Pediatric Aspects of Thrombophilia

Introduction

Compared with adults, children are relatively protected from venous and arterial thrombosis. Advances in the treatment and supportive care of critically ill children, along with heightened awareness of thrombotic complications, have resulted in an increase in the diagnosis of thromboembolic events. Greater recognition of genetic risk factors for thrombosis has led to controversy regarding whether children with thrombosis or a family history of thrombosis should be tested for inherited thrombophilia. Despite the fact that thrombotic events in children are increasing, in relative terms they are still rare. This has been the major impediment to conducting prospective clinical trials and has resulted in a lack of evidence-based treatment guidelines. Currently diagnosis and treatment are often extrapolated from the practice for adults, although this is unlikely to be the most appropriate approach.

Epidemiology

Epidemiologic studies of the incidence of thromboembolism in children are sparse. Small population-based studies in Canada and the Netherlands estimate the incidence of venous thromboembolism (VTE) in children younger than 18 years to be 0.7 to 1.4 per 100,000. In contrast to this low population incidence found abroad, neonates and children admitted to U.S. tertiary care hospitals have a much higher rate of VTE, which increased from 34 per 10,000 hospital admissions in 2001 to 58 per 10,000 admissions in 2007, suggesting that the overall incidence of VTE in children may also be increasing.

The age distribution of children with VTE is shown in Fig. 15.1 . Strikingly, infants younger than 1 year of age account for the largest proportion of those experiencing thrombotic events, and there is a second peak that occurs during adolescence.

Risk Factors

The majority of VTE occurs in children with underlying medical disorders, and idiopathic thrombosis is relatively rare, occurring in fewer than 10% of pediatric thrombosis cases. In fact, the majority of children with VTE have multiple coexisting risk factors. The presence of a central venous catheter is the single most prevalent risk factor for VTE in pediatric patients and is associated with approximately 90% of neonatal VTE and 60% of childhood VTE. These catheters are often necessary for the care of premature neonates and children with acute and chronic diseases; they are used for intravenous chemotherapy, anti­biotic administration, dialysis, hyperalimentation, and supportive therapy. Central venous catheters may damage the endothelial lining and/or disrupt blood flow, which increases the risk of thrombosis.

In addition to catheter use, multiple other acquired risk factors and medical conditions are associated with pediatric thrombosis, including prematurity, congenital heart disease, malignancy, infection, immobility, inflammatory disorders, surgery, dehydration, obesity, estrogen use, antiphospholipid syndrome (APLS), nephrotic syndrome, and administration of L-asparaginase.

Anatomic abnormalities that impede blood flow also predispose patients to thrombosis at an earlier age, often during adolescence. Atresia of the inferior vena cava has been described in association with acute and chronic lower extremity deep venous thrombosis (DVT). May-Thurner syndrome (compression of the left iliac vein by the overlying right iliac artery) should be considered in patients who spontaneously develop left ileofemoral thrombosis, and thoracic outlet obstruction (Paget-Schroetter syndrome) frequently presents with effort-related axillary-subclavian vein thrombosis.

Developmental Hemostasis

The hemostatic system in neonates differs from that in older children and adults and influences the frequency of thrombosis in this population as well as the response to therapeutic agents. Normal hemostasis is achieved through a dynamic balance between thrombin formation, thrombin inhibition, fibrin deposition, and fibrinolysis. Although the basic pathways for thrombus formation and degradation are the same in the developing fetus and neonate, the concentrations of many of the coagulation factors vary greatly.

Plasma concentrations of the vitamin K–dependent procoagulant factors (II, VII, IX, and X) are decreased at birth and are even lower in preterm infants. These concentrations increase rapidly and approach normal levels by 6 months of age ( Fig. 15.2A ). Similarly, levels of the anticoagulant factors protein C and protein S are also decreased in neonates, which balances the system (see Fig. 15.2B ). Protein C activity remains decreased throughout much of childhood.

Levels of the direct thrombin inhibitors antithrombin III (ATIII) and heparin cofactor II are also decreased in newborns, and thrombin inhibition is more dependent on α ₂ -macroglobulin, the level of which is increased. Finally, in the neonatal fibrinolytic pathway, plasminogen and α ₁ -antiplasmin levels are decreased, but levels of tissue plasminogen activator (tPA) are increased.

This evolving hemostatic system is largely physiologic, providing relative protection for infants from both bleeding and thrombosis. Ill and premature neonates may be at greater risk of imbalances in these procoagulant and anticoagulant pathways, which increases their risk of thrombosis or bleeding.

Although reference ranges for coagulation proteins in infants and children derived from a Canadian cohort were reported in the 1980s, followed by publication of more recent data from an Australian study, interpretation of the results of coagulation factor assays is often not straightforward. This is in part because these values are rapidly changing in neonates but also because most coagulation laboratories have not established pediatric age-related normal ranges using their reagents and analyzers. Therefore one must be cautious in interpreting levels of protein C, protein S, and ATIII, particularly in infants in whom physiologic values are changing rapidly. Rarely are there absolute cutoff values that are useful; the normal range may overlap with values found in children with heterozygous defects, and retesting may be required as the child matures.

Inherited Thrombophilia

In addition to the common risk factors already described, inherited coagulation defects may also contribute to pediatric thrombosis. The clinical usefulness of thrombophilia testing, in both adults and children, has become increasingly debated.

Chapter 14 provides a comprehensive review of the thrombophilias identified by laboratory testing. The inherited defects in which the pathogenic link is best understood include the factor V Leiden mutation, the prothrombin 20210 gene mutation, and deficiencies of protein C, protein S, or ATIII. Elevated levels of factor VIII, lipoprotein (a), and homocysteine are associated with thrombosis, but these disorders are less well characterized and are not necessarily genetically determined. Although additional alterations in coagulation have been associated with thrombotic risk, none has gained widespread acceptance as a target of routine testing for inherited thrombophilia in children.

The reported prevalence of inherited thrombophilia in children with venous and arterial thrombosis varies greatly depending on the population studied and the definition of thrombophilia used. A meta-analysis of pediatric VTE studies demonstrated a statistically significant association between the first episode of VTE and each thrombophilic defect tested, with odds ratios as shown in Table 15.1 . Children younger than 1 year of age were underrepresented in this meta-analysis. Although a meta-analysis of pediatric stroke studies (including acute ischemic stroke and cerebral sinovenous thrombosis) showed associations with many (but not all) of the common inherited thrombophilias (see Table 15.1 ), a large case-control study of children with perinatal stroke did not find an association. The association between inherited thrombophilia and thrombosis also depends on the clinical scenario: adolescents experiencing unprovoked thrombotic events have a very high prevalence of inherited defects (approximately 60%), whereas a role for thrombophilic defects in children experiencing catheter-related thrombotic events is questionable.

The management of a child experiencing a thrombotic event is rarely influenced by the results of thrombophilia testing. Although some inherited defects are associated with a higher risk of recurrent VTE in children (see Table 15.1 ), current treatment recommendations do not stratify treatment duration or intensity based on these findings. Prospective longitudinal studies of such patients to determine outcome and response to treatment as well as the impact of known thrombophilic states on these outcomes are clearly needed.

One group for which testing for inherited defects may have clinical relevance comprises the rare neonates with homozygous deficiency of protein C, protein S, or ATIII. These infants may have purpura fulminans, a condition characterized by rapidly spreading purpuric skin lesions resulting from thromboses of the small dermal vessels, followed by bleeding into the skin. In addition, these patients may develop cerebral thrombosis, ophthalmic thrombosis, disseminated intravascular coagulation, and large-vessel thrombosis. The estimated incidence of homozygous protein C deficiency is 1 in 250,000 to 500,000 births. There are only a few case reports in the literature of infants with homozygous ATIII or protein S deficiency. An infant with purpuric skin lesions of unknown cause should initially receive replacement with fresh frozen plasma and undergo testing for protein C, protein S, and ATIII deficiency. Definitive diagnosis can be difficult in the ill premature neonate, who may have undetectable levels of these factors but not have a true genetic deficiency; in this case, testing the parents may be helpful. Protein C and ATIII concentrates are also available and have been demonstrated to be effective.

Providers are increasingly asked to evaluate asymptomatic children (with no prior thrombosis) who have relatives with either thrombosis or thrombophilia. The decision to perform thrombophilia testing in an otherwise healthy child with a family history of thrombosis or thrombophilia should be made carefully, and the potential advantages and limitations of such an approach should be weighed. Given that the absolute risk of thrombosis in children is extremely low, it is unlikely that an inherited thrombophilia will have any impact on clinical decision making for a young child. The risk of thrombosis increases with age, so that identification of a thrombophilic defect in an adolescent may guide thromboprophylaxis in high-risk situations (e.g., lower extremity casting, prolonged immobility), inform the discussion about estrogen-based contraception, and promote lifestyle modification to avoid behavioral prothrombotic risk factors (sedentary lifestyle, dehydration, obesity, and smoking). Limitations of such testing include the cost as well as the potential for causing unnecessary anxiety or false reassurance.

Considerations regarding thrombophilia testing in children based on current understanding of the contribution of prothrombotic risk factors to pediatric thrombosis and the potential for benefit are outlined in Table 15.2 .

Clinical Features

Signs and symptoms of venous and arterial thrombotic events in children depend on the anatomic location. The most common thrombotic events in children are reviewed in the following sections.