We report a case of juvenile thrombophilia associated with a substitution of leucine for arginine at position 338 (R338L) in the factor IX gene (factor IX-R338L). The level of the mutant factor IX protein in plasma was normal, but the clotting activity of factor IX from the proband was approximately eight times the normal level. In vitro, recombinant factor IX-R338L had a specific activity that was 5 to 10 times as high as that in the recombinant wild-type factor IX. The R338 substitution causes a gain-of-function mutation, resulting in factor IX that is hyperfunctional.

Antithrombin and protein C and S defects, factor V Leiden mutation, and G20210A prothrombin gene mutation are well-recognized risk factors for venous thromboembolism (VTE) in adults, especially during circumstantial situations such as trauma, immobilization, surgery, or oral contraceptive treatment. The relevance of these defects in predisposing children to VTE is still undefined. In a prospective cohort study we assessed the incidence of spontaneous and risk period-related VTE in asymptomatic children (aged 1-14 years), who were family members of a proband with an objectively diagnosed venous thromboembolic event and a documented single thrombophilic abnormality. We enrolled 143 children from 63 families. Of them, 81 (56.6%) were carriers of an inherited defect, whereas the remaining 62 were free from known genetic or acquired causes of thrombophilia. The mean observation period was 5 years (range, 1-8 years) in each group. Thirty-one risk periods occurred in the carriers group and 20 in noncarriers. Neither spontaneous nor risk period-related VTE occurred in either group during 395 and 296 observation years, respectively. However, circumstances where most of the pediatric thromboses occur (insertion of central venous lines, cancer, and cardiovascular surgery) were not encountered. In conclusion, the thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be very low. Common triggering conditions for VTE in thrombophilic adults do not seem to increase the thrombotic risk in children carrying the same inherited defect. Accordingly, screening for thrombophilia in otherwise healthy children younger than 15 years who belong to families with inherited defects predisposing to thrombosis seems unjustified.

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.

Common tests for the assessment of blood coagulation in the acute phase of deep vein thrombosis are of limited value for the evaluation of the associated hypercoagulability. The new rotation thromboelastometry by rotation thrombelastogram has the potential to provide information on whole blood clot formation and prothrombotic state in patients with acute deep vein thrombosis. Rotation thrombelastogram parameters were evaluated in whole blood of 30 patients with a first episode of acute deep vein thrombosis and 40 healthy controls. The effect of factor VIII and fibrinogen levels on rotation thrombelastogram assays was also assessed in the study population and in a model of blood supplemented by increasing amounts of fibrinogen. All assays performed were consistent with a remarkable hypercoagulable profile in deep vein thrombosis patients as compared with controls. In particular, maximum clot firmness and the area under curve values, which are expected to better correlate with the hypercoagulable state in the acute phase of deep vein thrombosis, were significantly higher in patients than in controls. As expected, fibrinogen was shown to be one of the main determinants of the hypercoagulability in rotation thrombelastogram assays. In a small subset of acute deep vein thrombosis patients, inherited thrombophilia had no influence on rotation thrombelastogram parameters. The new rotation thrombelastogram thromboelastometry is a useful tool to detect acute deep vein thrombosis-related hypercoagulability. Prospective studies are needed to define the potential applications of rotation thrombelastogram in the management of deep vein thrombosis patients.