Impact of Thrombophilia and Incidence of Symptomatic Thromboembolism in First Degree Family Members (FM) of Pediatric Index Cases: a Prospective Cohort Study in FM > 14 Years of Age.

Venous thrombosis is a multifactorial disease and inherited genetic traits (IT) constitute a major risk factor. The aim of the present prospective cohort study was to determine i) the relative and absolute risks of first symptomatic thromboembolism [TE] in previously healthy family members of children with venous thromboembolism, and ii) whether to screen family members in a high risk population.

In 205 patients (neonate to 18 years) and 526 FM followed over a total person-time of 14157 years /1000 units [person-time] a comprehensive IT screening was performed along with recording of family histories of preexisting cardiovascular diseases. FM were followed until July 2009: study endpoint was cumulative time to first TE within FM. Survival analysis (Cox regression: hazard ratio (HR/95% Confidence intervals (CIs)] adjusted for age and gender and number of new cases divided by the total population at risk (incidence rate) were calculated (events (%) per 1000 person-years [CIs]).

The final study population included 526 FM with 462 subjects > 14 years. The cumulative TE –free survival in FM with IT was significantly lower compared to those without: HR/CI: 6.6/ 3.3-13.5. The overall rate of symptomatic TEs was 2.9%[2.07-3.9]. The hazard adjusted for age and gender in the group of antithrombin(AT)-/protein C[PC)-/protein S(PS)-deficient FM was 29.4%[13.3-62.5], and for carriers of factor (F) V G1691A, F II G202010A mutations or elevated lipoprotein (a) it was found to be 3.3%[1.3-8.3], 1.96% [0.4- 9.0] and 2.1%[1.04-3.8]. Corresponding annual incidence rates in FM > 14 years were 4.8% for AT-/PC- or PS-deficiency states, 0.72% in subjects carrying the FV mutation, 0.36 % in FII carriers, and 0.20% for subjects with elevated lipoprotein (a) compared with 0.19% in FM with no IT. Thus, compared to adult data from the view of adult index cases [Lijfering W et al. Blood 2009] i) the risk of TE in family members of pediatric index cases with TE depends on IT, ii) the age at TE in the index patient as well as in the family members has a strong effect on TE incidence, and iii) the first symptomatic TE in primary healthy family members > 14 years of age with respect to the IT investigated is comparable to or exceeds adult data.

i) Adult family members of pediatric index patients with an early onset of symptomatic thrombosis should be considered for IT testing, ii) primary thromboprophylaxis in family members derived from pediatric index patients should be considered in risk situations in adult carriers of AT/PC/PS-deficiencies & FV mutation. In addition, iii) larger prospective studies are needed to investigate the effects of multiple ITs and its interactions to take into account whether events are provoked or not to investigate the effect of screening.

Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.