Pediatric Thromboembolism 

Updated: May 23, 2019
Author: Scott C Howard, MD; Chief Editor: Hassan M Yaish, MD 

Overview

Background

Thromboembolism, or the development of a clot within blood vessels, can occur in arteries or veins. Venous thromboembolism, a leading cause of adult morbidity and mortality, has a lower incidence in children than in adults and carries significant morbidity in both. Arterial thromboembolism is less common in children and will be briefly addressed in this article. (See Epidemiology and Prognosis.)

In 1845, Virchow postulated that three factors were important in the development of thrombosis: (1) impairment of blood flow (stasis), (2) vascular injury, and (3) alterations of the blood (hypercoagulability). The Virchow triad still holds true to some extent in addressing the etiology of thrombosis in adults and children (see the diagram below). (See Etiology.)

Virchow triad for the pathophysiology of thrombus Virchow triad for the pathophysiology of thrombus formation.

A high index of suspicion for thromboembolism is required for timely diagnosis; indeed, many early reports on this condition were based on autopsy data. Symptoms of pulmonary embolism (PE) can be nonspecific and may include tachypnea, tachycardia, fever, pleuritic chest pain, cough, shortness of breath, and (less commonly) hemoptysis. Deep venous thrombosis (DVT) is absent in children with PE more often than it is in adults. (See Presentation and Workup.)

Risk factors for thromboembolism include the presence of a central venous catheter, immobility, heart disease, a ventriculoatrial shunt, trauma (especially fractures), cancer, surgery, infection, dehydration, shock, estrogen-containing contraceptives, pregnancy, smoking, and obesity. (See Etiology.)[1]

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 that stress differences in thromboembolism etiology, pathophysiology, and anticoagulant drug pharmacokinetics in children. (See Etiology, Presentation, Workup, Treatment, and Medication.)

Physiology

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

The process of hemostasis is traditionally divided into a cellular phase (primary hemostatic phase) and a fluid phase (secondary hemostatic phase). The former involves platelets and the vascular wall, and the latter involves plasma proteins.

The fluid phase is divided into the following 3 processes, abnormalities in any of which can contribute to hypercoagulable or hypocoagulable states (see the diagram below):

  • The multiple-step zymogen pathway that leads to thrombin generation

  • Thrombin-induced formation of a fibrin clot

  • Complex fibrinolytic mechanisms aimed at limiting clot propagation

    Coagulation cascade. Solid arrows represent activa Coagulation cascade. Solid arrows represent activation events, dashed arrows represent inhibition events, and dotted lines with circles represent inactivation events. a = active; APC = activated protein C; F = factor; FDP= fibrin degradation products; HMW = high molecular weight; PAI-1 = plasminogen activator inhibitor-1; PL = phospholipid; TM = thrombomodulin; t-PA = tissue type plasminogen activator; u-PA = urokinase plasminogen activator; XL= crosslinked.

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 age 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 increase the risk for heterozygous adults to develop thromboembolism.

levels of alpha-2-macroglobulin are higher in infants and children than in adults. Conversely, levels of protein C and S are low at birth. Protein S levels approach adult values by age 3-6 months, but protein C levels remain low even into childhood. Plasminogen levels are low in newborns and infants, which has implications for treatment of thromboembolism in newborns. Thrombin generation is decreased (probably because of low prothrombin levels) and delayed in newborns, who have a higher risk for bleeding relative to adults.

Patient education

Clearly define activity restrictions, especially in the case of adolescents. If a child is receiving oral anticoagulation, review the vitamin K content of various foods with the family. The proper fitting and need for daily use of compression stockings to prevent post-thrombotic syndrome after lower extremity venous thrombosis must be emphasized. After venous thrombosis occurs, the recurrence risk can be minimized by avoiding additional risk factors, so patients should receive education focused on reducing obesity, avoiding smoking, avoiding oral contraceptives, and, during pregnancy, close monitoring or (if needed) prophylactic therapy.

Etiology

Advances in technology have improved the survival of infants who are born prematurely and of children in intensive care units (ICUs). Approximately 95% of children with DVT and/or PE have one or more underlying risk factors; most have more than one. (A study by Ishola et al reported that 81% of adolescents with thromboembolism had two or more risk factors/comorbidities.[2] ) Therefore, a thorough evaluation is warranted, even when the cause of thromboembolism seems obvious.

A study by Yen et al indicated that in pediatric trauma patients, independent risk factors for venous thromboembolism include older age, blood transfusion, surgery, a higher Injury Severity Score, and a lower Glasgow Coma Scale score.[3]

Use of arterial catheters

The use of arterial catheters is the most common risk factor for arterial thromboembolism in children. Cardiac catheterization through the femoral artery to manage congenital heart disease is a frequent cause.

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 umbilical artery poses risks similar to these. The absolute incidence of thrombosis is 10-90% when angiographic diagnostic methods are used.

Use of central venous catheters

Central venous catheter–associated thrombosis was reported in 29% of children in a report by Nuss et al and in 33% of children in a Canadian series.[4] Thrombosis is associated with a central venous catheter in 80% of newborns and 50% of children with upper extremity thrombosis.[5]

According to a study by Sandoval et al, the incidence of clinically evident DVT in hospitalized children increased from 0.3 cases to 28.8 cases per 10,000 hospital admissions between 1992 and 2005, with central venous catheters accounting for 45% of DVTs that developed during the patient’s hospital stay (vs those that were already present on admission).[6]

Antiphospholipid antibody syndrome

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

In one study, in which 95 children with lupus anticoagulant were followed for a median of 5.3 years, bleeding symptoms were found in approximately 10% of these children, while 5% had a thrombotic event.

Disseminated intravascular coagulation

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

Surgery, immobilization, and prolonged bedrest

The effects of surgery, immobilization, and prolonged bed rest on thromboembolism risk have been studied extensively in adults, and evidence-based recommendations for prophylaxis against thromboembolism have been widely disseminated.

Compared with adults, children have a much lower risk of thrombosis after surgery. Therefore, prophylactic administration of heparin or low-molecular-weight heparin (LMWH) is not recommended for children unless additional risk factors are present (eg, obesity, oral contraceptive use, cancer, central venous catheter).[7]

Malignancy

Malignancy-associated thromboembolism 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 treatment with L-asparaginase. In addition, permanent central venous catheters are placed in many children with malignancies.

A Canadian study, by Pelland-Marcotte et al, reported that in patients below age 15 years with hematologic malignancy, risk factors for the development of thromboembolism include age less than 1 year, age 5-9.99 years, or age 10-14.99 years; hematopoietic stem cell transplantation; anthracyclines; and asparaginase. In children under age 15 years with solid tumors, thromboembolism risk factors include obesity, surgical treatment, radiotherapy, anthracyclines, and platinum drugs.[8]

Use of estrogen-containing medications

Oral contraceptives, especially those that contain estrogen, 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 venous thromboembolism 35-fold to 50-fold. In women with antithrombin, protein C, or protein S deficiency who are taking oral contraceptives, the risk rises 6-fold.

However, the absolute risk is only 0.3% per year, and pregnancy itself produces a prothrombotic state; thus, benefits must be weighed against risks when helping patients to decide whether or not to use contraceptives and which method to choose.

Nephrotic syndrome

Children with proteinuria at levels of more than 0.5 g/day may have a loss of anticoagulant proteins (eg, antithrombin), which increases the risk of thromboembolism. Most thromboembolisms develop within several months of diagnosis. Arterial thromboembolism and venous thromboembolism 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 from the base line after a patient is given unfractionated heparin for 5 days or longer; this is less common in patients treated with LMWH.

Heparin-induced thrombocytopenia can be complicated by venous and arterial thrombosis, so a high index of suspicion is needed to recognize this syndrome in children, including those who are receiving only heparin flushes to maintain the patency of intravenous or central lines. Management includes cessation of all forms of heparin and administration of a direct thrombin inhibitor until the platelet count normalizes and the patient can be transitioned to warfarin anticoagulation.

Inherited prothrombotic disorders

Several dominantly inherited deficiencies or abnormalities of proteins involved in the coagulation and fibrinolytic pathways are now recognized. Occasionally, more than 1 such abnormality may coexist in a single patient. The risk of venous thromboembolism in patients with these abnormalities depends not only on the number of concomitant inherited risk factors but also on the number of acquired risk factors such as orthopedic surgery or trauma, immobility, pregnancy, use of oral contraceptives, and dehydration.

Factor V Leiden

Resistance to activated protein C due to a point mutation in factor V (named factor V Leiden, after the city in which the discovery was made) is the most common genetic risk factor associated with venous thrombosis in adults and children. This mutation prevents cleavage of activated factor V Leiden by activated protein C and thus promotes ongoing clot development.

Approximately 3-8% of whites 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. Heterozygous factor V Leiden mutation is associated with a seven-fold increase in the incidence of thrombosis.

Double heterozygotes for factor V Leiden and for protein C, protein S, or antithrombin deficiency have been reported; these individuals have a further increase in their risk of thrombosis.

Among women who are heterozygous for factor V Leiden who also are taking oral contraceptives, the risk of thrombosis rises 35-fold. Even so, very few develop thrombosis during adolescence, and usually only do so when additional risk factors are present.

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 (Ceprotin) has been designated as an orphan drug for the treatment of protein C deficiency.

Patients with either protein C or protein S deficiency (both are vitamin-K dependent) who require anticoagulation can develop warfarin-induced skin necrosis unless heparin is started first.

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, even though the free protein S is the one that plays a role as anticoagulant.

As stated above, warfarin-induced skin necrosis can occur in patients with either protein C or protein S deficiency who require anticoagulation, 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 moderate hyperhomocysteinemia, in comparison with control subjects, was 4.4, indicating that it is a risk factor for pediatric venous thrombosis as well.

A German study of 163 children with venous thromboembolism showed a 3-fold increase in the risk for this condition among subjects with elevated fasting homocysteine levels.[9] Homozygous mutations in the gene for cystathionine beta synthetase, although rare, 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.[10] Studies have shown that this mutation increases the risk for pediatric arterial thrombosis, especially in the central nervous system (CNS).

Elevated lipoprotein(a) levels

Elevated lipoprotein(a) levels have been found in children with thromboembolism. Other disorders, such as dysfibrinogenemia and plasminogen deficiency, are rare but should be evaluated for if the rest of the workup yields negative results.

Factors VIII and XI

Studies in adults have implicated elevated levels of factor VIII and factor XI as risk factors for thrombosis, but whether they are risk factors in children is unknown.

Congenital heart disease

Congenital heart disease can be a thromboembolic risk factor for children with mechanical or prosthetic valves and for 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 is a cause of stroke in children and adults.

A study by Yamamura et al suggested that in patients with concurrent congenital heart disease and asplenia, thromboembolism is more likely to develop during management of the disease than it is in patients who have congenital heart disease but are not asplenic. The study involved 161 patients with congenital heart disease who underwent cardiac catheterization; 46 of the patients had asplenia, and 115 patients did not.[11]

The investigators found that, unlike the patients without asplenia, those who were asplenic had persistent thrombocytosis. There was also a higher incidence of thromboembolic complications in the asplenic patients than in the nonasplenic group (28% vs 10%, respectively). The finding emphasizes the fact that in children, usually multiple risk factors must be present to lead to a significant incidence of thrombosis.

Epidemiology

Occurrence in the United States

The rate of venous thromboembolism in pediatric tertiary care hospitals reportedly underwent a significant increase between 2001 and 2007. A study by Raffini et al found that the annual rate grew from 34 to 58 cases per 10,000 hospital admissions, a rise of 70%. According to the report, the increased rate encompassed newborns, infants, children, and adolescents.[12, 13]

International occurrence

In a German study, by Nowak-Gottl et al, the incidence of symptomatic neonatal thromboembolism was 5.1 cases per 100,000 births.[14]

In the aforementioned Canadian study by Pelland-Marcotte et al, the investigators reported that a clinically significant thromboembolism developed in 4% of children under age 15 years with cancer, as calculated using a population-based cohort.[8]

Race-, sex-, and age-related demographics

Although some prothrombotic risk factors are more common in particular racial groups, overall there is no evidence to suggest that children of any particular race are at higher risk for thromboembolism. With regard to sex predilection, male and female children are equally affected by thromboembolism.

The incidence of thromboembolism peaks in newborns and infants younger than 1 year, then remains very low until adolescence, when the incidence begins to increase.[12]

Prognosis

Potential complications of thromboembolism include the following:

  • Recurrent thrombosis

  • Pulmonary embolism

  • Postthrombotic syndrome

  • Bleeding

  • Death

Many children with thromboembolism have a persistent underlying risk factor, such as congenital heart disease.

Recurrent thromboembolism

Recurrence may occur secondary to inadequate anticoagulation because of a concern about bleeding and/or the persistence of underlying risk factors, such as the use of a central venous catheter.

A German study showed that a 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 noted an increased recurrence rate in children with venous thromboembolism and elevated levels of factor VIII and/or D-dimer after 3-6 months of anticoagulation therapy.[15]

Postthrombotic syndrome

Postthrombotic syndrome consists of chronically swollen, painful extremities with induration of the skin, ulceration, and pigmentary changes secondary to chronic venous stasis. From 20-67% of adults with DVT develop postthrombotic syndrome, while the Canadian registry of pediatric DVT and PE documented the syndrome in 21-25% of children with venous thrombosis.[16, 17]

Using a standardized score, investigators in a study from the Hospital for Sick Children in Toronto, Canada, observed postthrombotic syndrome in 63% of 153 children. Cases were mild in 83% and moderate in 17%.[18] The mild cases, which were detected only by use of prospective observation using a standard methodology and trained personnel, would be unlikely to appear in the registry cited above, which explains the apparently discrepant results.

Treatment of postthrombotic syndrome 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.

 

Presentation

History

Elicit a history of previous thrombosis. Document the age at which thrombosis occurred and the type of thrombosis (DVT, PE, myocardial infarction, stroke) that developed. Also obtain a thorough family history.

The contribution of the following factors to thrombosis is most thoroughly documented in adults, but these factors can contribute to thrombosis in children as well:

  • Recent surgery

  • Trauma

  • Immobilization

  • Prolonged bedrest

The use of estrogen-containing medications, such as oral contraceptives, increases the risk of thrombosis in women and female adolescents. The risk is further increased in those who are heterozygous for factor V Leiden or have other prothrombotic risk factors.

Heart disease

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

Malignancy

A history or symptoms suggestive of malignancy should prompt inquiry about use of central venous catheters and recent chemotherapy with L-asparaginase. Some advocate a search for occult malignancy in adults who develop thrombosis with few risk factors (“unprovoked thrombosis”), but this is not necessary in children since thrombosis is very rarely the first sign of cancer.

Deep venous thrombosis

Symptoms of DVT can include an acute onset of pain and swelling of the affected limb(s). These symptoms are nonspecific and can have multiple etiologies, including trauma, sports injuries, congestive heart failure, or nephrotic syndrome.

Pain and swelling

The amount of pain can range from none to severe. The degree of pain is typically associated with the speed of onset of thrombosis; a clot that develops quickly and causes a lot of blood flow blockage and inflammation typically hurts more than one that develops slowly with minimal blood vessel obstruction or a clot that causes obstruction gradually, leaving time for collateral circulation to develop.

A classic example of asymptomatic venous thrombosis is thrombosis around central venous catheters (in one study, 37% of children developed such thrombosis, but only a fifth of those had any symptoms).[19] However, swelling and pain in an upper extremity may suggest thrombosis if a central venous catheter or other localized risk factors are present.

Pulmonary embolism

Symptoms of PE can include an acute onset of chest pain and shortness of breath. Chest pain due to PE is usually not constant; most chest pain in children does not signify a significant medical condition. 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, and 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 precipitating causes of CNS thrombosis among infants and young children.

Renal vein thrombosis

Patients with renal vein thrombosis may present with flank pain and hematuria.

Physical Examination

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.

Although DVT is frequently asymptomatic, signs of the condition can 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 in patients with thromboembolism are predisposing conditions, such as those listed below:

  • Congestive heart failure or heart disease

  • Malignancy

  • Presence of a central venous catheter

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

Signs of PE are nonspecific and include the following:

  • Apprehension

  • Diaphoresis

  • Tachycardia

  • Tachypnea

  • Chest pain

  • Hypotension

Hemoptysis is seldom 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.

 

DDx

Diagnostic Considerations

Because thromboembolism is uncommon and its symptoms are often nonspecific in children, a high index of suspicion is required. Conditions to consider in the differential diagnosis of thromboembolism include the following:

  • Pneumonia

  • Sepsis

  • Vasculitis and Thrombophlebitis

  • Trauma

  • Congenital heart disease

  • Neoplasm of the CNS

Differential Diagnoses

 

Workup

Approach Considerations

No specific laboratory tests are available to diagnose thromboembolism. However, D-dimer levels may be useful, especially for ruling out thrombosis, because a normal value rarely occurs when significant thrombosis is present.

Many clotting factors are consumed in a clot, and a low factor level may be an effect rather than a cause of thrombosis; therefore, most clotting factors should be evaluated 1-2 months after successful treatment of the clot.

Neonatal thrombosis

Neonates have multiple risk factors for thromboembolism, including prematurity, sepsis, and frequent use of central arterial and venous lines.

Electrocardiography

Electrocardiographic findings are usually normal or show only sinus tachycardia. 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 present after PE.

Laboratory Studies

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

  • Complete blood count (CBC) with peripheral blood smears - Anemia, thrombocytopenia, and/or red blood cell (RBC) fragments may suggest disseminated intravascular coagulation; document a normal platelet count before heparin or low-molecular-weight heparin (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 - 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 careful assessment of the clinical probability. Of note, children often have other systemic disorders, such as sepsis or malignancy, which may elevate D-dimer concentrations, and so a negative D-dimer value can be significant in ruling out a thromboembolism in these patients.

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 or LMWH therapy is begun, remember that it affects antithrombin, as well as protein C, protein S, and activated protein C resistance. Warfarin also affects protein C, protein S, and antithrombin. Neither drug affects anticardiolipin antibodies, factor V Leiden, the prothrombin mutation, 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 ultrasonography is increasingly being 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 used to be 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 children, V/Q scanning has largely been replaced by computed tomography (CT) scanning or magnetic resonance angiography (MRA).

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 CT scanning or MRA reveal a defect in the vessel, a diagnosis of PE is confirmed.

MRI and MRA of the head

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

Head CT scanning with intravenous contrast enhancement

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

Chest radiography

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

 

Treatment

Approach Considerations

Initial care and evaluation for thromboembolism should occur in a pediatric inpatient ward or the ICU if severe respiratory distress or neurologic deterioration occurs. Management includes assessment of the extent of the thrombosis and clinical consequences, a search for thrombophilic risk factors, and anticoagulation therapy.

The duration of anticoagulation depends on the extent and location of the thrombosis, whether the thrombophilic risk factors have resolved, and, in some cases, the degree of thrombotic resolution after the initial therapy.[5, 6, 20, 21, 22, 23]

Neonatal care

Developmental differences in the hemostatic systems of newborns create difficulties in the management of thromboembolism. In addition, neonates have low levels of antithrombin and plasminogen, which cause relative resistance to heparin and thrombolytic agents, respectively.

Moreover, newborns need 11 times the usual concentration of urokinase given to adults and 5 times the usual concentration of tissue plasminogen activator (t-PA) in order to achieve the same rate of plasminogen activation.

Thrombectomy

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

Supportive care and symptom management

Pain management should include nonpharmacologic therapy (heating pad, elevation of the affected body part). When analgesics are needed, the selection depends on pain severity; mild pain can be treated with acetaminophen, while severe pain can be addressed with acetaminophen plus a narcotic analgesic.

Nonsteroidal anti-inflammatory drugs are generally safe in anticoagulated patients but should be avoided in patients with thrombocytopenia. These agents can be added to therapy for mild, moderate, or severe pain and may reduce the need for narcotics.

Consultations

A pediatric hematologist should be involved in the care of all neonates, infants, and children with thromboembolism, and a pediatric neurologist should be involved in the care of children with suspected or proven CNS thrombosis.

Inpatient Care

Admit patients with thromboembolisms to a pediatric or adolescent ward or ICU, depending on their respiratory and neurologic status.

Anticoagulation is begun with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), followed by oral anticoagulation with warfarin. Children require daily follow-up until their international normalized ratio (INR) is more than 2 on 2 successive days. Monitor the patient's INR more closely than usual if changes occur in the patient’s medications or diet.

Obtain daily CBC, prothrombin time (PT), and activated partial thromboplastin time (aPTT) values while children are inpatients. If LMWH is used, obtain an anti–activated factor X (anti-Xa) level and adjust the dose to achieve a level of 0.5-1 U/mL.

A patient's medication may include heparin or LMWH,[24] oral anticoagulants, thrombolytic agents, and, occasionally, antiplatelet agents (for arterial thrombosis). Avoid giving antiplatelet agents to children receiving anticoagulation unless they are absolutely necessary.

Duration of Therapy

The duration of therapy depends on the underlying problem. Children with mechanical heart valves or recurrent thromboembolism require anticoagulation indefinitely. Children with thromboembolism and persistent risk factors may be treated for 3 months and 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 for more than 4 weeks; obtain a CBC count every 1-4 weeks to look for heparin-induced thrombocytopenia and an anti–activated factor X level (every 2-6 wk once a therapeutic level is achieved). Enoxaparin may accumulate over time, and dosage adjustments may be necessary.

After discontinuation of anticoagulation, reducing subsequent risk factors for thrombosis is an important component of lifelong management. For example, patients with a history of thrombosis should avoid smoking and the use of oral contraceptives that include estrogens (desogestrel, gestodene, or drospirenone).[25]

Diet

Vitamin K directly interferes with the effectiveness of warfarin and potentially increases the risk for recurrent thrombosis. Daily intake of foods high in vitamin K, such as green, leafy vegetables, should be kept at a consistent level. For example, patients should eat similar amounts of vitamin-K rich foods each day. The patient or family should inform the physician of any changes in the patient’s diet or medications.

Maternal intake of vitamin K can affect levels in breast milk and cause problems in neonates and infants that are similar to those in other patients who consume vitamin K in food. Supplementation with a consistent amount of formula per day has been recommended. Formula-fed infants should receive formula with the lowest concentration of vitamin K available.

Vitamin K should be removed from parenteral nutrition or a constant, small amount should be used each day. Because regulation of dietary vitamin K intake is very difficult, one study found that daily administration of 1 mg of vitamin K plus a somewhat higher dose of warfarin led to more stable INR values in patients receiving long-term anticoagulation.[26]

Activity

Children with thromboembolism are sometimes restricted to bed rest for the first 24-48 hours to decrease the risk of PE. However, this practice has never been shown to reduce the risk of embolization, and adults treated for DVT as outpatients (without bed rest) have been found to have no higher incidence of PE than those treated as inpatients. Children with lower-extremity DVT should be fitted for compression stockings to reduce the risk of postthrombotic syndrome.[27, 28]

Patients should avoid participating in contact sports 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. Warfarin is teratogenic, so women on chronic warfarin therapy must not become pregnant.

Monitoring

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 heart valves) on 2 successive measurements obtained 1 week apart, the monitoring interval can be lengthened to every 2 weeks. In general, the INR is monitored monthly. Children taking warfarin for more than a year 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.

 

Medication

Medication Summary

Information continues to emerge on the use of antithrombotic agents in neonates and children.[23] Unfractionated heparin (UFH) has for years been the mainstay of initial therapy for thromboembolism in adults and children. However, low–molecular-weight heparin (LMWH) has similar efficacy, is easier to administer and monitor, and has a lower risk of heparin-induced thrombocytopenia.

In May 2019, dalteparin, an LMWH, became the first drug approved by the US Food and Drug Association (FDA) for pediatric venous thromboembolism therapy, being indicated for treatment of the symptomatic condition and the reduction of venous thromboembolism recurrence in children aged 1 month or older. Approval for children was based on a single trial with 38 pediatric patients with symptomatic DVT and/or pulmonary embolism. Patients underwent up to 3 months of dalteparin therapy, with resolution of venous thromboembolism achieved in 21 patients and regression occurring in seven.[38]

In the Reviparin in Childhood Venous Thromboembolism (REVIVE) trial,[29] researchers compared subcutaneous reviparin with UFH, followed by oral warfarin. The study was limited by the small number of patients but did show equivalence with respect to risk of bleeding and recurrent venous thromboembolism.

Medical therapy for venous thromboembolism in children is not evidence-based, because few randomized studies address important questions, such as duration of therapy for each type of venous thromboembolism. When one considers the subset of children with central venous catheter–associated thrombosis and cancer, clinical practice widely varies.[30]

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

Adults with cancer should be treated with LMWH for 6-12 months because the rate of recurrent thrombosis with warfarin therapy is unacceptably high. Similarly, children with thromboembolism and cancer should be treated with LMWH rather than warfarin because safe therapeutic levels of anticoagulation with warfarin can rarely be achieved in children undergoing cancer therapy, and the risk of bleeding and recurrent thrombosis are therefore unacceptably high.

Patients with thrombosis associated with a central venous catheter should receive anticoagulation therapy for 3-6 months if the catheter is removed and thrombotic risk factors have resolved. However, if the central line must remain in place once the period of anticoagulation has been completed, some advocate administration of prophylactic doses of LMWH (eg, enoxaparin at 0.5 mg/kg/day) until the central venous catheter is removed.[23]

Values from the chapter “Antithrombotic Therapy in Neonates and Children: Antithromboic Therapy and Prevention of Thrombosis," in the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, were used in some of the medication subsections below.[31]

Anticoagulants, Hematologic

Class Summary

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

Oral anticoagulants are used to prevent recurrent or ongoing thromboembolism-related occlusion. They are the mainstays of long-term outpatient therapy in patients who do not have cancer. Oral anticoagulants competitively interfere with vitamin K metabolism, decreasing plasma concentrations of the active forms of factors II, VII, IX, and X. Compared with adults, infants and children tend to require high maintenance doses and frequent dosage adjustments. Besides warfarin, acenocoumarol has also been used.

Dalteparin is indicated for the treatment of symptomatic venous thromboembolism and for the reduction of venous thromboembolism recurrence in children aged 1 month or older.

Warfarin (Coumadin)

Warfarin interferes with the hepatic synthesis of vitamin K-dependent coagulation factors. It is used for the prophylaxis and treatment of venous thromboembolism, PE, and embolic complications. The drug is used for long-term anticoagulation.

Warfarin has a half-life of 36-42 hours. PT and INR can be difficult to monitor in children because of variability in dietary vitamin K intake, effects of other drugs, and age.

Heparin

Unfractionated heparin (UFH) sodium augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse clots but it can inhibit further thrombogenesis. UFH prevents reaccumulation of clot after spontaneous fibrinolysis. This agent is usually started as the initial treatment for thromboembolism.

Monitor the patient's CBC count, PT, and aPTT daily after aPTT is therapeutic. For reversal, stopping infusion usually sufficient. If rapid reversal is needed, give protamine. The dose is based on the heparin received in previous 2 hours. If less than 30 minutes have passed since last dose of heparin, give 1 mg per 100 U of heparin received, not to exceed 50 mg, administered intravenously, over 10 minutes.

Enoxaparin (Lovenox)

Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. It also preferentially increases the inhibition of factor Xa.

The goal is to maintain an anti-Xa level of 0.5-1 U/mL (measured peak level 4 h postinjection). Enoxaparin may be used like UFH for 5-7 days, until oral anticoagulation yields an INR of greater than 2. As an alternative, LMWH may be continued for the entire 3-6 months of treatment.

For reversal, stopping the drug usually sufficient. If rapid reversal is needed, administer protamine. If less than 3-4 hours have passed since the last dose of LMWH, give 1 mg per 1 mg (or 100 U) of LMWH received, not to exceed 50 mg, administered intravenously, over 10 minutes.

Potential advantages to enoxaparin use include less osteoporosis, equivalent or less bleeding, and less heparin-induced thrombocytopenia. Enoxaparin is useful in infants and children with poor venous access.

Dalteparin (Fragmin)

LMWH with antithrombotic properties. It enhances the inhibition of Factor Xa and thrombin by antithrombin. Dalteparin is the first drug to gain FDA approval for treatment of VTE in children. It is indicated for the treatment of symptomatic venous thromboembolism and for the reduction of venous thromboembolism recurrence in children aged 1 month or older.

Thrombolytics

Class Summary

Thrombolytic agents convert plasminogen to plasmin, leading to clot lysis. Pediatric indications are not established. Because of developmental differences in the hemostatic system, infants require doses higher than those used in adults to generate the same amount of plasmin.

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

Alteplase (Activase)

Alteplase is a recombinant tissue plasminogen activator (rt-PA). It is the drug of choice for thrombolysis, given that urokinase is unavailable in the United States. Alteplase is a specific, fibrin-bound plasminogen activator. Pediatric data on this drug is limited.

However, in research using a small number of infants and neonates with large-vessel thromboses, dosages were 0.01-0.5 mg/kg/h intravenous. Intracranial hemorrhage has been observed at dosages of 0.4 mg/kg or higher.

Antiplatelet Agents, Cardiovascular

Class Summary

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

Aspirin (Ascriptin, Bayer Aspirin, Bufferin, Ecotrin)

Aspirin can be used in low doses to inhibit platelet aggregation and to treat the complications of venous stases and thrombosis. It irreversibly inactivates cyclo-oxygenase and ultimately prevents thromboxane A2 production in platelets. Platelet function does not fully recover until new platelets are made in 7-10 days.

Blood Components

Class Summary

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

Protein C concentrate, human (Ceprotin)

This agent is an orphan drug that is indicated for the prevention and treatment of life-threatening venous thromboembolism and purpura fulminans caused by severe congenital protein C deficiency. It is also indicated as replacement therapy for inherited protein C deficiency.

Protein C is an essential component of hemostasis. Thrombomodulin is necessary to convert protein C to its activated form.

The dosage and duration of protein C therapy depend on the severity of the patient's protein C deficiency and are adjusted to an individual pharmacokinetic profile.