Chapter 438. Diagnosis and Management of Thrombosis

Thrombosis, defined as excessive clotting, has three main causes: reduced blood flow (stasis), increase in blood coagulation factors (hypercoagulability), and abnormalities in the vessel wall. Once the endothelium is injured, platelet adhesion is accompanied by platelet aggregation and thrombin formation. This process is usually tightly regulated in order to prevent excessive bleeding or clotting. However, at times, the process is uncontrolled, and a thrombus can form in excessive amounts or in an unusual place, causing harm.

Thrombosis and thrombophilia in childhood is of increasing concern. Although symptomatic thrombotic disease in children is rare when compared with adults, its occurrence can lead to mortality or life-long sequelae. The reported rate of thrombosis is 5.3 per 10,000 hospitalized patients, with a bimodal peak in incidence in the neonatal and adolescent age groups.1-4 Less than 10% of events in children are idiopathic.1-4 Thrombosis during childhood is a multifactorial event caused by both genetic and acquired risk factors. Three or 4 different thrombotic risk factors are identified in most cases.1,4,5,6 Most children with thrombosis have an underlying medical condition that alters the hemostatic system to induce activation of coagulation and/or to prevent the inhibition of coagulation. The majority of conditions are related to inflammation or to abnormal blood flow (Table 438-1). In addition to the hemostatic changes secondary to underlying illness, many children also have the additional risk factor of a central venous catheter inserted to facilitate therapy for the underlying illness.1-3,7,8 The use of central venous catheter constitutes the most common acquired risk factor for thrombosis.5,7,8 As many as 60% of children with thrombosis will also have an inherited prothrombotic abnormality (Table 438-2), but the clinical relevance of congenital thrombophilia in asymptomatic children or in the presence of an acquired risk factor (eg, the presence of a central venous catheter) in childhood is still uncertain.1,9,10 There is debate about which children to screen, as well as when and how, for these genetic states. Families should be counseled about the significance of a prothrombotic state before testing is performed, especially in asymptomatic children. The pediatric community needs to be able to educate families about the signs and symptoms of thromboembolic disease, medical treatments and their potential adverse effects, and types of inherited and acquired thrombophilias.

Deep Vein Thrombosis (DVT) of Extremity

The signs and symptoms of acute DVT typically include swelling, pain, warmth, and a reddish purple discoloration of the extremity. Confirmation of diagnosis in a symptomatic patient is easily accomplished by a compression Doppler ultrasound of the affected extremity.4,11-14 Magnetic resonance venography and contrast venography can aid in the diagnosis if there is concern for central thrombosis (eg, in the superior vena cava) or if the ultrasound study is inconclusive. For thrombosis in the intrathoracic blood vessels (eg, subclavian vein) sonography may not be sensitive enough, so a venogram is required. The commonly used D-dimer test has not been well studied in children as a diagnostic tool for deep vein thrombosis.

Some specific thrombosis syndromes may be noted, particularly during adolescence. Paget-Schroetter syndrome (also referred to as exertional thrombosis or thoracic outlet syndrome) involves the axillary and subclavian venous systems, often identified in athletes who participate in activities involving repetitive motion of the arms leading to impingement of the vessels by the rib cage.15 Although surgical removal of the ribs has been advocated to treat and prevent new occurrences, anticoagulation remains the standard of therapy.15-18 More recently, thrombolysis has been suggested to improve the long-term outcome of these children, so this option should be discussed with the parents, with the risk and benefit explained.17,18

May-Thurner syndrome is the development of left-sided ileofemoral deep vein thrombosis secondary to chronic compression of the left common iliac vein by the overlying right common iliac artery, against the fifth lumbar vertebra.19 The estimated incidence of this anatomic variant is approximately 22% to 24%,19,20 but the incidence of May-Thurner syndrome is likely underestimated since many patients are initially asymptomatic. This condition is more likely to be identified in females due to an increase in lumbar lordosis that develops during maturation of the female pelvis; this pushes the lower lumbar vertebra forward, increasing compression of the left iliac vein by the right iliac artery. There is often a history of recent introduction of combined oral contraceptive agents in these young women as well.21 Treatment alternatives consists of angioplasty and vascular stenting, in addition to thrombolysis and anticoagulation, in order to prevent thrombus recurrence and prevent postthrombotic syndrome.21

Pulmonary Embolism

Pulmonary embolism (PE) is considered a rare event in children, but the incidence is likely underestimated as most cases are not detected until autopsy.1 No prospective clinical trial has evaluated all children who have symptomatic thrombosis for objective evidence of PE. Hence, its incidence remains unknown. Because affected children generally have a concurrent medical condition with symptoms that can mimic those of PE (ie, dyspnea, chest pain, hypoxia, fever), physicians do not often have a high index of suspicion for thrombosis. Diagnosis can be made with a spiral computed tomography (CT) scan, CT angiography, or by ventilation/perfusion (V/Q) scan.22 The incidence of PE associated with deep vein thrombosis is approximately 25%, and children with PE are likely to have a hypercoagulable state identified.22 A lupus anticoagulant can be identified in up to half of the children with pulmonary embolism.23 In addition, 50% of children diagnosed with deep vein thrombosis who have a lupus anticoagulant will subsequently develop pulmonary embolism.23,24

Catheter-Related Thrombosis

As many as 60% of thrombotic events in children and 90% of thrombotic events in neonates are associated with the use of indwelling catheters.1,7 Catheter-related thrombosis can be of several types: (1) fibrin sleeves, (2) catheter tip thrombosis, and (3) catheter-related central venous thrombosis (eFig. 438.1).7

Nearly all indwelling catheters are coated with fibrin within days after insertion.25 When this thrombotic matrix overlies the catheter tip, it can cause a ball-valve effect that leads to catheter dysfunction manifesting as inability to aspirate through the catheter, although the capacity to infuse through it is preserved. Such a sleeve also can become a source for deep vein thrombosis formation and a nidus of bacterial infection.26 Intraluminal thrombus within the catheter tip can also cause catheter dysfunction. Local instillation of a thrombolytic agent is usually effective in reestablishing the ability to aspirate and flush the catheter.27,28 Central venous thrombosis or deep vein thrombosis can be initiated at the site of catheter insertion through the vessel wall or develop near the tip of the catheter where endothelium has been irritated chronically.7,29

The prevalence of catheter-related central venous thrombosis is as high as 50% in children who have cancer, hemophilia, chronic malnutrition, and other medical conditions.7,30-33 Although the majority of central venous catheters (CVCs) in children are inserted into the veins of the upper extremities and chest, catheter-related thrombosis can be seen in any extremity and within the right atrium. The gold standard test to identify catheter-related deep vein thrombosis (DVT), particularly of the upper extremity, is contrast venography.11-14 However, this test is considered by some to be invasive and carries a very small risk of anaphylaxis or renal injury related to the use of contrast medium. Compression Doppler ultrasonography (appropriate for screening lower extremities) may not identify thrombi in the subclavian and central veins, but is often better at identifying occlusion of jugular veins.11,14 Therefore, it is recommended that both modalities be used to assess the vessels of the upper venous system. Magnetic resonance venography is an appealing alternative because it can image all veins,13 but it is sensitive to motion artifact and many young children will require sedation to undergo the study.7

Although clinically overt DVT develops in association with an indwelling CVC, the incidence of subacute or “silent” thrombi in children who have catheters is far greater. These subacute DVTs still have clinical significance because numerous studies have demonstrated the association of catheter-related DVT, catheter-related infection, and catheter occlusion.7,34-41 Microbiologic studies have shown that proteins within a clot, such as fibrinogen and fibronectin, attract staphylococcal species and promote their adherence to the catheter surface, thereby increasing the risk of catheter infection.34 In addition, many organisms causing catheter-related infection are thrombogenic. Studies in children receiving intensive care and undergoing cancer therapy have suggested that the use of urokinase or recombinant tissue plasminogen activator flushes, antibiotic-coated catheters, and heparin-coated catheters prevent both infective and thrombotic complications.34-37

There is debate in the literature about catheter-associated risk factors that may lead to the development of deep vein thrombosis (DVT). Large-bore catheters that are placed in small vessels of young children likely increase the risk of thrombosis. The location of the catheter tip also is important. If the tip is above T3 or in the right atrium, the patient may be at greater risk of thrombosis, although this may not be true for neonatal umbilical artery catheters.42-46 Several reports suggest that location of catheter insertion plays a role in DVT. Catheters placed in femoral and subclavian veins are more likely to be associated with thrombosis than those that are inserted into the jugular veins. There are conflicting data regarding laterality of catheter placement and DVT risk.47,48

When catheter-related thrombosis is identified, many issues arise about its management, including the necessity for anticoagulation and its intensity and duration once initiated. Although the best management includes removal of the catheter,49 this may be impractical in a critically or chronically ill child who has limited intravenous access. The most recent consensus guidelines for treatment of central venous catheter–related thrombosis in children recommend anticoagulation to prevent propagation or sequelae of the thrombus if the catheter cannot be removed.49 The natural history of catheter-related deep vein thrombosis has not been defined. It is not know how often the thrombus resolves, nor do we understand the long-term sequelae that are associated with asymptomatic vascular occlusion. Prospective studies are needed.

Cerebral Sinovenous Thrombosis

Cerebral venous thrombosis is seen much more commonly in the neonatal period than in any other age group.50,51 However, the complication develops in older children at a rate of 0.67 per 100,000 per year.51 Most commonly it occurs in conjunction with a deep tissue infection of the head and neck, dehydration, hypoxia, perinatal complications, cardiac disease, the use of central venous catheters, and inherited thrombophilia.51,52 Seizure is the most common presenting symptom, but decreased level of consciousness, hemiparesis, and cranial nerve palsies may also occur.51 More severe chronic neurologic impairment develops in the children and neonates who present with seizures or have associated venous infarction.51 Cerebral venous thrombosis can be diagnosed by CT or magnetic resonance venography.

In adults with cerebral venous thrombosis, anticoagulant therapy is instituted to prevent neurological sequelae.53 Anticoagulation is recommended even when the thrombus is associated with a small parenchymal hemorrhage, as the accumulation of blood is considered to be a continuation of the coagulation process.49,50,54 Treatment of children, and especially neonates, has been demonstrated to be safe, but its efficacy has not been well studied in clinical trials.49,54,55 The risks and benefits of anticoagulation or thrombolytic therapy need to be determined on an individual basis. Current guidelines suggest anticoagulation for 3 months.49

Perinatal Stroke

Perinatal stroke, defined as a cerebrovascular event that occurs between 28 weeks gestation and 7 days of age, occurs in 4 of 1000 live births.56 There is a male predominance.57 Seizure is the most common clinical presentation. However, many children do not present for several months, when they are noted to have hemiparesis or early hand preference. It is often very difficult to determine whether the stroke occurred in utero, at the time of delivery, or within the first week.58 Most neonatal stroke occurs in the distribution of the left middle cerebral artery. Magnetic resonance imaging and angiography are the best tests for determining the extent of disease.59,60

There is no standard approach for the evaluation and treatment of perinatal stroke. At the time of diagnosis, though, it is important to determine whether the thrombotic event was related to an underlying disorder such as congenital heart disease, blood disorders, coexisting infections such as a TORCH infection (toxoplasmosis, syphilis, herpes, cytomegalovirus), systemic bacterial infections, or metabolic diseases.58,61,62 Obtaining a thorough prenatal and birth history is also important in determining the cause of stroke. Maternal drugs and medical conditions, placental disorders, perinatal asphyxia, and birth trauma have all been associated with neonatal cerebrovascular events. Several studies have demonstrated an association between inherited prothrombotic conditions and neonatal stroke.52 In a report of the Childhood Stroke Study Group, 68% of the evaluated stroke patients had at least 1 prothrombotic risk factor compared to 24% of a control group.63 However, the Canadian Pediatric Ischemic Stroke Registry found the presence of a prothrombotic factor in only 38%.2

Fortunately, the incidence of recurrent stroke is extremely low (less than 5%), and as many as 50% of these children will be neurologically normal by 12 to 18 months of age.63,64 Long-term sequelae such as mild hemiparesis, speech or learning problems, behavioral problems, and seizures are more likely to persist in patients who present outside the newborn period.63,65 Treatment generally involves supportive care alone.2 There have been no clinical trials to evaluate the necessity of anticoagulant or antiplatelet therapy for stroke in the newborn.

Childhood Stroke

Stroke affects 3 to 15 children per 100,000 per year, with a male predominance.57 As many as 65% of affected children will have lifelong disabilities such as neurological defects and seizures, and the risk of a second stroke is 20%.66 Despite therapy, mortality rates as high as 10% have been reported.

There are certain comorbid conditions that are highly correlated with stroke, including congenital or acquired cardiac disease, that can cause embolic phenomena and sickle cell disease.63,64,66 Numerous systemic disorders can contribute to stroke, and inherited prothrombotic states are causative as well.66 Although there has been a decline in the incidence of stroke after varicella infection, recent case reports describe a similar syndrome developing after the varicella vaccine.67 A rare cause of stroke in childhood is severe iron deficiency anemia.68 Despite the extensive list of potential causes, 50% of children with stroke will have no known primary disorder.8

There is often a delay in the diagnosis of childhood stroke as the signs and symptoms of an acute event can be subtle. Children often have focal neurologic deficits (cranial nerve palsies, hemiparesis), but more systemic problems such as headache, lethargy, and seizures can occur.61

There is limited published information about the etiology and outcome of childhood stroke, and very little evidence in the literature about appropriate management and prevention approaches. Most treatment strategies have been extrapolated from the practice in adult medicine and the results of retrospective cohort studies in children. It is hoped that The International Pediatric Stroke Study will help clarify our understanding of childhood stroke.

Embolic stroke resulting from cardiac disease or carotid dissection and stroke associated with severe prothrombotic conditions (eg, congenital homozygous protein C deficiency or antiphospholipid antibody syndrome) appears to benefit from anticoagulation.61 Warfarin, unfractionated heparin, or low-molecular-weight heparin has been successful in treating and preventing recurrence of acute stroke in children with these underlying disorders.49,63,66,69 Unfortunately, for strokes of other etiologies,anticoagulation does not improve outcome better than treatment with antiplatelet agents. Although the use of thrombolytic agents within 3 hours of initiation of the signs of stroke can be successful in improving outcomes in adults,70 the safety and efficacy of this strategy in children has not been demonstrated. Any use of thrombolytic agents ideally should be in conjunction with a clinical trial to answer questions of dosing, timing, safety, and outcome. Surgical management of stroke and chronic ischemic disease in adults includes carotid stenting and angioplasty. However, these are invasive and potentially risky procedures that have not been well studied in children.

Renal Vein Thrombosis

Renal vein thrombosis usually presents within the first month of life. The classic triad of flank mass, macroscopic hematuria, and thrombocytopenia occurs only in about 25% of patients.71 Risk factors include maternal gestational diabetes, perinatal asphyxia, and dehydration, but these are identified in less than one third of babies.71 Outside of the neonatal period, most children will have associated nephrotic syndrome.72 Aggressiveness of treatment will be determined by extent of thrombosis. Anticoagulation with or without thrombolytic therapy is recommended for bilateral thrombosis, unilateral thrombosis extending into the inferior vena cava, or signs of impending renal failure.71,72 However, there is no clear evidence that anticoagulation therapy improves renal outcome.71

Portal Vein Thrombosis

Portal vein thrombosis can lead to the serious and life-threatening complication of portal hypertension, esophageal varices, and gastrointestinal bleeding. Initially, portal vein obstruction can present as asymptomatic splenomegaly. Causes include umbilical vein catheterization (particularly if the line is in place for more than 3 days or is subdiaphragmatic in position), compression by tumors in the abdomen, abdominal trauma or infection, dehydration, and inherited hypercoagulable states. Unfortunately, the majority of cases have no identifiable etiology. Diagnosis is typically made by Doppler ultrasonography. Most portal vein thrombosis outside of the neonatal period is diagnosed in the chronic stage after cavernous transformation has occurred. Anticoagulation is not generally indicated in this setting due to increased risk of variceal bleeding. These children may need surgical interventions such as portosystemic shunting or splenectomy. Aggressive antithrombotic therapy may help prevent late complications if thrombosis is identified in the acute stage.73 However, one recent prospective study showed that neonatal portal vein thrombosis diagnosed through screening ultrasound usually resolved without antithrombotic therapy.

Thrombophilia is the increased likelihood for development of thrombosis. It may be hereditary, due to abnormality of the coagulation system, or acquired.

Inherited Conditions

The lifetime risk of thrombosis in a child who is a carrier of thrombophilia is estimated to be fourfold higher compared to normal population.7,74 However, healthy young children who have single thrombophilic defects rarely present with thrombosis during childhood.75,76 The risk of thrombosis seems to increase with multiple thrombophilia traits and with the addition of exogenous risk factors.77

Certain genetic mutations predispose to the development of thrombosis. The first such prothrombotic risk factor, deficiency of antithrombin, was discovered in 1965.78 The second form of thrombophilia, protein C deficiency, was reported in 1981.79 Protein S deficiency was linked to recurrent thrombosis in 1984.80 Subsequently, discoveries of new thrombophilic traits have been reported at an accelerated rate. The list of current known thrombophilias is shown in Table 438-2.

Protein C, protein S, and antithrombin are the natural anticoagulants regulating hemostasis. Although deficiencies of these proteins are rare (0.03% to 0.1% of population), they are strongly associated with a first thrombotic event prior to age 40 years. Severe homozygous congenital protein C or protein S deficiency usually presents within a few days of birth with disseminated intravascular coagulation, purpura fulminans, and large vessel thrombosis that affects the eyes, central nervous system, aorta, vena cavae, and renal veins.81 Early and indefinite anticoagulation therapy is necessary for these severe deficiencies. A plasma-derived protein C concentrate is available through a US Food and Drug Administration prelicensure study (Baxter Pharmaceuticals, Deerfield, IL) and can be potentially life-saving in these patients.82 Antithrombin deficiency is generally identified in later childhood, as severe deficiencies are rare and in the homozygous state may be incompatible with life.83

These antithrombotic regulatory proteins can be affected by age and acute health status. For example, they are decreased in newborn infants.3,84 In addition, underlying medical conditions, including sepsis, nephrotic syndrome, liver disease, inflammatory bowel disease, and childhood leukemia therapy can cause acquired deficiencies in the natural anticoagulation regulatory proteins.83,85 Finally, they can be consumed in a massive thrombus.

Factor V Leiden is the most common inherited thrombophilia mutation. Its estimated prevalence is 5% in those of European ancestry. It is rare in persons of African or Asian ancestry. This mutation in factor V leads to resistance of factor V inactivation by activated protein C and protein S. The heterozygous state causes a 5-fold to 8-fold increased risk for thromboembolic complications. The homozygous state confers an 80-fold increased lifetime risk.77

The prothrombin G20210A mutation occurs in approximately 3% of the general population. Its presence increases the risk for thrombosis mainly by causing excess prothrombin production. The heterozygous state increases the risk for thromboembolic events threefold. However, a recent meta-analysis demonstrated that the presence of this mutation is significantly associated with the risk of recurrence for thrombosis in children.77

Lipoprotein (a), which is involved in cholesterol metabolism, competes with plasminogen for binding to fibrin. It therefore slows fibrinolysis and is associated with thrombosis. Elevations in lipoprotein (a) are associated with accelerated arterial vascular disease in adults. Preliminary studies of children describe elevations in lipoprotein (a) in association with venous and arterial thrombosis, but these data require confirmation.77,86 Elevated levels of plasma homocysteine are also associated with vascular disease in adults and thought to be a risk factor for stroke in children. Polymorphisms of the thermolabile methylenetetrahydrofolate reductase (MTHFR) gene may contribute to elevations of homocysteine levels.87

Elevations in the procoagulant activities of factors VIII, IX, and XI are risk factors for venous thrombosis in adults88-90; increased levels of fibrinogen, factor VII, and C-reactive protein have been linked to early arterial vascular disease in adults.91 However, these proteins have not been well studied as risk factors in children. The presence of elevated factor VIII at the time of diagnosis of deep vein thrombosis and its persistence has been shown to be associated with increased risk of recurrent events.92 Other genetic polymorphisms that predispose to thrombosis have yielded conflicting results or are still under initial investigation.

Acquired Conditions

Malignancy

As in adults, cancer is one of the primary conditions associated with thromboembolism in children. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. At diagnosis, these children demonstrate activated coagulation as evident by having increased levels of thrombin-antithrombin complexes stimulated by tumor cells.93 However, they also may have long-term tunneled central venous catheters for administration of intravenous therapy.93-95 Also, they are treated with chemotherapeutic agents that are caustic to vessel walls and/or can induce a transient hypercoagulable state.93,96 For example, asparaginase significantly reduces the amount of circulating antithrombin and fibrinogen.96,97 If asparaginase is given along with steroids, particularly prednisone, the risk for thrombosis may be potentiated.98 The most common thrombotic event in children with ALL is a catheter-related complication, but central nervous system events (arterial ischemic stroke and cerebral venous thrombosis) also may occur.93,95,99 Several studies have been performed to determine if thrombosis can be prevented in children with ALL by giving antithrombin concentrate or anticoagulants, but there were not enough data to make definite conclusions.97 Current prophylactic anticoagulation is not recommended, but thrombotic events are treated only when they develop. Secondary prophylaxis can usually be achieved with low-molecular-weight heparin without using antithrombin concentrate.

Infection

Thrombosis may occur as a complication of systemic or invasive local infection. Head and neck infections may trigger cerebral sinovenous thrombosis.51 Musculoskeletal infections, particularly those associated with Staphylococcus aureus, are being recognized as predisposing to venous thrombosis.100,101

Liver Disease

Liver disease will lead not only to a decreased production of all of the coagulation factors except factor VIII but also reduction in concentrations of the natural anticoagulant proteins C and S and antithrombin. Accordingly, thrombosis may result.

Congenital and Acquired Heart Disease

Another condition highly associated with both venous and arterial thrombotic events is complex congenital heart disease.102 Cardiac catheterization required for diagnosis and treatment carries a risk of arterial thrombosis at the site of catheterization, primarily the femoral artery. Late complications of femoral artery thrombosis include leg growth retardation (8%) and persistence of arterial occlusion (30%).103

Most cardiac defects are treated by surgery. The Fontan procedure and its variations are performed for lesions where a biventricular circulation is not feasible. The systemic venous return is diverted directly to the pulmonary arteries, and systemic arterial blood is ejected by a single ventricle. After this procedure, children are at risk of venous (vena caval) and right atrial thrombosis in the Fontan circuit. These thromboembolic complications can obstruct blood flow or embolize into the pulmonary or systemic arterial vessels.104 The most common site of arterial embolism is the central nervous system.104 Although half of the events occur within the first 3 months after surgery, thrombi may develop decades later, so most patients will require indefinite prophylactic anticoagulation.105,106

Children with dilated cardiomyopathy or heart conditions that require a mechanical valve are also at risk for embolic events, primarily to the central nervous system. Indefinite anticoagulation with either aspirin or oral vitamin K antagonists is recommended.49

Kawasaki disease, first described in 1967 as a syndrome of fever for more than 5 days, rash, nonexudative conjunctivitis, erythema of oral mucosa, lymphadenopathy, and swelling of the hands and feet, is associated with vasculitis of medium and large arteries, myocarditis, and coronary artery aneurysms. If initial treatment with intravenous immunoglobulin and anti-inflammatory agents is delayed, the incidence of coronary artery aneurysm is 20% to 25%.107 Because these patients are at risk for thrombosis involving the aneurysmal vessels, with resultant myocardial infarction, prophylactic aspirin therapy should be continued after the initial inflammatory phase has subsided.49,108 If giant aneurysms develop on subsequent echocardiogram monitoring, long-term anticoagulation with a vitamin K antagonist such as warfarin is indicated. (Target prothrombin international normalized ratio [INR] = 2.0 – 3.0.)49

Antiphospholipid Antibodies

Antiphospholipid antibodies include the lupus anticoagulant (LA), and anticardiolipin, antiphosphatidyl serine, antiprothrombin, and anti-β-2-glycoprotein I antibodies.109 The LA is present in approximately 25% of children who develop thrombosis.23 Children who have LA should be retested at least 12 weeks after the first test, and at least 2 screening methods should be used. The association of a persistent antiphospholipid antibody with symptomatic thromboembolism defines the antiphospholipid antibody syndrome, which is associated with a high recurrence rate; thus, long-term (indefinite) anticoagulation should be considered.49 In contrast, studies of children who present for surgery, especially tonsillectomy, show a 2% prevalence of transient LA detection with no apparent pathologic consequence.110 The prognostic significance of the LA in children who present with thrombosis in the setting of concurrent infection and a transient LA probably is similar to that of children who have an asymptomatic LA. No biochemical assays can discriminate prothrombotic LA from transient LA. Retesting at least 12 weeks apart and the persistence of LA is the only reliable indicator of chronicity and potential complications.

Oral Contraceptive Pills (Ocps)

Oral contraceptives are commonly prescribed to teenage girls for a variety of medical indications. Oral contraceptive pill use has been associated with threefold to tenfold increased incidence of deep vein thrombosis (DVT) in an otherwise young, healthy female population. The incidence of DVT is highest in the first year of use.111 This risk is further increased in the presence of hypercoagulable disorders, particularly factor V Leiden.112 Risk of DVT development in patients with factor V Leiden is increased by approximately 35-fold when they are taking OCPs. Screening patients for factor V Leiden prior to initiating use of OCPs has been debated. However, because of the cost of testing and the low mortality related to DVT, the consensus has been to screen only those patients with a personal or family history of venous throboembolism.111 Having inherited thrombophilia without a personal history of thrombosis is a relative contraindication for use of OCPs. However, in adolescents with thrombophilia, alternatives to OCP for medical conditions such as acne and menorrhagia should be strongly considered.

Screening for Thrombophilia

The need for thrombophilia screening, particularly in asymptomatic children, is debatable. The incidence of thromboembolism in children who are younger than 15 years of age with confirmed thrombophilia is low.75 Anticoagulation prophylaxis in high-risk situations such as major surgeries or trauma could prevent thrombosis in children who are identified with thrombophilia,112,113 although this is theoretical and has not been tested in clinical trials. Pediatricians favor prevention over treatment, but it is not known whether prevention of symptomatic thrombosis yields an outcome that is superior to physician awareness of the signs of thrombosis, prompt diagnosis, and institution of therapy when indicated. Screening may simply promote additional anxiety in a family and child about a problem that is unlikely to affect them until adulthood.114 Potentially, there may be problems with insurability. Those opposing screening asymptomatic family members state that knowing about the tendency for thrombosis has the same benefits as laboratory screening.114 Many inherited causes of thrombophilia are unknown, so a negative screening test in a child with a significant family history does not guarantee that the child will not develop thrombosis. Currently, there is no screening test for thrombosis risk analogous to the activated partial thromboplastin time and prothrombin time for bleeding tendency.115

Some experts recommend screening symptomatic children for all known thrombophilic conditions at the time of diagnosis. However, after an acute thrombotic event, transient reductions due to consumption of some natural anticoagulant proteins may occur.116 A low level should always prompt measurement 3 to 6 months later to confirm a congenital deficiency. Despite the potential for transient deficiency, identifying significantly low protein C, protein S, or antithrombin levels at the time extensive or progressive life-threatening thrombosis is diagnosed would provide an opportunity to replace the factor with protein concentrates or fresh-frozen plasma.116 Genetic (polymerase chain reaction–based) testing for the thrombophilic mutations can be performed reliably at any time and is accurate at the time of acute thrombosis. Testing at the onset may obviate difficulties with patient follow-up. Table 438-3 outlines one approach to testing a symptomatic child for prothrombotic conditions.

Increasingly, it is evident that thrombophilia is a multifactorial disorder. As new information becomes available regarding the determinants of hemostatic balance, it becomes more difficult to interpret laboratory test results. Children who have natural anticoagulant protein deficiencies and combined thrombophilic traits are at high risk of recurrence with minimal provocation, but the risks are less clear for others who have thrombophilia.77

Guidelines for the treatment of thromboembolic events in neonates and children have been extrapolated from the experience in adults. Virtually no randomized clinical trials have been completed in children that successfully define optimal duration and dosing. However, published guidelines by the American College of Chest Physicians are acknowledged by many as reasonable and rational, even though not strongly evidence based.49eTables 438.1 and 438.2 provide details about treatment.

Unfractionated Heparin and Low-Molecular-Weight Heparin

Unfractionated heparin administered as a continuous infusion functions by binding to antithrombin, which allows inhibition of thrombin as well as factor Xa.117 Because it is a large molecule, it can bind other plasma proteins, macrophages, platelets and platelet factor 4, osteoclasts, and endothelial cells, leading to the potential complications related to heparin, such as heparin-induced thrombocytopenia and bone loss. Low-molecular-weight heparins (LMWHs) given subcutaneously are smaller molecules that lack a pentasaccharide subunit. Therefore, this compound has reduced binding to plasma proteins, macrophages, and endothelial cells, which makes for more predictable pharmacokinetics and a longer half-life. It also has reduced platelet and osteoclast binding, which decreases the rates of heparin-induced thrombocytopenia and osteoporosis.117 However, because of the shortened length, it cannot bind to antithrombin and thrombin simultaneously. The main mechanism of action is via factor Xa inhibition.

Because the activity of heparin relies on the presence of antithrombin, some children may be resistant to standard doses of anticoagulation and cannot achieve therapeutic levels. Antithrombin levels are often reduced in very young or ill children.118For example, newborns have physiologically low levels of antithrombin, and certain conditions (ie, sepsis, liver failure, protein-losing states, and use of asparaginase) are associated with an acquired deficiency.84 Antithrombin supplementation may be necessary for these patients who appear to be resistant to heparin therapy or who cannot achieve therapeutic levels. Neonates may require higher doses of heparin because the clearance is more rapid secondary to a large volume of distribution.119,120 The risk of bleeding associated with the use of heparin is 1.5% to 10%.119 Heparin-induced thrombocytopenia is reported occasionally in pediatric patients receiving unfractionated heparin, but is rare with LMWHs.120 Osteoporosis has occurred in children on standard heparin, primarily in conjunction with the use of steroids or long-term heparin use.49 There is also a theoretical risk of osteoporosis with low-molecular-weight heparin (LMWH) use, so children who are treated with LMWH for over 3 months should be monitored with bone densitometry.121

Low-molecular-weight heparin (LMWH) is administered by subcutaneous injection. Because many neonates (especially preterm) have minimal subcutaneous tissue, making injection impractical, the intravenous route should be considered.122 LMWH is advantageous over both unfractionated heparin and oral anticoagulants because it has more predictable pharmacokinetics and requires less monitoring.123 In addition, it requires adequate renal function for drug clearance. Therefore, because most LMWH therapy is instituted in critically or chronically ill children, monitoring with anti-factor Xa levels is still advocated.

Vitamin K Antagonists

Oral vitamin K antagonists (VKA) or warfarin use is problematic in very young children. First, newborns have reduced levels of the vitamin K–dependent proteins.84 Infant formulas containing vitamin K supplements can cause resistance to VKAs, whereas breast-fed infants are very sensitive to VKAs, because negligible amounts of vitamin K are present in breast milk.49 Second, infants and even some older children have inadequate venous access for the frequent monitoring of prothrombin INR that is required. Third, monitoring oral anticoagulant therapy is affected by febrile illnesses, dehydration, concurrent use of antibiotics for common childhood infections, dietary changes, and weight gain.124 The major complication of VKA use is bleeding, occurring in 3% to 12% of patients.124 Reported nonhemorrhagic complications in children treated with VKA therapy for over a year include hair loss, tracheal calcification, and loss of bone density.49 “Point of care” whole blood monitors have made regulating VKA therapy more convenient for families because they can perform the test regularly at home.49

Alternative Thrombin Inhibitors and Xa Inhibitors

The successful use of alternative thrombin inhibitors such as lepirudin, hirudin, argatroban, and danaparoid sodium has been reported in a small number of children primarily in the setting of heparin-induced thrombocytopenia.125,126 There are ongoing studies of the use of argatroban and bivalirudin in children. Fondaparinux, a direct Xa inhibitor given as a once daily injection, is also being studied in children.

Antiplatelet Agents

Aspirin is the most commonly used antiplatelet agent. Indications for long-term aspirin therapy include stroke prevention in patients with some forms of congenital heart disease, history of arterial stroke, and Kawasaki disease.49,69,127 The dose is generally 1 to 5 mg/kg daily but there is variability in the dose required to inhibit platelet aggregation in children.49 The primary side effect of long-term aspirin therapy is bleeding, but it is rarely seen except in neonates who have slower clearance, patients with concurrent bleeding disorders, or children receiving anticoagulation therapy.49 There is also a theoretical risk of developing Reye syndrome in children with intercurrent influenza or varicella infection, but this complication does not usually occur unless the dose of aspirin is greater than 40 mg/kg, which is necessary for an anti-inflammatory effect.49

Dipyridamole in doses of 2 to 5 mg/kg is an alternative to aspirin therapy.49 Drugs that selectively inhibit ADP-induced platelet aggregation, such as ticlopidine and clopidogrel, have not been well studied in children.49 A recent study of clopidogrel in neonates undergoing congenital heart surgery suggested that a dose of 0.2 mg/kg was as effective as aspirin. However, this has not been confirmed in older children, and the medication must be compounded.49

Thrombolytic Agents

The use of tissue plasminogen activator (tPA) at low doses (1 to 2 mg) has been shown to be safe and effective at restoring patency to occluded central venous catheters in 80% to 90% of cases.128 Higher systemic doses (0.1 to 0.5 mg/kg/hour continuously for 6 hours) have been used to treat massive pulmonary embolism and arterial and extensive venous thrombosis, with success rates of 65% to 90%.129,130 Recently, investigators have reported that using lower doses of systemic tPA (0.03 to 0.06 mg/kg/hour) or urokinase given over a longer duration is effective and has potentially fewer bleeding complications than standard-dose tPA.131 Important considerations in the use of tPA are the need for plasminogen supplementation (using fresh-frozen plasma) and concurrent heparin administration. At birth, plasma concentrations of plasminogen are reduced by 50% compared with adults, and this makes thrombolytic therapy less effective.84 Because thrombolytic agents do not inhibit clot propagation or alter blood hypercoagulability, heparin at prophylactic doses must be used to prevent recurrent thrombosis. Plasma fibrinogen levels should also be monitored before and 2 hours after initiating tPA therapy and also if bleeding occurs.49 The major complication of systemic thrombolytic therapy is bleeding. Up to 65% of patients will experience some degree of hemorrhage, usually oozing from mucous membranes and at puncture sites, but 10% to 39% will require blood transfusions.49 The rate of intracranial hemorrhage is 0.4% to 13.2%, with the highest rates found in preterm neonates.129 The risk of bleeding increases with prolonged administration of tPA. Children receiving tPA must be monitored closely for bleeding, and supplemental use of blood products (cryoprecipitate, platelets, packed red blood cells) may be necessary during treatment. Because of this severe complication, the current recommendation for tPA at standard doses is to limit its use to life-, organ-, or limb-threatening thrombosis, such as massive pulmonary emboli, thrombosis of the vena cava, bilateral renal vein thrombosis when there is potential of renal failure, and atrial thrombosis that is causing significant cardiac dysfunction and in which surgery is contraindicated.49 There are currently no recommendations for its use in the treatment of other deep vein thrombosis or arterial ischemic stroke, but studies are ongoing.130 Contraindications for the therapy (history of stroke, brain tumor, major surgery within past 10 days, neurosurgery within past 3 weeks, uncontrolled hypertension, and active major bleeding or potential for uncontrolled bleeding) should be balanced against the risks and benefits of lysing the thrombus on an individual basis. eTable 438.3 describes indications and management of thrombolytic therapy with tissue plasminogen activator.

Antithrombin Concentrates

Antithrombin concentrates have been approved for congenital antithrombin deficiency. They have also been used successfully off label in infants and children with heparin resistance and in those with acquired deficiencies who are at high risk for thrombosis (post surgery, pregnancy). In the United States, available products include a human plasma-derived antithrombin (Thrombate III® by Talecris Biopharmaceuticals) and Recombinant antithrombin (ATryn®; by Lundbeck Inc., manufactured by GTC Biotherapeutics, Inc.).

The potential complications of deep vein thrombosis (DVT) include death, pulmonary embolism, loss of central venous access, recurrent thrombosis, and postthrombotic syndrome. Results of the largest registries of children who had thrombosis describe a mortality rate from DVT/pulmonary embolism of 2.2% and a DVT recurrence rate of 8.1% to 21%.3 More prospective data related to specific therapies are needed to determine the true incidence of these complications.

Recurrence risk for stroke in children differs by etiology. It is increased for embolic stroke and systemic disorders and decreased in neonates.132 Recurrent strokes tend to occur within 3 months and involve the same vascular distribution in cases of arterial dissection or transient vasculopathy, whereas recurrences secondary to systemic disease, cardiac abnormalities, or moyamoya disease can be delayed many years and involve different cerebral territories.132 In one series, recurrence was increased in children who had stroke related to an elevated lipoprotein (a) or protein C deficiency in addition to vascular abnormalities.133 The long-term neurologic and neuropsychologic morbidities in children who have arterial ischemic stroke are substantial. Approximately 50% manifest moderate to severe motor and cognitive deficits.134 Intelligence quotients decrease in most children; however, the decrease is less marked in children who are aged 5 years or younger at the time of the event. Cerebral sinovenous thrombosis disproportionately affects neonates; it results in death or neurologic impairment in approximately half of the cases, particularly in those who presented with seizures or associated venous infarction.51

Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that is a direct consequence of injury to the venous valves, with resultant venous obstruction and ultimately venous hypertension.135 Signs and symptoms are heaviness, pain, swelling, and paresthesias of the affected limb as well as skin changes such as redness, dependent cyanosis, and even ulceration.135,136 Severe postthrombotic syndrome involving the legs can limit functional status, and studies in adults have demonstrated the benefit of anticoagulation and compression stockings in its prevention.135 Thrombolytic agents may help prevent postthrombotic syndrome (PTS) by hastening clot resolution.135-137 A recent report suggested that PTS and recurrence of thrombosis can be predicted by laboratory studies. Children with elevated levels of both quantitative D-dimer and factor VIII at the time of diagnosis and 3 to 6 months later were more likely to have long-term complications.92 The incidence of PTS has been reported to be as high as 65% to 80% in adults with acute DVT involving the upper or lower extremity, but the rate in children is not as well defined. Reports in children have estimated PTS to occur in 12% to 60% of cases of DVT, but the disability is generally classified as mild.139 In children, most DVT is associated with central venous catheters and therefore is more likely to involve the upper body venous system.1,42 Postthrombotic syndrome occurs less frequently after upper extremity DVT, particularly catheter-related, likely due to the reduced effect of gravity on blood flow. However, patients can manifest this complication weeks or even years after acute DVT.135,139,140 In adults, the majority of patients develop signs and symptoms within 2 years of diagnosis, but it is not known how long it can be apparent after childhood thromboembolic events.141 Treatment of PTS includes the use of analgesics and compression stockings.139

Thrombosis in children is becoming more prevalent. Providers need to be able to recognize the risk factors and the signs and symptoms for this problem so that early treatment can be given to prevent later complications. Additionally, the impact of inherited thrombophilia has not been fully defined, and more families are being identified as having risk for thromboembolic disease. Pediatricians and other primary care physicians will need to provide the initial education and counseling to families.