AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Thromboembolism (TE) is a leading cause of morbidity and mortality in adults. Although the incidence of TE is lower in children than in adults, TE-related pediatric morbidity and mortality are still clinically significant.

The diagnosis and treatment of thrombosis in children were initially based on standards of care for adults. However, since the early 1990s, pediatric data have emerged, stressing differences in the etiology, pathophysiology, and drug pharmacokinetics of TE in children.

In 1845, Virchow postulated that 3 factors were important in the development of thrombosis: (1) impairment of blood flow (stasis), (2) vascular injury, and (3) alterations of the blood (hypercoagulability) (see Image 1). These factors also play a role in pediatric thrombosis. Developmental differences are discussed in this article.

Pathophysiology

The physiology of hemostasis is remarkably complex and reflects a fine balance between uninterrupted flow of blood (ie, fluid) and rapid, localized responses to vascular injury (ie, clotting).

The process of hemostasis is traditionally divided into a cellular phase and a fluid phase. The former involves platelets and the vascular wall, whereas the latter involves plasma protein.

The fluid phase is divided into 3 processes: (1) the multiple-step zymogen pathway that leads to thrombin generation, (2) thrombin-induced formation of a fibrin clot, and (3) complex fibrinolytic mechanisms aimed at limiting clot propagation (see Image 2). Abnormalities in any of these steps can contribute to hypercoagulable or hypocoagulable states.

Regarding the fluid phase, many age-dependent differences are present in the hemostatic system of infants and children. Adult levels of the vitamin-K–dependent coagulation factors II, IX, and X, as well as contact factors, are not achieved until the age of 3-6 months. Levels of thrombin inhibitors, such as antithrombin and heparin cofactor II, are similarly low at birth. That is, they are in the ranges that may cause heterozygous adults to develop TE.

Levels of alpha-2-macroglobulin are higher in infants and children than in adults. In the converse, levels of protein C and S are low at birth. Protein S levels approach adult values by the age of 3-6 months, but protein C levels remain low even into childhood. Furthermore, plasminogen levels are low in newborns and infants. This condition has a profound effect on treatment of TE in newborns.

Thrombin generation is decreased (probably because of low prothrombin levels) and delayed in newborns compared with adults.

Overall, during infancy, the tendency is greater for bleeding than for TE.

Frequency

United States

Deep venous thrombosis (DVT) or pulmonary embolism (PE) develops in approximately 2.5-5% of adults in the United States.

The National Hospital Discharge Survey recently demonstrated an incidence of 4.2 cases per 100,000 population per year for DVT. PE is seldom considered in children, but the same study revealed a rate of 0.9 case per 100,000 population per year.

PE has been found in 3.7% of children during autopsy.

Strokes occur with an incidence of approximately 2.5 cases per 100,000 children per year.

International

In the Canadian Registry, the incidence of venous TE (VTE) was estimated to be 0.07 case per 10,000 children and 5.3 per 10,000 hospital admissions in 1994.

In a German study by Nowak-Gottl et al (2004), the incidence of symptomatic neonatal TE was 5.1 cases per 100,000 births.¹

Mortality/Morbidity

Pulmonary embolism

In adults, the mortality rate associated with untreated PE is 18-30%. Even if PE is diagnosed early, the mortality rate is 8%.

In the Canadian Registry, the mortality rate was 2.2%, and deaths were mainly due to PE or direct extension of DVT into the heart.

In the Canadian Pediatric Ischemic Stroke Registry, a mortality rate of 6% was found, and 22% of the children fully recovered neurologic function.

A high index of suspicion is required because many early reports were based on autopsy data. Symptoms can be nonspecific and include tachypnea, tachycardia, fever, pleuritic chest pain, cough, shortness of breath, and (less commonly) hemoptysis. DVT is absent in children with PE more often than it is in adults. Risk factors include presence of a central venous catheter (CVC), immobility, heart disease, a ventriculoatrial shunt, trauma, cancer, surgery, infection, dehydration, shock, and obesity.

Recurrent TE

TE recurs in 4-7% of adults. In the Canadian Registry, 19% of children developed recurrent TE.

Recurrent TE might be secondary to inadequate anticoagulation because of a concern about bleeding and/or the persistence of underlying risk factors, such as use of a CVC.

A recent study in Germany showed that the number of underlying genetic risk factors affected recurrence rates. Children with no genetic risk factors had a 4.8% recurrence rate, whereas those with 1 genetic risk factor had a 17.6% recurrence rate. In children with 2 or more genetic risk factors, the risk of recurrence was almost 50%.

Goldenberg et al (2004) noted an increased recurrence rate in children with VTE and elevated levels of factor VIII and/or D-dimer after 3-6 months of anticoagulation.²

Postthrombotic syndrome

Postthrombotic syndrome (PTS) consists of chronically swollen, painful extremities with induration of the skin, ulceration, and pigmentary changes secondary to chronic venous stasis. About 20-67% of adults with DVT develop PTS.

According to the Canadian Registry, PTS occurs in 21-25% of children with venous thrombosis.

Using a standardized score, investigators in a recent study from the Hospital for Sick Children in Toronto, Ontario, Canada, observed PTS in 63% of 153 children. Cases were mild in 83% and moderate in 17%.

Treatment of PTS consists of the use of elastic compression stockings, elevation of the extremity above the level of the heart, and administration of analgesics or narcotics as necessary.

Sex

Most pediatric studies show a male-to-female ratio of essentially 1:1.

Age

The incidence of TE peaks in infants younger than 1 year and in adolescents. If newborns and infants are considered, the highest risk period for TE is in the first year of life.

CLINICAL

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History

Signs and symptoms

• Deep venous thrombosis
• • Symptoms potentially due to DVT include pain and swelling of acute onset. These symptoms are obviously nonspecific.
  • Swelling and pain in the lower extremities can have multiple etiologies, including trauma, sports injuries, congestive heart failure, or nephrotic syndrome.
  • Swelling and pain in an upper extremity suggests thrombosis more than DVT.
• Pulmonary embolism
• • Symptoms potentially due to PE include an acute onset of chest pain or shortness of breath. Chest pain due to PE is usually inconstant.
  • Remember that chest pain in children is usually benign.
  • In adults, the first sign of PE may be cardiovascular collapse, cardiac arrest, or sudden death.
• CNS thrombosis
• • Symptoms of CNS thrombosis include vomiting, lethargy, seizures, or weakness in an extremity.
  • Most strokes that occur in utero cause early pathologic hand preference late in the first year of life.
  • Neonates often present with seizures and lethargy.
  • Older children usually present with headaches and an acute onset of weakness in an extremity.
  • Infection and dehydration are common among infants and young children with CNS thrombosis.
• Renal vein thrombosis: Patients with renal vein thrombosis may present with flank pain and hematuria.

Risk factors

• The following factors are most thoroughly documented in adults, but they can contribute to thrombosis in children as well:
• • Recent surgery
  • Trauma
  • Immobilization
  • Prolonged bedrest
• In women and female adolescents, the use of estrogen-containing medications, such as oral contraceptives, increase the risk of thrombosis in women and female adolescents. The risk is further increased in women who are heterozygous for the factor V Leiden mutation.

History taking

• Look for a history or symptoms suggestive of heart disease or congestive heart failure. Congenital heart disease and/or recent cardiac catheterization are the most common causes of arterial thrombosis in children. Noteworthy factors include the following:
• • Dizziness
  • Bilateral extremity swelling
  • Poor weight gain
• Also look for a history or symptoms suggestive of malignancy. If the patient has a history of malignancy, inquire about use of CVCs and recent chemotherapy with L-asparaginase. Relevant findings include these:
• • Fevers
  • Bone pain
  • Weight loss
  • Bruising
  • Fatigue
• Elicit a history of previous thrombosis. Document the age at which thrombosis occurred and the type of thrombosis (DVT, PE, myocardial infarction, stroke).
• Also obtain a thorough family history.

Physical

• In children, as well as in adults, findings from the physical examination are often misleading. A diagnosis of thrombosis may be missed or delayed because of the nonspecific nature of the patient's presenting signs.
• Signs of DVT include the following:
• • Leg or arm edema
  • Erythema
  • Increased warmth
  • Palpable cord
  • Tenderness
  • Positive Homans sign (ie, pain on dorsiflexing the foot)
• Other important features are predisposing conditions, such as those listed below:
• • Congestive heart failure or heart disease
  • Malignancy
  • Presence of a CVC
• Thrombosis of the inferior vena cava and/or renal vein can cause nephromegaly and flank tenderness.
• Signs of PE are nonspecific and include these:
• • Apprehension
  • Diaphoresis
  • Tachycardia
  • Tachypnea
• Hemoptysis is seldom present in children, but it can be a sign in adolescents or adults.
• Signs of arterial thrombosis include absent or diminished peripheral pulses and a cool extremity with or without mottling of the skin.

Causes

Advances in technology have improved the survival of infants who were born prematurely and children in intensive care units. Approximately 95% of children with DVT and/or PE have one or more underlying risk factor; most have more than one. Therefore, perform a thorough workup, even when the cause of TE seems obvious.

Acquired conditions

Use of arterial catheters

Use of arterial catheters or CVCs is the most common risk factor in children with TE.

Cardiac catheterization through the femoral artery to manage congenital heart disease is the most common risk factor for arterial thrombosis in children. Prophylaxis with heparin 100-150 U/kg during the procedure lowers the incidence of thrombosis from 40% to 8% in children younger than 10 years. In neonates, catheterization of the poses risks similar to these. The absolute incidence of thrombosis is 10-90%, as based on angiographic diagnosis.

Use of CVCs

CVC-associated thrombosis was reported in 29% of children in a report from Denver and in 33% of children in a Canadian series.³ Several other studies of children with central lines for malignancy, sickle cell anemia, total parenteral nutrition, and critical care support reported thrombosis in 8-67%, depending on how the diagnosis was made (clinical vs radiographic evidence). Approximately 80% of newborns and 60% of children with upper extremity thrombosis also had CVCs in place.

Antiphospholipid antibody syndrome

Antiphospholipid antibodies, which are detected by finding positive lupus anticoagulant or anticardiolipin antibodies, are associated with thrombosis in both adults and children. In 2 studies of children with systemic lupus erythematosus, the incidences of TE were 9.2% and 17%. However, most children with antiphospholipid antibody syndrome acquire it incidentally and do not have systemic lupus erythematosus.

In a recent study, 95 children with lupus anticoagulant were followed up for a median of 5.3 years. About 10% had bleeding symptoms, whereas 5% had a thrombotic event.

Disseminated intravascular coagulation

Sepsis and disseminated intravascular coagulation have been associated with TE both in children and adults. Microvascular thrombosis consumes clotting factors, predisposing the patient to both hemorrhage and TE. Treatment of the underlying cause is essential.

Surgery, immobilization, and prolonged bedrest

The risk factors of surgery, immobilization, and prolonged bedrest have been studied most extensively in adults, and findings have generated recommendations regarding prophylaxis against TE. Children have a reduced risk of thrombosis with surgery. Therefore, prophylactic administration of heparin or low-molecular-weight heparin (LMWH) is not recommended for children.

Malignancy

Malignancy-associated TE has been studied most extensively in children with acute lymphoblastic leukemia. The underlying mechanisms are complex and include the effect of leukemia itself and the use of chemotherapy, especially L-asparaginase. In addition, CVCs are placed in any children with malignancies.

Use of estrogen-containing medications

Oral contraceptives alone are associated with a 4-fold increase in the risk of venous thrombosis and a 22-fold increase in the risk of cerebral thrombosis. This risk may be explained by the acquisition of resistance to activated protein C. Administration of oral contraceptives to patients who are heterozygous for the factor V Leiden mutation increases the risk of VTE 35- to 50-fold. In women with antithrombin, protein C, or protein S deficiency who are taking oral contraceptives, the risk rises 6-fold.

Nephrotic syndrome

In children with proteinuria at levels of more than 0.5 g/d may have a loss of anticoagulant proteins (eg, antithrombin), which increases the risk of TE. Most TEs develop within several months of diagnosis. Both arterial TE and VTE can occur; renal vein thrombosis is most common.

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by a decrease of more than 50% in the platelet count after a patient is given unfractionated heparin (UFH) for 5 days or longer. The risk of VTE mainly affects adults, but a high index of suspicion is needed to recognize this risk in children, even those who are receiving only heparin flushes to maintain the patency of intravenous or central lines.

Inherited prothrombotic disorders

Several dominantly inherited deficiencies or abnormalities of proteins involved in the coagulation and fibrinolytic pathways are now recognized. On occasion, more than 1 such abnormality may coexist in a single patient. Furthermore, the expression of these abnormalities (ie, development of a clot) frequently reflects the additive effects of acquired risk factors such as orthopedic surgery or trauma, immobility, pregnancy, use of oral contraceptives, and dehydration, among others.

Factor V Leiden

Resistance to activated protein C is the most common genetic risk factor associated with venous thrombosis in adults and children. Most cases are due to a point mutation in the gene for factor V. This mutation prevents cleavage of activated factor V by activated protein C and thus promotes ongoing clot development. Approximately 3-8% of Caucasian adults are heterozygous for the mutation, but many have no history of thrombosis. Several pediatric studies have demonstrated that 10-50% of children with thrombosis are heterozygous for the factor V Leiden mutation.

Double heterozygotes for factor V Leiden and for protein C, protein S, or antithrombin deficiency have been reported and have a further increased risk of thrombosis. Among women heterozygous for factor V Leiden who also are taking oral contraceptives, the risk of thrombosis rises 35-fold.

Antithrombin deficiency

Produced in the liver, antithrombin is the most important inhibitor of activated clotting factors. Most patients with antithrombin deficiency are heterozygous (with levels <50%), and thrombosis in this population is usually venous. Thrombosis can occur in children as young as 10 years.

Homozygous deficiency of antithrombin is rare but devastating. Patients usually present within hours of birth and have extensive thrombosis. Most infants die soon after birth.

Protein C deficiency

Protein C deficiency is usually transmitted in an autosomal dominant manner with incomplete penetrance. Thrombosis occurring in association with protein C deficiency is most often venous and in the lower extremities. DVT in heterozygotes can be observed as early as the teenage years. Similar to homozygotes with antithrombin deficiency, homozygotes with protein C deficiency usually present in the newborn period, with purpura fulminans.

A purified protein C concentrate was recently designated as an orphan drug and is available under the trade name Ceprotin.

Protein S deficiency

Protein S deficiency is similar to protein C deficiency and antithrombin deficiency except that it enhances an individual's predisposition to develop arterial thrombosis. Most protein S is bound to C4-binding protein. Therefore, one must measure both free and total concentrations of protein S to rule out a deficiency.

Patients with either protein C or protein S deficiency can develop warfarin-induced skin necrosis unless heparin is started first.

Hyperhomocysteinemia

In adults, hyperhomocysteinemia is an independent risk factor for arterial vascular disease and venous thrombosis.

A study of 45 children with ischemic stroke demonstrated that their odds ratio for developing moderate hyperhomocysteinemia was 4.4, as compared with control subjects.

A German study of 163 children with VTE showed a 3-fold increase in risk among subjects with elevated fasting homocysteine levels.

Homozygous mutations in the gene for cystathionine beta-synthetase are rare but account for most cases of severe hyperhomocysteinemia. Mild-to-moderate hyperhomocysteinemia can occur in heterozygotes with mutations affecting cystathionine beta-synthetase or methylene tetrahydrofolate reductase.

Prothrombin gene 20210A mutation

A Turkish study of 32 children with cerebral infarcts revealed that 21.8% were heterozygous for the prothrombin gene 20210A mutation. Recent studies have shown this mutation is a risk factor for pediatric arterial thrombosis, especially in the CNS.

Elevated lipoprotein(a) levels

Elevated lipoprotein(a) levels have been found in children with TE. Other disorders, such as dysfibrinogenemia and plasminogen deficiency, are rare but should be explored if the rest of the workup yields negative results. Also, recent studies in adults have implicated elevated levels of factor VIII and factor XI as risk factors for thrombosis. These risk factors have not yet been explored in children.

Congenital heart disease

Congenital heart disease involves children with mechanical or prosthetic valves and those undergoing Blalock-Taussig shunt placement or a Fontan procedure.

As noted above, cardiac catheterization is the most common risk factor for arterial thrombosis.

Cardiogenic embolism due to atrial fibrillation or cardiomyopathy, for example, is a cause of stroke in both children and adults.

DIFFERENTIALS

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Other Problems to be Considered

Trauma
Congenital heart disease
Neoplasm of the CNS

WORKUP

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Lab Studies

No specific laboratory tests are available to diagnose a clot. However, some studies of adults suggest that the newer methods to determine D-dimer levels may be useful, especially for ruling out thrombosis.

Many clotting factors are consumed in a clot, and a low factor level may be an effect rather than a cause of thrombosis.

Once a clot is documented, the patient's workup should include the following:

• CBC count with peripheral blood smears: Anemia, thrombocytopenia, and/or RBC fragments may suggest disseminated intravascular coagulation. It is important to document a normal platelet count before heparin or LMWH is started.
• Measurement of the prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level: A prolonged PT or aPTT and/or a low fibrinogen level may suggest disseminated intravascular coagulation. A prolonged aPTT at baseline may be due to the use of an inhibitor or lupus anticoagulant.
• D-dimer measurement: To the authors' knowledge, no pediatric studies have been conducted to evaluate the utility of D-dimer values in diagnosing TE. Data from several studies of adults suggest that the D-dimer level may be useful in ruling out DVT and/or PE, in conjunction with the clinical probability. Of note, children often have other systemic disorders, such as sepsis or malignancy, which may elevate D-dimer concentrations.
• First-line workup for hypercoagulation: This workup should include evaluations of the following:
• • Activated protein C resistance and/or the factor V Leiden mutation
  • Protein C
  • Free and total protein S
  • Antithrombin
  • Lupus anticoagulant (which may be screened by using the dilute Russell viper venom test)
  • Anticardiolipin antibodies
  • Prothrombin gene 20210A mutation
  • Lipoprotein (a) levels
  • Plasma homocysteine values (which can be measured after fasting or at 4 h after a loading dose of methionine 100 mg/kg)

After heparin therapy is begun, remember that it affects antithrombin, as well as protein C, protein S, and activated protein C resistance. Warfarin affects protein C, protein S, and antithrombin. Neither drug affects anticardiolipin antibodies, factor V Leiden, the prothrombin mutation, or lipoprotein(a) or homocysteine levels.

Imaging Studies

Contrast venography

Contrast venography is considered the reference standard for documenting DVT in children. Venograms are reliable in any portion of the venous system except the jugular veins. Limitations of this study include difficulty in cannulating small veins in children and the occasional patient with an allergy to the contrast medium.

Duplex ultrasonography or real-time B-mode ultrasonography with color Doppler imaging

In adults, duplex ultrasonography compares favorably with contrast venography, especially for diagnosing DVT of the lower extremities. Duplex sonography is increasing used as the primary diagnostic tool to confirm thrombosis in adults and children.

No randomized trials in children have been performed to validate its usefulness. However, one study of children with acute lymphoblastic leukemia demonstrated that ultrasonography was insensitive for DVT in the superior vena cava, subclavian veins, or brachiocephalic veins.

In vessels with thrombosis, Doppler signals are absent, and the lumen cannot be compressed with direct pressure.

Ventilation-perfusion scanning

Ventilation-perfusion (V/Q) scanning is the procedure of choice in children with suspected PE. A high-probability scan is one that shows a peripherally based perfusion defect with normal ventilation (mismatch). In adults, a high probability scan with high clinical suspicion is correctly predictive of PE 96% of the time. A difficult situation may occur when the scan is interpreted as suggesting an intermediate probability for PE; for adults with this finding, PE is ultimately proven in 33%.

In adults, pulmonary angiography is recommended as the reference standard. However, no data are available for validating either V/Q scanning or pulmonary angiography in children with suspected PE. Given that pulmonary angiography is invasive and that heavy sedation may be required in children, V/Q scanning is recommended as the diagnostic test of choice.

As an alternative, the D-dimer test may be used to help screen for clinically significant clots, as suggested by data from studies in adults. If the D-dimer level is elevated and if the V/Q scan indicates intermediate probability, spiral CT may be useful. However, this strategy has not been evaluated in children.

MRI and magnetic resonance angiography of the head

MRI and magnetic resonance angiography (MRA) of the head are probably the modalities of choice for evaluating a child with suspected CNS thrombosis. Diffusion-weighted MRI is highly sensitive for detecting hyperacute strokes in adults.

Head CT with intravenous contrast enhancement

Head CT performed with intravenous contrast material is sometimes useful for detecting sinovenous thrombosis. MRI and MRA are better than CT for detecting early arterial ischemic stroke, as CT findings are often normal.

Chest radiography

Chest radiography may be most helpful for suggesting alternative diagnoses, such as pneumonia, than for diagnosing thromboembolism. Radiographic findings are most often normal. Classic findings of PE include small pleural effusions with a wedge-shaped pleural-based opacity of pulmonary infarction. In children, pneumonia is far more common than thromboembolism.

Other Tests

ECG findings are usually normal, or only sinus tachycardia is depicted. In children, the classic findings of T-wave inversion in the right precordial leads, right-axis deviation, and an incomplete or complete bundle branch block are rarely detected as evidence of PE.

TREATMENT

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Medical Care

Initial care and evaluation should occur in a pediatric inpatient ward. Manage severe respiratory distress or neurologic deterioration in an intensive care setting.

Surgical Care

On occasion, surgical thrombectomy may be necessary, especially after major cardiac surgery or if thrombolytic agents fail or are contraindicated.

Consultations

• Pediatric hematologist and/or oncologist: A pediatric hematologist and/or oncologist should be involved in the care of all neonates, infants, and children with TE.
• Pediatric neurologist: 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 rethrombosis. 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 total parenteral nutrition.

Activity

Children with TE are usually restricted to bedrest for the first 24-48 hours to decrease the risk of PE. Children with lower-extremity DVT should be fitted for compression stockings.

MEDICATION

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For years, UFH has been recommended as the primary intravenous anticoagulant for initially managing TE in adults. Two recent studies have demonstrated equivalent efficacy and toxicity of subcutaneous LMWH and UFH.

In a similar study in children, 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 sample, but it did show equivalence with respect to risk of bleeding and recurrent VTE.

Initial anticoagulation with LMWH is being viewed as a feasible alternative in children, as in adults. Potential advantages include rapid attainment of therapeutic levels, therapy for small infants in whom intravenous access is hard to obtain, reduced heparin-induced thrombocytopenia, and reduced osteoporosis.

If thrombosis or PE is not extensive, oral anticoagulation with warfarin is started on the second or third day and continued for 3-6 months unless risk factors for rethrombosis persist. Pediatric studies have not yet been performed to identify the optimal length of therapy.

Drug Category: Heparin anticoagulants

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

Drug Name	Enoxaparin (Lovenox)
Description	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. 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 Dose	Treatment: 1 mg/kg/dose SC q12h Prophylaxis: 30 mg SC q12h
Pediatric Dose	Treatment (see Image 4) <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
Contraindications	Documented hypersensitivity; major bleeding, thrombocytopenia
Interactions	Possible increased risk of bleeding with platelet inhibitors or PO anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine)
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

Drug Name	Reviparin (Clivarine)
Description	Goal of therapy is to maintain an anti-Xa level of 0.5-1 U/mL. Potential advantages similar to those of enoxaparin. Not available in United States.
Adult Dose	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 Dose	Treatment (see Image 7): <5 kg: 150 U/kg/dose SC q12h >5 kg: 100 U/kg/dose SC q12h
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Possible increased risk of bleeding with platelet inhibitors or PO anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studies 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

Drug Category: Oral anticoagulants

Oral anticoagulants are used to prevent recurrent or ongoing TE-related occlusion. They are the mainstays of long-term outpatient therapy. 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.

Drug Category: 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.

Drug Name	Urokinase (Abbokinase)
Description	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 Dose	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 Dose	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
Contraindications	Documented hypersensitivity; internal bleeding; recent trauma; history of intracranial or intraspinal surgery or trauma; cerebrovascular stroke; intracranial neoplasm
Interactions	Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
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

Drug Name	Streptokinase (Streptase, Kabikinase)
Description	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 Dose	Systemic thrombolytic treatment: Loading dose: 250,000 U IV over 30 min Infusion: 100,000 U/h IV for 6-12 h
Pediatric Dose	Systemic thrombolytic treatment: Loading dose: 2000 U/kg IV Infusion: 2000 U/kg/h IV for 6-12 h
Contraindications	Documented hypersensitivity; active internal bleeding, intracranial neoplasm, aneurysm, diathesis, severe uncontrolled arterial hypertension
Interactions	Coadministration of antifibrinolytic agents may decrease effects; concurrent use of heparin, warfarin, and aspirin may increase risk of bleeding
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studies 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

Drug Category: Antiplatelet agents

Antiplatelet agents are used as prophylaxis of arterial thrombosis (stroke) and after Blalock-Taussig or endovascular shunt placement.

Drug Category: 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.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit patients to a pediatric or adolescent ward or intensive care unit, depending on their respiratory or neurologic status.
• Anticoagulation is begun with heparin or LMWH, followed by oral anticoagulation with warfarin-type medications. Children remain inpatients until their international normalized ratio (INR) is more than 2 on 2 successive days.
• Obtain daily CBC count, PT, and aPTT values while children are inpatients. If LMWH is used, obtain an anti–activated factor X (ie, anti-Xa) or heparin level, and adjust the dose to achieve a level of 0.5-1 U/mL.

Further Outpatient Care

Monitoring of patients receiving oral anticoagulation

For patients receiving oral anticoagulation, monitor the PT and/or INR within 3 days of their discharge from the hospital. Always check the INR 5-7 days after adjusting the dose. After the INR is 2-3 (or 2.5-3.5 in patients with mechanical valves) on 2 successive measurements obtained 1 week apart, the monitoring interval can be lengthened to every 2 weeks. Monitor the INR at least once a month.

Children taking warfarin long term (>1 y) should be monitored for decreased bone density.

Point-of-care monitoring of oral anticoagulation may be available for home use or at specialized pediatric anticoagulation clinics. Point-of-care monitoring is especially helpful for children who require indefinite oral anticoagulation as part of treatment for congenital heart disease or inherited hypercoagulable disorders.

The patient or family should inform the physician of any changes in diet or medications.

Duration of therapy

The duration of therapy depends on the underlying problem. Children with mechanical heart valves or recurrent TE require anticoagulation indefinitely. Children with TE and persistent risk factors may be treated for 3 months then switched to low-dose warfarin until the risk factor is no longer present. Uncomplicated DVT can be treated for 3-6 months.

Monitor children who are taking LMWH long term (>4 wk) with weekly CBC counts to look for heparin-induced thrombocytopenia. Also, check anti–activated factor X levels twice a month.

Enoxaparin may accumulate over time, and dosage adjustments may be necessary.

In/Out Patient Meds

• A patient's medication may include heparin or LMWH, oral anticoagulants, thrombolytic agents, and, occasionally, antiplatelet agents.
• Avoid giving antiplatelet agents to children receiving anticoagulation unless they are absolutely necessary.
• Monitor the patient's INR more closely than usual if his or her medications or diet changes.

Deterrence/Prevention

• Patients should avoid participating in contact sports and weight lifting while they are receiving anticoagulation.
• Sexually active female adolescents should use some form of birth control, preferably not oral contraceptives if they are receiving oral anticoagulants.

Complications

Potential complications of thromboembolism include the following:

• Recurrent thrombosis
• Pulmonary embolism
• Postphlebitic syndrome
• Bleeding
• Death

Prognosis

• Many children with TE have a persistent underlying risk factor, such as congenital heart disease.
• Recurrent thrombosis occurs in as many as 19% of children.
• The mortality rate associated with PE or arterial ischemic stroke is 6-20%.

Patient Education

• If a child is receiving oral anticoagulation, review the vitamin K content of various foods with the family.
• Clearly define activity restrictions, especially with adolescents.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

Because TE is uncommon and because its symptoms are often nonspecific in children, a high index of suspicion is required.

Special Concerns

• Neonatal thrombosis is a special concern.
• • Neonates have multiple risk factors for TE, including prematurity, sepsis, and frequent use of central arterial and venous lines.
  • Also, developmental differences in their hemostatic systems create difficulties in management.
  • Neonates have low levels of antithrombin and plasminogen, which cause relative resistance to heparin and thrombolytic agents, respectively.
  • In addition, newborns need 11 times the usual concentration of urokinase given to adults and 5 times the usual concentration of tissue plasminogen activator to achieve the same rate of plasminogen activation.
• To the authors' knowledge, no randomized controlled trials have been conducted to determine whether anticoagulation is superior to observation alone in neonates.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Virchow triad for the pathophysiology of thrombus formation.
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Media type:  Graph

Media file 2:  Coagulation cascade. Solid arrows represent activation events; dashed arrows, inhibition events; and dotted lines with circles, 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.
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Media type:  Image

Media file 3:  Nomogram for adjusting the dosage of heparin. Reproduced with permission from Michelson et al (1998). APTT = activated partial thromboplastin time.
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Media type:  Chart

Media file 4:  Dosing of low-molecular-weight heparins (LMWHs) in children. Reproduced with permission from Michelson et al (1998).
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Media type:  Chart

Media file 5:  Warfarin dosing in children. INR = international normalized ratio. Reproduced with permission from Michelson et al (1998).
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Media type:  Chart

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Apr 5, 2007