonates and infants. Supplementation with a consistent amount of formula per day has been recommended. Formula-fed infants should receive formula with the lowest concentration of vitamin K available. Vitamin K should be removed from parenteral nutrition or a constant small amount should be used each day.
Activity
Children with thromboembolism are sometimes restricted to bed rest for the first 24-48 hours to decrease the risk of pulmonary embolism (PE). However, this practice has never been shown to reduce the risk of embolization, and adults whose deep venous thrombosis (DVT) was treated as an outpatient (without bed rest) had no higher incidence of PE than those treated as an inpatient. Children with lower-extremity DVT should be fitted for compression stockings to reduce the risk of postthrombotic syndrome.
Medication
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
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.
Adult
Initial dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV; as an alternative, 50 U/kg/h IV initially, followed by continuous IV infusion of 15-25 U/kg/h; increase by 5 U/kg/h q4h prn on basis of aPTT
Pediatric
Initial dose: 75 U/kg IV over 10 min
Maintenance IV infusion:
<1 year: 28 U/kg/h IV
>1 year: 20 U/kg/h IV
Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity
Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Not for IM use; development of thrombocytopenia should prompt testing for antibodies (heparin-induced thrombocytopenia) because of increased risk of bleeding and progression of thrombosis
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.
Adult
Treatment: 1 mg/kg/dose SC q12h
Prophylaxis: 30 mg SC q12h
Pediatric
Treatment
<2 months: 1.5 mg/kg/dose SC q12h
>2 months: 1 mg/kg/dose SC q12h
Prophylaxis:
<2 months: 0.75 mg/kg/dose SC q12h
>2 months: 0.5 mg/kg/dose SC q12h
Possible increased risk of bleeding with platelet inhibitors or PO anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine)
Documented hypersensitivity; major bleeding, thrombocytopenia
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Not intended for IM use; should not be mixed with other injections or infusions; caution with bleeding, uncontrolled arterial hypertension or history of recent GI bleed, diabetic retinopathy, and hemorrhage; renal insufficiency may delay elimination; epidural and/or spinal hematomas reported in adults receiving spinal or epidural anesthesia (recommend withholding 2 doses before lumbar puncture or surgery; cannot be used interchangeably (unit for unit) with heparin or other LMWH
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.
Adult
DVT treatment:
35-45 kg: 7000 U SC qd or divided q12h
46-60 kg: 8400 U SC qd or divided q12h
>60 kg: 12,600 U SC qd or divided q12h
DVT prophylaxis: 4200-1750 U SC qd
Pediatric
Treatment:
<5 kg: 150 U/kg/dose SC q12h
>5 kg: 100 U/kg/dose SC q12h
Prophylaxis
<5 kg: 50 U/kg/dose SC q12h
>5 kg: 30 U/kg/dose SC q12h
Possible increased risk of bleeding with platelet inhibitors or PO anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine)
Documented hypersensitivity; major bleeding; thrombocytopenia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Not intended for IM use; should not be mixed with other injections or infusions; caution with bleeding, uncontrolled arterial hypertension or history of recent GI bleed, diabetic retinopathy, and hemorrhage; renal insufficiency may delay elimination; epidural and/or spinal hematomas reported in adults receiving spinal or epidural anesthesia (recommend withholding 2 doses before lumbar puncture or surgery); cannot be used interchangeably (unit for unit) with heparin or other LMWH
Oral anticoagulants
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)
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.
Adult
5-15 mg/d PO qd initially; adjust dosage to desired INR
Pediatric
Loading dose: 0.2 mg/kg/d PO; adjust per nomogram
Infants: 0.31 mg/kg/d PO on average
1-5 years: 0.16 mg/kg/d PO
6-10 years: 0.13 mg/kg/d PO
Anticoagulant effects may decrease with coadministration of griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, or sucralfate; anticoagulant effects may increase with coadministration of PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, or sulindac
Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Do not switch brands after therapeutic response achieved; caution in active tuberculosis or diabetes; risk of skin necrosis in patients with protein C or protein S deficiency
Thrombolytic agents
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)
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.
Adult
Blocked central venous lines:
>30 kg: Instill 2 mg (1 mg/mL), dwell 30 min; if catheter function not restored, allow 90 additional min of dwell time (120 min total); may repeat process once prn
PE: 100 mg IV infused over 2 h
Pediatric
Blocked central venous lines:
Bolus: Instill 0.01-0.5 mg/kg (1 mg/mL), dwell 30-120 min, repeat once prn; not to exceed 2 mg
Infusion: 0.01-0.5 mg/kg/h IV for 2-10 h
Systemic thrombolysis: 0.1-0.6 mg/kg/h IV for 6-12 h
Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
Documented hypersensitivity; major surgery in last 10 d; history of severe intracranial, pulmonary, or GI bleeding
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adjust dosage to maintain fibrinogen value >100 mg/dL; bleeding is primary concern; avoid IM injections and nonessential handling of patient during systemic infusions; perform venipuncture carefully and only as required
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.
Adult
Blocked central venous lines: Instill 5000 U/mL to volume of catheter; dwell 2-4 h, repeat once prn
Systemic thrombolysis:
Bolus: 4400 U/kg IV
Infusion: 4400 U/kg/h IV for 6-12 h
Pediatric
Blocked central venous lines: Administer as in adults
Infusion: 200-400 U/kg/h IV for 12-36 h
Systemic thrombolysis bolus and infusion: Administer as in adults
Neonates often require increased doses to achieve fibrinolysis because of decreased plasminogen levels in this population
Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
Documented hypersensitivity; internal bleeding; recent trauma; history of intracranial or intraspinal surgery or trauma; cerebrovascular stroke; intracranial neoplasm
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
IM medication; severe hypertension, trauma, or surgery in last 10 d; avoid dislodging possible DVT; do not measure BP in lower extremities; monitor PT, aPTT, thrombin time, or fibrinogen level about 4 h after start of therapy
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.
Adult
Systemic thrombolytic treatment:
Loading dose: 250,000 U IV over 30 min
Infusion: 100,000 U/h IV for 6-12 h
Pediatric
Systemic thrombolytic treatment:
Loading dose: 2000 U/kg IV
Infusion: 2000 U/kg/h IV for 6-12 h
Coadministration of antifibrinolytic agents may decrease effects; concurrent use of heparin, warfarin, and aspirin may increase risk of bleeding
Documented hypersensitivity; active internal bleeding, intracranial neoplasm, aneurysm, diathesis, severe uncontrolled arterial hypertension
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adjust dosage to maintain fibrinogen level >100 mg/dL; caution in severe hypertension, IM medication, trauma or surgery in previous 10 d; measure hematocrit, platelet count, aPTT, PT, thrombin time, or fibrinogen levels before start of therapy; thrombin time or aPTT should be <2 times normal control value after infusion of streptokinase and before starting or resuming heparin; do not measure BP in the lower extremities (may dislodge possible DVT); monitor PT, aPTT, thrombin time, or fibrinogen 4 h after start of therapy
Antiplatelet agents
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)
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.
Adult
Minimum effective antiplatelet dose: 50-100 mg/d PO
Pediatric
Prophylaxis: 1-5 mg/kg/d PO
Kawasaki disease: 80-100 mg/kg/d PO for first 14 d, then 3-5 mg/kg/d for 7 wk or longer if evidence suggests coronary artery narrowing
Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels of salicylate; coadministration of anticoagulants may have additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; dosages >2 g/d may potentiate glucose-lowering effect of sulfonylureas
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; because of association of aspirin with Reye syndrome, do not use in children (<16 y) with flu
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Pregnancy category D in third trimester; may transiently decrease renal function and aggravate chronic kidney disease; avoid in patients taking anticoagulants and patients with severe anemia or history of defects in blood coagulation
Blood Product Derivative
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)
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.
Adult
Acute episode or short-term prophylaxis: 100-120 IU/kg IV once initially; 60-80 IU/kg IV q6h for next 3 doses; then 45-60 IU/kg IV q6-12h as maintenance
Long-term prophylaxis: 45-60 IU/kg IV q6-12h
Pediatric
Administer as in adults
Data limited; coadministration of tPA or anticoagulants may increase risk of bleeding
None known
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include rash, itching, and lightheadedness; contains heparin and human albumin; acquired from pooled human plasma (risk of infectious transmission); hemothorax and hypotension reported; discontinue if allergic reaction occurs; after initial dose for acute episodes and short-term prophylaxis, subsequent doses should maintain target peak protein C activity of 100% (chromogenic assay recommended); target dosage for maintenance after acute episode resolves or for long-term prophylaxis should maintain protein C activity level >25%; if switching to PO anticoagulant (eg, warfarin), continue protein C replacement therapy until stable anticoagulation achieved
More on Thromboembolism |
| Overview: Thromboembolism |
| Differential Diagnoses & Workup: Thromboembolism |
 Treatment & Medication: Thromboembolism |
| Follow-up: Thromboembolism |
| Multimedia: Thromboembolism |
| References |
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Young G, Manco-Johnson M, Gill JC, et al. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study. J Thromb Haemost. May 2003;1(5):958-62. [Medline].
Further Reading
Keywords
thrombosis, clots, thrombus, embolism, thrombus embolism, TE, thrombi, blood clot, venous thromboembolism, VTE, deep venous thrombosis, deep vein thrombosis, DVT, pulmonary embolism, PE, postthrombotic syndrome, post-thrombotic syndrome, PTS, central venous catheter, CVC, stasis, CNS thrombosis, renal vein thrombosis, antiphospholipid antibody syndrome, APLA, stroke, obesity, nephrotic syndrome, systemic lupus erythematosus, acute lymphoblastic leukemia
