**3. Thrombosis in infants and children**

Thromboembolism (TE) is still regarded as a rare event in childhood and therefore knowledge of diagnostics, therapy and prophylaxis is limited among general pediatricians. During the past years, however, it is increasingly recognized as having significant impact on mortality, chronic morbidity and the normal development of children, which has led to an enhanced sensitivity toward considering such events in respective patients. Besides the greater awareness, an objective increase in childhood thrombosis is due to the medical progress in the treatment of critically ill patients. This seemingly contradictory observation is easily explained by the increasing use of central catheters and innovative interventional procedures in the treatment of premature infants, neonates and older children who are critically ill, suffering from complex cardiac defects, and from malignant disease, respectively. Therapeutic and prophylactic measures have subsequently become increasingly important, but in addition to the complexity of the clinical background and the heterogeneity in the pattern of acquired and inherited risk factors for TE among patients, the physiological significant differences of the coagulation system between newborns, young children and adolescents and differences in drug metabolism do not allow general recommendations for therapeutic interventions like thrombolysis and prophylactic anticoagulation for the different clinical conditions. This situation is further complicated by a lack of availability of pediatric formulations and pediatric data for new drugs.

The increasing knowledge of exogenous and endogenous thrombophilic risk factors has initiated a number of studies to assess the impact of such factors with respect to their contribution to the thrombophilic state, both individually but also in concert with other factors. In addition to their impact on a first thrombotic event, much of the interest is now focused on their importance for thrombotic relapses. Only such studies will give us an answer to questions concerning the indications for treatment, prophylaxis and its optimal duration. All management recommendations are reflecting the authors' experiences and opinions and are not based on evidence gained by controlled trials as such trials are either completely lacking or still ongoing.

#### **3.1 Epidemiology**

The annual incidence of TE in childhood in general is considerably lower than in adults, with a reported frequency of 0.07 to 0.14 per 10.000 children or 5.3 per 10,000 referrals of children to the hospital. The results of a prospective German study suggested an incidence of 5.2 per 100,000 neonates, and a prospective Dutch study resulted in an estimate of 1.4 per 100,000 children and adolescents (Parasuraman & Goldhaber , 2006). More than 80% of TE in childhood were on a background of a severe preceding illness or other comparable predisposing factors. (Kuhle et al, 2004) Arterial TE in children is less common than venous thrombosis (Kuhle et al, 2004) with the exception of stroke. The estimated yearly incidence of stroke in childhood is between 3–8 per 100,000. (Giroud et al, 1995; Lynch et al, 2002). The highest incidence of 25–35 per 100,000 live births has been reported for neonates (Chalmer, 2005). In addition to its impact on the development of children, stroke also quantitatively plays the most important role.

The reasons for the lower incidences of TE in children compared to adults are not completely understood; an intact vascular endothelium, the lower capacity of thrombin generation (Haidi et al, 2006) and elevated levels of -2-macroglobulin, an inhibitor of thrombin, are possible age-dependent modifying factors in children. There are two agerelated peaks in the frequency of thromboembolic disorders in children and adolescents: the first peak corresponds to the perinatal/neonatal period, with the highest relative incidence, and the second is observed post puberty in adolescents, with a higher frequency in females.(Kuhle et al, 2004; Stein et al, 2004).

The relatively higher incidence in neonates as compared to older children may be due to higher hematocrit, and the greater lability of the hemostatic system in neonates due to the generally decreased levels of both coagulation factors and their inhibitors in this age group, except factor VIII (FVIII) and von Willebrand factor (VWF) which are normal or even elevated.(Monagle et al, 2006) In adolescents the incidence equals that of young adults, probably due to the hormonal status, the use of contraceptives or pregnancy in young women, obesity and smoking.(Stein et al, 2004).

Clearly, these epidemiological data have to be considered when assessing the individual absolute thrombotic risk of children with thrombophilia.
