AUTHOR INFORMATION

Section 1 of 12

Authored by Philip M Monteleone, MD, Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania and Children's Hospital of Philadelphia

Philip M Monteleone, MD, is a member of the following medical societies: American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Edited by J Martin Johnston, MD, Consulting Staff, Department of Pediatrics, Division of Hematology-Oncology, St Luke's Mountain States Tumor Institute; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; James L Harper, MD, Associate Chair for Medical Education in Pediatrics, Associate Professor of Pediatric Hematology-Oncology, University of Nebraska Medical Center; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Philip M Monteleone, MD
Editor's Email:	J Martin Johnston, MD

eMedicine Journal, April 7 2006, VOLUME 7, Number 4

INTRODUCTION

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Background: Thromboembolism (TE) in adults is a leading cause of morbidity and mortality. Although incidence of TE in children is much lower than in adults, morbidity and mortality are still significant. Diagnosis and treatment of thrombosis in children was initially based on adult standards of care. However, since the early 1990s, pediatric data have emerged, stressing some of the differences in etiology, pathophysiology, and drug pharmacokinetics in children with TE.

In 1845, Virchow postulated 3 factors important in the development of thrombosis: impairment of blood flow (stasis), vascular injury, and alterations of the blood (hypercoagulability) (Image 1). These factors also play a role in pediatric thrombosis, with developmental differences discussed below.

Pathophysiology: The physiology of hemostasis is remarkably complex, reflecting the necessity of a fine balance between uninterrupted flow of (fluid) blood and rapid, localized responses to vascular injury (clotting). Traditionally, the processes of hemostasis are divided into cellular (platelets, vascular wall) and fluid (plasma protein) phases. The latter phase similarly is divided into 3 processes: the multiple-step zymogen pathway leading to thrombin generation, the thrombin-induced formation of a fibrin clot, and the complex fibrinolytic mechanisms aimed at limiting clot propagation (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, X, and contact factors are not approached until age 3-6 months. Similarly, inhibitors of thrombin, such as antithrombin and heparin cofactor II, are low at birth (in the range that may cause heterozygous adults to develop TE).

Alpha-2-macroglobulin levels are higher in infants and children than in adults. Conversely, protein C and S levels are low at birth. Protein S levels approach adult values by age 3-6 months, but protein C levels remain low even into childhood. In addition, plasminogen levels in the newborn and infant are low. This has a profound effect on treatment of TE in newborns. Thrombin generation is decreased (probably due to low prothrombin levels) and delayed in newborns compared to adults. Overall, in infancy, there is a greater tendency toward bleeding than TE.

Frequency:

• In the US: 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 reported an incidence of 4.2 cases per 100,000 per year for DVT. PE is seldom considered in children, but the same study noted a rate of 0.9 per 100,000 per year. PE has been found at autopsy in 3.7% of children. Strokes occur with an incidence of approximately 2.5 cases per 100,000 children per year.

• Internationally: Incidence of venous thromboembolism (VTE) was estimated by the Canadian Registry to be 0.07 per 10,000 children and 5.3 per 10,000 hospital admissions in 1994. In a German study by Nowak-Gottl et al, incidence of symptomatic neonatal TE was reported to be 5.1 per 100,000 births.

Mortality/Morbidity: In adults, mortality from untreated PE ranges from 18-30%. Even if diagnosed early, mortality is 8%. In the Canadian Registry, mortality was found to be 2.2%, 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 only 22% of the children fully recovered neurological function.

• Recurrent thromboembolism occurs in 4-7% of adults. In the Canadian Registry, 19% of children developed recurrent TE. It was speculated that this recurrence might be secondary to inadequate anticoagulation (fear of bleeding) and/or persistence of underlying risk factors such as central venous catheter (CVC). A recent German study found recurrence rates (RR) were affected by the number of underlying genetic risk factors (GRF) present. Children with no GRF had a 4.8% RR while 17.6% of those with 1 GRF had a recurrence. If they had 2 or more GRF, the risk of recurrence was almost 50%. Goldenberg et al noted an increased RR in children with VTE and elevated factor VIII and/or D-dimer levels at the end of 3-6 months of anticoagulation.

• Post-thrombotic syndrome (PTS) consists of chronically swollen, painful extremities with induration of the skin, ulceration, and pigmentary changes secondary to chronic venous stasis. Twenty to 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, a recent study from the Hospital for Sick Children in Toronto, Canada reported PTS in 63% of 153 children (83% were mild, 17% moderate). Treatment consists of elastic compression stockings, elevation of the extremity above heart level, and analgesics or narcotics, as necessary.

• Pulmonary embolism requires a high index of suspicion, as many of the early reports were based on autopsy data. Symptoms can be nonspecific, such as tachypnea, tachycardia, fever, pleuritic chest pain, cough, shortness of breath, and, less commonly, hemoptysis. Unlike adults, DVT more often is absent in children with PE. Risk factors include presence of a CVC, immobility, heart disease, ventriculoatrial shunt, trauma, cancer, surgery, infection, dehydration, shock, and obesity.

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

Age: Peak incidence is in children younger than 1 year and adolescents. If newborns are included, the highest risk period for TE is in the first year of life.

CLINICAL

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History:

• Symptoms potentially caused by DVT include the pain and swelling of acute onset. These symptoms obviously are 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 is more suspicious for thrombosis.



• Symptoms potentially due to PE include the acute onset of chest pain or shortness of breath. The chest pain from PE usually is not constant. Keep in mind that chest pain in children usually is benign. In adults, the first presentation of PE may be cardiovascular collapse, cardiac arrest, or sudden death.



• Symptoms of CNS thrombosis include vomiting, lethargy, seizures, or extremity weakness. Most strokes that occur in utero present with pathological early hand preference late in the first year of life. Neonates often present with seizures and lethargy. Older children usually present with headaches and extremity weakness of acute onset. Infection and dehydration also have been found to be common in infants and young children with CNS thrombosis.



• Renal vein thrombosis may present with flank pain and hematuria.



• Recent surgery, trauma, immobilization, or prolonged bedrest are factors that can contribute to TE. These factors have been documented most thoroughly in adults but can contribute to thrombosis in children as well.



• Look for a history or symptoms suggestive of heart disease or congestive heart failure, including dizziness, bilateral extremity swelling, and poor weight gain. Congenital heart disease and/or recent cardiac catheterization are the most common causes of arterial thrombosis in children.



• Also look for a history or symptoms suggestive of malignancy. This includes fevers, bone pain, weight loss, bruising, or fatigue. If a history of malignancy is present, inquire about central venous catheters (CVCs) and recent chemotherapy with L-asparaginase.



• Elicit a history of previous thrombosis. Similarly, obtain a thorough family history, documenting age at thrombosis as well as type of thrombosis (DVT, PE, myocardial infarction [MI], stroke).



• Estrogen-containing medications, such as oral contraceptive pills (OCPs), have been shown to increase the risk of thrombosis in adult women, including adolescents. This risk is even higher in women who are heterozygous for the factor V Leiden mutation.

Physical:

• In children, as well as adults, the physical examination often is misleading. Diagnosis of thrombosis may be missed or delayed because of the nonspecific nature of presenting signs.



• Signs of DVT include leg or arm edema, erythema, increased warmth, a palpable cord, tenderness, and positive Homans sign (pain on dorsiflexing the foot). Other important features include predisposing conditions such as CHF or heart disease, malignancy, and the presence of a CVC.



• Thrombosis of the inferior vena cava and/or renal vein(s) can cause nephromegaly and flank tenderness.



• Signs of PE also are nonspecific. They include apprehension, diaphoresis, tachycardia, and/or tachypnea. Hemoptysis seldom is present in children but 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:

• With advances in technology, premature infants and children in intensive care units have improved survival. One or more underlying risk factor is present in 95% of children with DVT/PE. Most have more than one risk factor. Therefore, perform a thorough workup, even in the face of seemingly obvious causes of TE.



• Acquired conditions


• • Arterial catheters: Central venous or arterial catheters are the most common risk factor found in children with TE. Cardiac catheterization via the femoral artery for 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, umbilical artery catheterization carries similar risks, although the absolute incidence of thrombosis ranges from 10-90% based on angiographic diagnosis.
  
  
  
  • CVC-associated thrombosis has been reported in 29% of children in one report from Denver (in Nuss et al, Childhood thrombosis from Pediatrics) and 33% of children in the Canadian series. 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 (APLA): Antiphospholipid antibodies (diagnosed by either positive lupus anticoagulant [LA] or anticardiolipin antibodies) are associated with thrombosis in both adults and children. In children with systemic lupus erythematosus (SLE), the incidence of TE was 9.2% and 17% in 2 studies. However, most children with APLA have the condition incidentally and do not have SLE. In one recent study, the cases of 95 children with LA were followed for a median of 5.3 years. Ten percent had bleeding symptoms, while 5% had a thrombotic event.
  
  
  
  • Disseminated intravascular coagulation (DIC): Sepsis and DIC 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/prolonged bedrest: These risk factors have been studied most extensively in adults and have generated recommendations regarding prophylaxis against TE. Children have a much lower risk of thrombosis with surgery, so prophylactic heparin or low molecular weight heparin is not recommended.
  
  
  
  • Malignancy: TE has been studied most extensively in children with acute lymphoblastic leukemia (ALL). Mechanisms are complex and include the effect of leukemia itself and the use of chemotherapy, especially L-asparaginase. Many of these children also are managed with CVCs.
  
  
  
  • Estrogen-containing medications: OCPs alone are associated with a 4-fold increased risk of venous thrombosis and a 22-fold increased risk of cerebral thrombosis. This risk may be explained by development of acquired resistance to activated protein C. Administration of OCPs to patients who are heterozygous for the factor V Leiden mutation increases the risk of VTE 35- to 50-fold. Those with antithrombin, protein C, or protein S deficiency taking OCPs have about a 6-fold higher risk.
  
  
  
  • Nephrotic syndrome: In children with proteinuria greater than 0.5 g/d, loss of anticoagulant proteins, such as antithrombin, has been documented, leading to an increased risk of TE. Most TEs develop within several months of diagnosis. Both arterial and venous TE can occur, with renal vein thrombosis being the most common site.
  
  
  
  • Heparin-induced thrombocytopenia: This is characterized by a greater than 50% drop in platelet count after 5 or more days of unfractionated heparin (UHF). Risk for venous TE is present mainly in adults, but a high index of suspicion is needed to recognize this in children (even if only receiving heparin flushes for intravenous or central lines).
  
  
  
• Inherited prothrombotic disorders: Several dominantly inherited deficiencies or abnormalities of proteins in the coagulation and fibrinolytic pathways now are recognized. On occasion, more than one such abnormality may coexist in a single patient. Furthermore, the expression of these abnormalities (ie, the development of a clot) frequently reflects the additive effects of acquired risk factors: orthopedic surgery or trauma, immobility, pregnancy, OCPs, dehydration, etc.


• • Factor V Leiden: Resistance to activated protein C is the most common genetic risk factor associated with venous thrombosis in adults and children. The majority of cases are due to a point mutation in the factor V gene (factor V Leiden [FVL]), which prevents the cleavage of activated factor V by activated protein C, thus promoting ongoing clot development. Approximately 3-8% of white adults are heterozygous for the mutation, but many of these individuals have no history of thrombosis. Several pediatric studies have demonstrated that, as in adults, 10-50% of children with thrombosis are heterozygous for the FVL mutation. Double heterozygotes with FVL and protein C, protein S, or antithrombin deficiency have been reported with further increased risk of thrombosis. Women heterozygous for FVL who also are taking OCPs increase their risk of thrombosis 35-fold.
  
  
  
  • Antithrombin (AT) deficiency: Produced in the liver, antithrombin is the most important inhibitor of activated clotting factors. Most patients with AT deficiency are heterozygous (levels <50%), and thrombosis usually is venous. Thrombosis can occur in children as young as 10 years. Homozygous deficiency of AT is rare but devastating. Presentation usually is within hours of birth, and patients have extensive thrombosis. Most infants die soon after birth.
  
  
  
  • Protein C deficiency: This usually is transmitted in an autosomal dominant manner with incomplete penetrance. Thrombosis also is most often venous, in the lower extremities. DVT in heterozygotes can be seen as early as the teenage years. As with AT deficiency, homozygotes with PC deficiency usually present in the newborn period with purpura fulminans. A purified protein C concentrate is being studied as treatment in these children.
  
  
  
  • Protein S deficiency: Similar to Protein C and AT deficiency except that patients have a greater predisposition to arterial thrombosis. Most of PS is bound to C4-binding protein so one must measure both free and total PS to rule out a deficiency. Patients with either PC or PS deficiency can develop warfarin-induced skin necrosis unless heparin is started first.
  
  
  
  • Hyperhomocystinemia (HHC) has been shown in adults to be an independent risk factor for arterial vascular disease and venous thrombosis. One study of 45 children with ischemic stroke found an odds ratio for moderate HHC of 4.4 (versus controls). A German study of 163 children with VTE found a 3-fold increased risk in those with elevated fasting homocysteine levels. Homozygous mutations in the gene for cystathionine beta synthetase (CBS) are rare but account for most cases of severe HHC. Mild-to-moderate HHC can be seen in heterozygotes with CBS or methylene tetrahydrofolate reductase mutations.
  
  
  
  • Prothrombin gene 20210A mutation (PGM): A Turkish study of 32 children with cerebral infarcts reported that 21.8% were heterozygous for the PGM. Recent studies have shown the PGM to be a risk factor in pediatric arterial thrombosis, especially in the central nervous system.
  
  
  
  • Elevated lipoprotein (a) has also 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 is negative. Also, recent studies in adults have implicated elevated levels of factor VIII and XI as risk factors for thrombosis. They have not been explored in children yet.
  
  
  
• Congenital heart disease (CHD): This includes children with mechanical or prosthetic valves and those undergoing Blalock-Taussig shunt or Fontan procedure. As noted above, cardiac catheterization is the most common risk factor for arterial thrombosis. Cardiogenic embolism due to, for example, atrial fibrillation or cardiomyopathy, is one cause of stroke in both children and adults.

DIFFERENTIALS

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Acute Lymphoblastic Leukemia
Acute Myelocytic Leukemia
Antiphospholipid Antibody Syndrome
Cardiomyopathy, Hypertrophic
Consumption Coagulopathy
Head Trauma
Meningitis, Bacterial
Nephrotic Syndrome
Pneumonia
Vasculitis and Thrombophlebitis

Other Problems to be Considered:

Trauma
Sepsis
Baker cyst
Congenital heart disease
Atrial fibrillation
Neoplasm, central nervous system

WORKUP

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Lab Studies:

• No specific laboratory tests exist that diagnose the presence of a clot. However, some adult studies suggest that the newer methods to determine D-dimer may be useful, especially in ruling out thrombosis.



• Clinicians must recognize that many of the clotting factors are consumed in a clot and a low factor level may be an effect of thrombosis rather than a cause. Once a clot is documented, the workup should include the following:


• • Complete blood count with peripheral blood smear: Anemia, thrombocytopenia, and/or red cell fragments may suggest DIC. It is important to document a normal platelet count before starting a patient on heparin or low-molecular weight heparin.
  
  
  
  • Prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and/or low fibrinogen may suggest DIC. Prolonged aPTT at baseline also may be due to an inhibitor or lupus anticoagulant.
  
  
  
  • D-dimer: No pediatric studies have evaluated the utility of D-dimer in diagnosis of TE. Several adult studies suggest that it may be useful in ruling out DVT/PE (in conjunction with clinical probability). However, children often have other systemic disorders, such as sepsis or malignancy, which may elevate the D-dimer.
  
  
  
  • First-line hypercoagulable workup should include activated protein C resistance (APCR) and/or FVL mutation, protein C, protein S (free and total), antithrombin, lupus anticoagulant (may be screened with the dilute Russell viper venom test), anticardiolipin antibodies, prothrombin gene 20210A mutation, lipoprotein (a), and plasma homocysteine (can be measured fasting or 4 hours after loading with 100 mg/kg methionine).
  
  
  
• Once heparin therapy is begun, keep in mind that it affects protein C, protein S, activated protein C resistance, and antithrombin. Warfarin affects protein C, protein S, and antithrombin. Neither drug affects anticardiolipin antibodies, FVL, prothrombin mutation, lipoprotein (a), or homocysteine levels.

Imaging Studies:

• Contrast venography: This 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 include difficulty cannulating small veins in children and the occasional allergy to radiocontrast media.



• Duplex ultrasonography (or real-time B-mode ultrasonography with color Doppler): In adults, duplex ultrasonography (US) compares favorably with contrast venography, especially when diagnosing DVT of the lower extremities. It is being used more often as the primary diagnostic tool to confirm the diagnosis of 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 found that US was insensitive for picking up DVT in the superior vena cava, subclavian, or brachiocephalic veins. In vessels with thrombosis, Doppler signals are absent, and the lumen cannot be compressed with direct pressure.



• Ventilation-perfusion scanning


• • This is the procedure of choice in children with suspected PE. A high-probability scan shows a peripherally based perfusion defect with normal ventilation (mismatch). In adults, a high probability scan with high clinical suspicion correctly predicts PE 96% of the time. A more difficult situation occurs when the scan is read as intermediate probability for PE. In that setting, only 33% of adults ultimately prove to have PE.
  
  
  
  • In adults, pulmonary angiography (PA) is recommended as the reference standard. However, no data exist to validate either V/Q scanning or PA in children with suspected PE. Given that PA is invasive and may require heavy sedation in children, V/Q scanning is recommended as the diagnostic test of choice.
  
  
  
  • Alternatively, adult studies have suggested using the D-dimer test to help screen for significant clot. If the D-dimer is elevated and the ventilation-perfusion (V/Q) scan is intermediate probability, then spiral CT may be useful. However, this strategy has not been evaluated in children.
  
  
  
• MRI and magnetic resonance angiography (MRA) of the head: These are probably the modalities of choice for evaluating a child with suspected CNS thrombosis. Diffusion-weighted MRI has been shown to be very sensitive in detecting hyperacute strokes in adults.



• CT of the head with IV contrast: This is sometimes useful for detecting sinovenous thrombosis. MRI and MRA are better at picking up early arterial ischemic stroke (CT findings are often normal).



• Chest radiography: This may actually be more helpful in suggesting alternative diagnoses, such as pneumonia. Findings are most often normal. Classic findings of PE include small pleural effusions with a wedge-shaped pleural-based density of pulmonary infarction. Again, pneumonia is far more common in children.

Other Tests:

• ECG: Findings are usually normal, or only sinus tachycardia is depicted. The classic findings of T-wave inversion in the right precordial leads, right axis deviation, and incomplete or complete bundle branch block rarely can be seen in children as evidence for PE.

TREATMENT

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Medical Care:

• Initial management and evaluation should occur in a pediatric inpatient ward.



• Manage severe respiratory distress or neurologic deterioration in an intensive care setting.

Surgical Care: Occasionally, surgical thrombectomy may be necessary, especially following major cardiac surgery or when thrombolytic agents have failed or are contraindicated.

Consultations:

• Pediatric hematology/oncology should be involved in the care of all neonates, infants, and children with TE.



• Pediatric neurology should be involved in the care of children with suspected or proven CNS thrombosis.

Diet: Vitamin K interferes directly with the effectiveness of warfarin, potentially increasing the risk for rethrombosis.

• Daily intake of foods high in vitamin K, such as green leafy vegetables, should be kept at a consistent level (ie, eating similar amounts of vitamin-K rich foods each day).



• Maternal intake of vitamin K also can affect levels in breast milk and cause similar problems in infants. Supplementing 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 usually are restricted to bedrest for the first 24-48 hours to decrease the risk of PE. Children with lower-extremity DVT also should be fit with compression stockings.

MEDICATION

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Unfractionated heparin (UFH) has been recommended for years as the primary intravenous anticoagulant in the initial management of adults with TE. Two recent studies have demonstrated equivalent efficacy and toxicity of subcutaneous (SC) low molecular weight heparins (LMWH) compared with UFH.

A similar study in children compared SC reviparin with UFH followed by oral warfarin (Reviparin in childhood venous thromboembolism [REVIVE] trial). The study was limited by small sample size, but it did show equivalence with respect to risk of bleeding and recurrent VTE. As with adults, initial anticoagulation with LMWH is being viewed as a viable alternative. Potential advantages include rapid attainment of therapeutic levels, use in small infants with difficult IV access, less heparin-induced thrombocytopenia (HIT), and less osteoporosis. Unless an extensive thrombosis or PE is present, oral anticoagulation with warfarin is started on the second or third day and continued for 3-6 months unless risk factors for rethrombosis persist. No pediatric studies identifying the optimal length of therapy have been performed.

Drug Category: Heparin anticoagulants -- Inhibition of thrombin prevents formation and/or extension of thrombus, thus allowing recanalization of the blood vessel over time.

Drug Name	Unfractionated heparin sodium -- Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents re-accumulation of clot after spontaneous fibrinolysis. Usually started as initial treatment of TE. The dose is titrated to keep aPTT 60-85 sec (see Image 3). Monitor CBC, PT, and aPTT daily once the aPTT is therapeutic. Stopping the infusion usually is sufficient for reversal. If rapid reversal is needed, administer protamine (dose based on amount of heparin received in previous 2 h); if <30 min since last heparin dose, administer 1 mg per 100 mg heparin received, not to exceed 50 mg IV over 10 min.
Adult Dose	Initial dose: 40-170 U/kg IV Maintenance infusion: 18 U/kg/h IV; alternatively, 50 U/kg/h IV initially, followed by continuous IV infusion of 15-25 U/kg/h and increase dose by 5 U/kg/h q4h prn using aPTT results
Pediatric Dose	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
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not for IM use; development of thrombocytopenia should prompt testing for antibodies (HIT) because of increased risk of bleeding and progression of thrombosis

Drug Name	Enoxaparin (Lovenox) -- Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa. Goal of therapy is to maintain an anti-Xa level of 0.5-1 U/mL. May be used like UFH for 5-7 d until PO anticoagulation yields INR >2. Alternatively, LMWH may be continued for the entire 3-6 mo of treatment. Stopping the drug usually is sufficient for reversal. If rapid reversal is needed, administer protamine; if <3-4 h since last LMWH dose, administer 1 mg per 1 mg (or 100 U) LMWH received to maximum of 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 such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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 cause delayed elimination; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia, recommend holding 2 doses prior to LP or surgery; cannot be used interchangeably (unit for unit) with heparin or other LMWH

Drug Name	Reviparin (Clivarine) -- Goal of therapy is to maintain an anti-Xa level of 0.5-1 U/mL. Similar potential advantages as 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 4): <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 such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine
Pregnancy	C - Safety for use during pregnancy has not been established.
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 cause delayed elimination; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia, recommend holding 2 doses before LP or surgery; cannot be used interchangeably (unit for unit) with heparin or other LMWH

Drug Category: Oral anticoagulants -- Used to prevent recurrent or ongoing thromboembolic occlusion. They are the mainstay of long-term outpatient management. Oral anticoagulants competitively interfere with vitamin K metabolism, thus decreasing plasma concentrations of the active forms of factor II, VII, IX, and X. Infants and children tend to require higher maintenance doses and more frequent dosage adjustments than adults. Besides warfarin (discussed below), phenprocoumon and acenocoumarol have been used.

Drug Name	Warfarin (Coumadin) -- Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Used for long-term anticoagulation. Warfarin has a half-life of 36-42 h. More difficult to monitor (PT/INR) in children because of variability in dietary vitamin K intake, effects of other medications, and age.
Adult Dose	5-15 mg/d PO qd initially; adjust dose according to desired INR
Pediatric Dose	Loading dose: 0.2 mg/kg/d PO; adjust per nomogram (see Image 5) Infants: 0.31 mg/kg/d PO average 1-5 years: 0.16 mg/kg/d PO 6-10 years: 0.13 mg/kg/d PO
Contraindications	Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Interactions	Possible decreased anticoagulant effects with coadministration of griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; possible increased anticoagulant effects 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, and sulindac
Pregnancy	X - Contraindicated in pregnancy
Precautions	Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or protein S deficiency are at risk of developing skin necrosis

Drug Category: Thrombolytic agents -- These convert plasminogen to plasmin, leading to clot lysis. Pediatric indications are not established. Because of developmental differences in the hemostatic system, infants require much higher doses to generate the same amount of plasmin as adults. Used most frequently for blocked central catheters and less often for PE and stroke.

Drug Name	Alteplase (Activase) -- Recombinant tissue plasminogen activator. DOC for thrombolysis, given the current shortage of urokinase. Specific fibrin-bound plasminogen activator. Limited pediatric data exist. Several small series of infants and neonates with large vessel thromboses used a wide range of doses from 0.01-0.5 mg/kg/h IV. Intracranial hemorrhage was observed at doses of 0.4 mg/kg and higher.
Adult Dose	Blocked CVLs: >30 kg: Instill 2 mg (concentration 1 mg/mL), dwell 30 min, if catheter function not restored, allow 90 additional min of dwell time (120 min total); if needed, may repeat process once Pulmonary embolism: 100 mg IV infused over 2 h
Pediatric Dose	Blocked CVLs: Bolus: Instill 0.01-0.5 mg/kg (concentration 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
Contraindications	Documented hypersensitivity; major surgery during the last 10 d; history of severe bleeding (intracranial, pulmonary, GI)
Interactions	Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage should be adjusted to maintain fibrinogen >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

Drug Name	Urokinase (Abbokinase) -- Direct plasminogen activator that acts on the endogenous fibrinolytic system and converts plasminogen to the enzyme plasmin, which, in turn, degrades fibrin clots, fibrinogen, and other plasma proteins. Until recent shortage, this was the drug most often used to clear blocked CVLs. Low-dose infusions (200 U/kg/h) do not cause systemic fibrinolysis.
Adult Dose	Blocked CVLs: 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 CVLs: 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 much higher 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 - Usually safe but benefits must outweigh the risks.
Precautions	Patients receiving IM administration of medications; patients with severe hypertension, trauma or surgery in previous 10 d; avoid dislodging a possible deep vein thrombi, do not measure blood pressure in lower extremities; monitor therapy by performing PT, aPTT, TT or fibrinogen approximately 4 h after initiation of therapy;

Drug Name	Streptokinase (Streptase, Kabikinase) -- Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. Increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with intravenous infusion of streptokinase. First thrombolytic agent used in children, also the cheapest. Usage limited by potential for allergic reactions.
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	Possible decreased effects with coadministration of antifibrinolytic agents; possible increased risk of bleeding with concurrent use of heparin, warfarin, and aspirin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage should be adjusted to maintain fibrinogen over 100 mg/dL; caution in severe hypertension, IM administration of medications, trauma or surgery in previous 10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen levels before therapy is implemented; either TT or aPTT should be less than twice normal control value following infusion of streptokinase and before (re)instituting heparin; do not take blood pressure in the lower extremities as it may dislodge possible deep vein thrombi; PT, aPTT, TT or fibrinogen should be monitored 4 h after initiation of therapy

Drug Category: Antiplatelet agents -- Used as prophylaxis after Blalock-Taussig shunts, endovascular stents, and to prevent recurrence of arterial thrombosis (stroke).

Drug Name	Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin) -- Used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Irreversibly inactivates cyclooxygenase, ultimately preventing thromboxane A2 production in platelets. Platelet function does not fully recover until new platelets are made. This takes 7-10 d.
Adult Dose	Minimum effective antiplatelet dose: 50-100 mg/d PO
Pediatric Dose	Prophylaxis: 1-5 mg/kg/d PO Kawasaki disease: 80-100 mg/kg/d for first 14 d, then 3-5 mg/kg/d for 7 wk or longer if evidence of coronary artery narrowing is present
Contraindications	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
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose lowering effect of sulfonylurea drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in third trimester; may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients taking anticoagulants and patients with severe anemia or history of blood coagulation defects

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Admit patients to a pediatric/adolescent ward or ICU depending on respiratory or neurologic status.



• Anticoagulation is begun with heparin or LMWH, followed by institution of oral anticoagulation with warfarin-type medications. Children remain inpatient until the international normalized ratio (INR) is maintained greater than 2 for 2 successive days.



• Obtain daily CBC, PT, and aPTT while children are inpatient. If using LMWH, obtain an anti-activated factor X (anti-Xa) or heparin level, and adjust the dose to achieve a level of 0.5-1 U/mL.

Further Outpatient Care:

• For patients on oral anticoagulation, monitor PT/INR within 3 days of discharge from the hospital. Always check an INR 5-7 days after adjusting the dose. Once the INR is 2-3 (or 2.5-3.5 for mechanical valves) on 2 successive occasions a week apart, the interval can be lengthened to every 2 weeks. Monitor the INR a minimum of once a month.


• • Children on long-term warfarin (> 1 y) should be monitored for decreased bone density.
  
  
  
  • Point-of-care monitoring of oral anticoagulation may be available for home or in specialized pediatric anticoagulation clinics. This is especially true for children who require indefinite oral anticoagulation for CHD or inherited hypercoagulable disorders.
  
  
  
  • The patient should inform the physician of any changes in diet or medications.
  
  
  
• Duration of therapy varies, depending 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 on long-term LMWH (greater than 4 weeks) with weekly CBC (looking for heparin-induced thrombocytopenia) and twice monthly anti-Xa levels. Enoxaparin may accumulate over time necessitating dose adjustments.
  
  
  

In/Out Patient Meds:

• Medications include heparin or LMWH, oral anticoagulants, thrombolytic agents, and occasionally, antiplatelet agents.



• Avoid antiplatelet agents in children on anticoagulation unless absolutely necessary.



• Monitor INR more closely if changes in medications or diet occur.

Deterrence/Prevention:

• Avoid contact sports and weightlifting while on anticoagulation.



• Sexually active adolescent girls on oral anticoagulants should use some form of birth control, preferably not OCPs.

Complications:

• Recurrent thrombosis



• Pulmonary embolism



• Postphlebitic syndrome



• Bleeding



• Death

Prognosis:

• Many children with TE have an underlying risk factor that is persistent, such as CHD.



• Recurrent thrombosis occurs in as many as 19% of children.



• Mortality from PE or arterial ischemic stroke is 6-20%.

Patient Education:

• Review vitamin K content of various foods with the family of a child on oral anticoagulation and clearly define activity restrictions (especially with adolescents).

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

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

Special Concerns:

• Neonatal thrombosis: Neonates have multiple risk factors for TE, including prematurity, sepsis, and the frequent use of central arterial and venous lines. Also, developmental differences in the hemostatic system create difficulties in management. Neonates have lower levels of antithrombin and plasminogen, which causes a relative resistance to heparin and thrombolytic agents, respectively. Newborns need 11 times the usual concentration of urokinase and 5 times the usual concentration of tissue plasminogen activator to achieve the same rate of plasminogen activation as an adult.


• • No randomized controlled trials exist to determine whether anticoagulation is superior to observation alone in neonates.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: A previously healthy 6-year-old boy presents with thrombosis of transverse and superior sagittal sinuses and an activated partial thromboplastin time (aPTT) of 56 seconds. Which of these risk factors is most likely present?

A: Factor V Leiden
B: Antiphospholipid antibody (APLA) syndrome
C: Trauma
D: Homozygous protein C deficiency
E: Congenital heart disease

The correct answer is B: Although a normal aPTT does not rule out a lupus anticoagulant (LA), APLA should be suspected in children when the aPTT is prolonged. Most of these children present after a recent upper respiratory viral infection and do not have systemic lupus erythematosus. Testing for both LA and anticardiolipin antibodies (ACA) should be performed as soon as possible as they are often transient. LA and ACA are the most common risk factors found in children with CNS thrombosis.

CME Question 2: An 8-year-old girl with acute lymphoblastic leukemia (ALL) presents 3 weeks into induction with a swollen left arm for 2 days. She has a percutaneously inserted central catheter in the left antecubital fossa. Which chemotherapy drug may have contributed to the development of a deep venous thrombosis?

A: Intrathecal methotrexate
B: Prednisone
C: Vincristine
D: L-asparaginase
E: Doxorubicin

The correct answer is D: L-asparaginase interferes with protein synthesis by depleting asparagine. Synthesis of most of the procoagulant and anticoagulant proteins is diminished. Patients are at risk for both bleeding and thrombosis. In addition, many of these children have other risk factors for thromboembolism, such as central venous catheters.

Pearl Question 1 (T/F): Protein C deficiency is the most common genetic risk factor for thrombosis in children.

The correct answer is False: Heterozygosity for the factor V Leiden mutation is the most common genetic risk factor, found in approximately 13-52% of children with thromboembolism and in as many as 31% of children with CNS thrombosis. Protein C deficiency has been found in 3-5% of children with thrombosis.

Pearl Question 2 (T/F): Heparin or low molecular weight heparin are the 2 drugs most often used in the initial treatment of children with deep venous thrombosis or pulmonary embolism.

The correct answer is True: Unfractionated heparin sodium or low molecular weight heparin (enoxaparin or reviparin) are the most common drugs started when a thrombus is found. Inhibition of thrombin prevents formation and/or extension of thrombus, thus allowing recanalization of the blood vessel over time.

Pearl Question 3 (T/F): No differences exist in the hemostatic system of infants and children, compared with adults.

The correct answer is False: Infants and children have lower levels of antithrombin, plasminogen, protein C, and protein S; higher levels of alpha-2-macroglobulin; decreased and delayed thrombin generation.

Pearl Question 4 (T/F): Venography is the best test to diagnose upper extremity deep venous thrombosis (DVT) in children with central venous catheters (CVCs).

The correct answer is True: Venography is still the standard in children. Venograms are reliable in any portion of the venous system. Limitations include difficulty cannulating small veins in children and the occasional allergy to radiocontrast media.

PICTURES

Section 11 of 12

Caption: Picture 1. Thromboembolism. Virchow triad. Pathophysiology of thrombus formation.
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Caption: Picture 2. Thromboembolism. Coagulation cascade. Solid lines with arrows represent activation events; dashed lines with arrows represent inhibition events; dotted lines with circles represent inactivation events. Abbreviations: F, factor; a, active; TM, thrombomodulin; PL, phospholipid; HMW, high molecular weight; APC, activated protein C; XL, crosslinked; FDP, fibrin degradation products.
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Caption: Picture 3. Thromboembolism. Nomogram for adjusting heparin dose. Reproduced with permission from Chest 1998; 114: 748S-769S.
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Caption: Picture 4. Thromboembolism. Dosing of low-molecular-weight heparins in children. Reproduced with permission from Chest 1998; 114: 748S-769S.
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Caption: Picture 5. Thromboembolism. Warfarin dosing in children. Reproduced with permission from Chest 1998; 114: 748S-769S.
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Section 12 of 12

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