Venous thromboembolism (VTE) is increasingly recognized in children. In the 1990s, the annual incidence was estimated to be 0.07–0.14 per 10,000 children (1, 2). Since then, studies showed more and more children developing thromboembolic complications as a result of improved diagnosis, increased survival of children with severe underlying diseases, and increased use of invasive procedures and instruments such as central venous catheters. From 2001 to 2007, diagnosis of VTE increased from 34 to 58 cases per 10,000 hospital admissions in the United States (3). This increase was observed in all age categories. Neonates and adolescents have the greatest risk for VTE (4). It is a serious disease, which leads to mortality and morbidity. The mortality rate is about 2%. Morbidity includes lack of thrombus resolution in 50% of the patients and the development of post thrombotic syndrome in about 30% of the patients (5).

In contrast to adults, most of the venous thrombi in children are associated with clinical risk factors. In neonates, more than 90% of the thrombi are catheter related. In older children, catheters are important risk factors as well, as about 50% of VTE are associated with central venous catheters (4). In addition, other clinical risk factors contribute to the thrombotic risk, including cardiac disease, malignancy, surgery, immobility, and medications such as asparaginase and estrogen-containing contraceptives. These clinical risk factors may trigger VTE in thrombophilia carrier patients. It is still a matter of debate whether it is useful to test thrombophilia in children with a first venous thrombotic event. This article will discuss the potential arguments for testing of inherited thrombophilia, including factor V Leiden mutation (FVL), prothrombin mutation (FIIm), and deficiencies of antithrombin, protein C, or protein S and suggests some pediatric patient groups, which may be candidates for testing.

Inherited thrombophilia is defined as an inherited coagulation disorder associated with an increased risk for thrombosis. The most frequent inherited thrombophilic defects include deficiencies of antithrombin, protein C, protein S, FVL, and FIIm.

Antithrombin deficiency was the first identified genetic risk factor for VTE. In 1965, Egeberg reported a family with increased risk for venous thrombosis due to antithrombin deficiency (6). He was the first who used the term thrombophilia. Antithrombin deficiency appears to be very scarce with a prevalence of about 0.02% in the general population (7).

Antithrombin inhibits several enzymes of the coagulation system including factor IIa, IXa, Xa, and XIIa. Type I deficiency is associated with low antithrombin antigen and activity levels. Type II deficiency is characterized by decreased functional activity. Homozygous antithrombin deficiency type I patients have not been described, assuming complete antithrombin deficiency is not compatible with life.

Protein C and protein S act together to inactivate factor Va and factor VIIIa. Protein C deficiency has been recognized since 1981 (8). Since then, more than 160 mutations have been identified. The prevalence of protein C deficiency is estimated to be about 2% (7). Two types of protein C deficiency have been described. Type 1 deficiency is associated with decreased antigenic levels as well as functional activities of protein C. In type II deficiency, the activity levels of protein C are more decreased than the antigenic levels.

Protein S deficiency has first been described in 1984 (9). The prevalence is low and varies between 0.026 and 0.13% (7). Two forms of protein S are present in the plasma: about 60% is bound to complement regulator C4b-binding protein and the remaining 40% circulates as free protein S. Only free protein S can serve as a cofactor for activated protein C. There are three types of protein S deficiency. Types I and III are quantitative deficiencies. In type I, levels of both free and total protein S are low, whereas only free protein S levels are decreased in type III deficiency. Type II deficiency is a qualitative disorder with normal antigen and decreased activity levels of protein S.

Both protein C and S deficiency can present in heterozygous, homozygous, or compound heterozygous forms, although the last two forms are extremely rare. These patients present with neonatal purpura fulminans (10, 11). In infancy, diagnosis of homozygous protein C or S deficiency can be made by measuring the functional activity of protein C or S, which will be undetectable. Diagnosis of heterozygous protein C, S, or antithrombin deficiency, however, will be challenging as all anticoagulant protein levels are physiologically lower in healthy (preterm) neonates compared to adult levels as result of developmental hemostasis (12). Protein S and antithrombin levels reach adult levels over the first 6 months of life. Protein C levels may remain low until adolescence (13).

FVL is the most common inherited thrombophilic defect although its prevalence varies widely. Prevalences of heterozygous FVL range from 1 to 9% in European countries, whereas it is rarely found in African and Asian individuals (14). FVL is characterized by a substitution of glutamine by arginine on position 506 of the factor V protein at the activated protein C cleavage site. It causes resistance of factor Va to cleavage by activated protein C leading to an excess of factor Va and, consequently, a hypercoagulable state (15, 16).

FIIm is the second most common inherited thrombophilic defect. In Caucasians, the prevalence of this mutation is about 2% (17). It is characterized by a point mutation (nucleotide 20210 G to A) in the prothrombin gene, which is associated with increased levels of prothrombin, the precursor of thrombin (18). Increased levels of prothrombin increase the half-life of factor Va. As factor Va, bound in the prothrombin-factor Va complex, is resistant to activated protein C cleavage, increased levels of prothrombin increase the half-life of factor Va, leading to a hypercoagulable state.

In general, there are three possible arguments to test for thrombophilia in children with a first venous thrombotic event. First, if there is an association between inherited thrombophilia and the development of pediatric thrombosis, identification of a thrombophilic defect may help to learn why a young patient developed thrombosis, especially if the thrombotic event was unprovoked. Second, testing should be performed if a positive test result will change the patient’s management, such as prolongation of anticoagulant prophylaxis of recurrent thrombotic events. Finally, testing pediatric patient with VTE may help to identify asymptomatic relatives who may avoid thrombotic risk factors and benefit from thromboprophylaxis in high-risk situations.

One of the disadvantages of testing children with VTE could be the psychological stress of knowing to be a carrier of an inherited thrombophilic defect. No studies are available investigating the psychological impact of thrombophilia testing on children. In adults, thrombophilia testing does not seem to trigger psychological stress or worry (37, 38). Another disadvantage may be the potential problems with health insurance or life insurance in future. One of the patients in the study of Bank et al. had been discriminated by an insurance company because of FVL. The other 16 patients had not informed the insurance companies (39). Finally, thrombophilia testing is expensive. Many tests are ordered inappropriately (40, 41). Proper thrombophilia testing will reduce costs.

As mentioned before, the chance of finding inherited thrombophilia varies between pediatric patient groups with VTE. Inherited thrombophilia seems to be present in adolescents with unprovoked thrombosis and children with a positive family history. In the study of Revel-Vilk et al., thrombophilia was detected in only 13% of all 171 pediatric patients with VTE, but in 60% of the adolescents with unprovoked thrombosis (22). Ruud et al. showed in a cross-sectional study that a positive family history for VTE increased the relative risk of a child having inherited thrombophilia to 2.35 (95% CI, 1.1–5.2) (42). In addition, in a prospective cohort study of 100 neonates and children with VTE, positive family history appeared to be the only predictor for presence of inherited thrombophilia (OR 14.9; 95% CI, 1.9–113) (24). In neonates and children with catheter-related thrombosis, thrombophilia was found less frequently. For example, Salonvaara et al. described 10 neonates with symptomatic catheter-related thrombosis. Only 1 of the 10 patients had FVL (26). Albisetti et al. studied the prevalence of thrombophilia in cancer patients with and without catheter-related thrombosis. Thrombophilia was found in 4% of cancer patients with VTE and in 12% of patients without VTE (21). Finally, Thom et al. could not find an association between catheter-related VTE and thrombophilia in cardiac pediatric patients (23).

So, thrombophilia testing seems to be advisable in adolescents with unprovoked VTE and in children with a positive family history for VTE and less useful in neonates and children after a first episode of catheter-related VTE.

The presence of inherited thrombophilic defects in neonates and children with a first event of VTE does not influence primary antithrombotic management and while it may be one of the causes of the thrombotic event, it infrequently alters long-term management. However, the presence of antithrombin deficiency with its high risk of recurrent thrombosis may warrant adjustment of long-term management. In these children, intermittent anticoagulation in high-risk situations may aid to prevent recurrent thrombotic episodes. Furthermore, testing might be helpful to identify asymptomatic female relatives with thrombophilia who may get better informed about a healthy lifestyle and the risks of combined oral contraceptives at fertile age.

On the other hand, one might argue that all children with first VTE are candidates for prophylactic anticoagulation in high-risk situations, not only antithrombin deficient children. And a positive family history for VTE might be enough to choose less thrombotic contraceptive methods, such as progesterone-only preparations (Table 2).

Consequently, testing for inherited thrombophilia in children with a first episode of VTE should not be performed on a routine basis. In neonates and children with catheter-related thrombosis, inherited thrombophilia seems to contribute less to the thrombotic event than in adolescents with unprovoked thrombosis and children with a positive family history for VTE. Therefore, especially these latter groups seem candidates for testing.

In these children, the decision of testing should be made on an individual base after proper counseling before and after testing by an experienced physician, discussing the disadvantages and benefits of testing, the preference of the patient, and the consequences of the test results after testing.

CO and UN-G were both involved in drafting the concept of the manuscript. CO wrote the manuscript, UN-G read, edited, and approved final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.