Multicentre evaluation of combined prothrombotic: defects associated with thrombophilia in childhood

To evaluate the role of multiple established and potential causes of childh ood thrombophilia, 285 children with a history of thrombosis aged neonate t o 18 years (first thrombotic onset) were investigated and compared with 185 healthy peers. APC-resistance (FV:Q(506)), protein C, protein S, antithrom bin, heparin cofactor II (HCII), histidine-rich glycoprotein (HRGP), and pr othrombin (F.II), factor XII (F.XII), plasminogen, homocysteine and lipopro tein (a) (Lp(a)) were investigated. In 59% of patients investigated one thr ombotic defect was diagnosed, 19.6% showed two thrombotic risk factors, whi le in 21.4% of children investigated no risk factor could be identified. Si ngle defects comprised established causes of inherited thrombophilia: FV:Q( 506) (homozygous n = 10, heterozygous n = 69), protein C (homozygous n = 1; heterozygous n = 31), heterozygous type I deficiency states of protein S ( n = 7), antithrombin (n = 7) and homocystinuria (n = 6); potentially inheri ted clotting abnormalities which may be associated with thrombophilia: F.XI I (n = 3), plasminogen (n = 2), HCII (n = 1), increased HRGP (n = 4); new c andidate risk factors for thrombophilia: elevated plasma levels of Lp(a) (n = 26), F.II (n = 1). Heterozygous FV:Q(506) was found in combination with heterozygous type I deficiency states of protein C (n = 2), protein S (n = 13), antithrombin (n = 8) and HCII (n = 1), increased Lp(a) (n = 13), and o nce each with elevated levels of F.II, moderate hyperhomocysteinemia, fibri nogen concentrations > 700 mg/dl and increased HRGP. In addition to the ass ociation with FV:Q(506), heterozygous protein C type I deficiency was combi ned with deficiencies of protein S (n = 2), antithrombin (n = 1), and incre ased Lp(a) (n = 3). One patient showed protein C deficiency along with fami lially increased von Willebrand factor > 250%. Besides coexistence with FV: Q(506) and protein C deficiency, protein S deficiency was combined with dec reased F.XII and increased Lp(a) in one subject each. Furthermore, we found combinations of antithrombin deficiency/elevated Lp(a), hyperhomocysteinem ia/Lp(a), deficiency of HCII/plasminogen, and plasminogen deficiency along with increased Lp(a) each in one. Increased prothrombin levels were associa ted with fibrinogen concentrations > 700 mg/dl and with HCII deficiency in one child each. Carrier frequencies of single and combined defects were sig nificantly higher in patients compared with the controls. Conclusion In conclusion, data of this multicentre evaluation indicate that paediatric thromboembolism should be viewed as a multifactorial disorder.