eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thromboembolism

Author: Scott C Howard, MD, Associate Professor, University of Tennessee College of Medicine; Associate Member, Department of Oncology, Director of Clinical Trials, International Outreach Program, St Jude Children's Research Hospital
Coauthor(s): Philip M Monteleone, MD, Associate Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania and Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Jan 13, 2009

Introduction

Background

Thromboembolism, or the development of a clot within blood vessels, can occur in arteries or veins. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in adults. Although the incidence of venous thromboembolism is lower in children than in adults, the morbidity associated with venous thromboembolism is clinically significant when it occurs. Arterial thromboembolism is also an important cause of morbidity in adults but is less common in children and is only briefly addressed in this article.

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

In 1845, Virchow postulated that 3 factors were important in the development of thrombosis: (1) impairment of blood flow (stasis), (2) vascular injury, and (3) alterations of the blood (hypercoagulability).

Pathophysiology

The physiology of hemostasis is remarkably complex and reflects a fine balance between 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 and a fluid phase. The former involves platelets and the vascular wall, and the latter plasma proteins.

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

Regarding the fluid phase, many age-dependent differences are present in the hemostatic system of infants and children. Adult levels of the vitamin-K–dependent coagulation factors II, IX, and X, as well as contact factors, are not achieved until 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 may cause 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.

Frequency

United States

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

In 2004, The National Hospital Discharge Survey demonstrated an annual incidence of 4.2 cases of DVT and 0.9 cases of PE per 100,000 population.¹ PE has been found in 3.7% of children at autopsy. Strokes occur with an annual incidence of approximately 2.5 per 100,000 children.

International

In the Canadian Registry, the incidence of venous thromboembolism was estimated at 0.07 cases per 10,000 children and 5.3 cases per 10,000 hospital admissions in 1994.²

In a German study by Nowak-Gottl et al (2004), the incidence of symptomatic neonatal thromboembolism was 5.1 cases per 100,000 births.³

Mortality/Morbidity

Pulmonary embolism

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

In the Canadian Registry, the mortality rate in children was 2.2%, and deaths were mainly due to PE or direct extension of DVT into the heart.² In the Canadian Pediatric Ischemic Stroke Registry, 6% of children died after ischemic stroke, 72% had residual neurologic deficits, and 22% fully recovered.

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

Recurrent thromboembolism

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

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

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

Goldenberg et al (2004) noted an increased recurrence rate in children with venous thromboembolism and elevated levels of factor VIII and/or D-dimer after 3-6 months of anticoagulation therapy.⁴

Postthrombotic syndrome

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

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

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

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

Race

Although some prothrombotic risk factors are more common in particular racial groups, overall no evidence suggests that children of any particular race are at higher risk for thromboembolism.

Sex

Male and female children are equally affected by thromboembolism.

Age

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

Clinical

History

Signs and symptoms

• Deep venous thrombosis (DVT)
  • Symptoms of DVT can include the 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.
  • Swelling and pain in an upper extremity suggest thrombosis if a central venous catheter (CVC) or other localized risk factors are present.
• Pulmonary embolism (PE)
  • Symptoms of PE can include an acute onset of chest pain or 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, or weakness in an extremity.
  • Most strokes that occur in utero cause early pathologic hand preference late in the first year of life.
  • Neonates often present with seizures and lethargy.
  • Older children usually present with headaches and an acute onset of weakness in an extremity.
  • Infection and dehydration are common 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.

Risk factors

• The following factors are most thoroughly documented in adults, but they can contribute to thrombosis in children as well:
  • Recent surgery
  • Trauma
  • Immobilization
  • Prolonged bedrest
• 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.

History

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

Physical

• In children, as well as in adults, findings from the physical examination are often misleading. A diagnosis of thrombosis may be missed or delayed because of the nonspecific nature of the patient's presenting signs.
• Although frequently asymptomatic, signs of DVT 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 are predisposing conditions, such as those listed below:
  • Congestive heart failure or heart disease
  • Malignancy
  • Presence of a CVC
• Thrombosis of the inferior vena cava and/or renal vein can cause nephromegaly and flank tenderness.
• Signs of PE are nonspecific and include 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.

Causes

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

Acquired Conditions

Use of arterial catheters

Use of arterial catheters or CVCs is the most common risk factor for arterial thromboembolism in children, and 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

CVC-associated thrombosis was reported in 29% of children in a report by Nuss et al and in 33% of children in a Canadian series.⁵  Thrombosis is associated with CVC in 80% of newborns and 50% of children with upper extremity thrombosis.⁶ The incidence of clinically evident DVT in hospitalized children has increased over the past 15 years, from 0.3 cases to 28.8 cases per 10,000 hospital admissions.⁷ . 

Antiphospholipid antibody syndrome

Antiphospholipid antibodies, which are detected by finding positive lupus anticoagulant or anticardiolipin antibodies, are associated with thrombosis in both adults and children. In 2 studies of children with systemic lupus erythematosus, the incidences of 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, 95 children with lupus anticoagulant were followed up for a median of 5.3 years. About 10% had bleeding symptoms, whereas 5% had a thrombotic event.

Disseminated intravascular coagulation

Sepsis and disseminated intravascular coagulation have been associated with thromboembolism both in children and adults. Microvascular thrombosis consumes clotting factors, predisposing the patient to both 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, CVC).

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 L-asparaginase. In addition, permanent CVCs are placed in many children with malignancies.

Use of estrogen-containing medications

Oral contraceptives alone are associated with a 4-fold increase in the risk of venous thrombosis and a 22-fold increase in the risk of cerebral thrombosis. This risk may be explained by the acquisition of resistance to activated protein C. Administration of oral contraceptives to patients who are heterozygous for the factor V Leiden mutation increases the risk of 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 is a prothrombotic state; thus, benefits must be weighed against risks when helping patients decide about whether to use contraceptives and which method to choose.

Nephrotic syndrome

Children with proteinuria at levels of more than 0.5 g/d may have a loss of anticoagulant proteins (eg, antithrombin), which increases the risk of thromboembolism. Most thromboembolisms develop within several months of diagnosis. Both 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 after a patient is given unfractionated heparin (UFH) for 5 days or longer, and in a smaller number of patients treated with LMWH. Heparin-induced thrombocytopenia can be complicated by both venous and arterial thrombosis, but a high index of suspicion is needed to recognize this syndrome in children, even 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 one 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 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.

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

Antithrombin deficiency

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

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

Protein C deficiency

Protein C deficiency is usually transmitted in an autosomal dominant manner with incomplete penetrance. Thrombosis occurring in association with protein C deficiency is most often venous and in the lower extremities. DVT in heterozygotes can be observed as early as the teenage years. Similar to homozygotes with antithrombin deficiency, homozygotes with protein C deficiency usually present in the newborn period, with purpura fulminans. A purified protein C concentrate (Ceprotin) was recently designated as an orphan drug. See Medication.

Protein S deficiency

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

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

Hyperhomocysteinemia

In adults, hyperhomocysteinemia is an independent risk factor for arterial vascular disease and venous thrombosis. A study of 45 children with ischemic stroke demonstrated that their odds ratio for moderate hyperhomocysteinemia was 4.4 compared with control subjects. A German study of 163 children with venous thromboembolism showed a 3-fold increase in VTE risk among subjects with elevated fasting homocysteine levels.⁸ Homozygous mutations in the gene for cystathionine beta-synthetase are rare but account for most cases of severe hyperhomocysteinemia. Mild-to-moderate hyperhomocysteinemia can occur in heterozygotes with mutations affecting cystathionine beta-synthetase or methylene tetrahydrofolate reductase.

Prothrombin gene 20210A mutation

A Turkish study of 32 children with cerebral infarcts revealed that 21.8% were heterozygous for the prothrombin gene 20210A mutation.⁹ Recent studies have shown this mutation is a risk factor for pediatric arterial thrombosis, especially in the CNS.

Elevated lipoprotein(a) levels

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

Congenital heart disease

Congenital heart disease involves children with mechanical or prosthetic valves and those undergoing Blalock-Taussig shunt placement or a Fontan procedure. As noted above, cardiac catheterization is the most common risk factor for arterial thrombosis. Cardiogenic embolism due to atrial fibrillation or cardiomyopathy is a cause of stroke in both children and adults.

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