In children, there is an increasing off-label use of low molecular weight heparin (LMWH). However, there is an absence of information on dosing and pharmacokinetics of LMWH over all age groups. The objectives of the current study were to determine i) the once daily dose required to achieve anti-Xa levels of 0.5-1.0 IU/mL, ii) the pharmacokinetics and iii) preliminary safety data using tinzaparin. The study took the form of a single centre open-label Phase II study performed in 35 children requiring anticoagulation for treatment of thromboembolism. Age groups studied were: 0- < 2 months; 2 months- < 1 year; 1- < 5 years; 5- < 10 years; 10-16 years. Both population pharmacokinetic analysis using nonlinear mixed-effect modeling techniques and model-independent pharmacokinetic methods were employed. Results showed a relationship of age and dose requirements, clearance, time to peak anti-Xa level and volume of distribution. Younger children required an increased dose, cleared tinzaparin more rapidly, had anti-Xa levels peak earlier and had an increased volume of distribution. Younger children were more likely to be below target range than older children,with up to 75% of children < 1 year being below the target anti-Xa level. Four recurrences and one major bleed occurred. In conclusion, there is an inverse relationship of age on dose requirements related to volume of distribution, clearance and time to peak anti-Xa. Children < 5 years likely require dose adjustment samples to be drawn 2-3 hours post injection. Infants require anti-Xa levels to be monitored at least twice monthly.

Impaired fibrinolysis is considered a sensitive marker of endothelial dysfunction. Persistent endothelial dysfunction occurs in some patients following Kawasaki disease. The aim of the present study was to assess whether impaired fibrinolysis is present in long-term survivors of Kawasaki disease. The study included 42 children with a documented history of Kawasaki disease presenting with or without coronary lesions, and 26 healthy controls. Blood samples were collected from patients and controls prior to and following venous occlusion stress testing. Significantly decreased fibrinolytic response to venous occlusion was detected in patients compared with controls due to decreased tissue plasminogen activator. In addition, patients had significantly increased plasma concentrations of plasminogen and fibrinogen, which were related to similar increases of alpha2 -macroglobulin. Decreased fibrinolytic response was found in patients with coronary aneurysms but also in those without coronary lesions. In summary, a decreased fibrinolytic response to venous occlusion may reflect persistent endothelial damage following acute Kawasaki disease, potentially predisposing these patients to accelerated atherosclerosis and cardiovascular disease in early adult life.

Background: Kawasaki disease produces a vasculitis which may injure the coronary arteries and predispose these patients to early atherosclerosis. Previously, case reports have documented that Kawasaki patients may develop coronary calcifications and may die of sudden death many years after their acute illness. Ultrafast computer tomography (UCT) has been successful at detecting coronary calcifications in adults with atherosclerosis. The goal of this study is to show that UCT can be utilized as a non-invasive technique to identify Kawasaki patients at high risk for coronary disease and who would require long-term surveillance through adulthood.Methods and Results: Eighteen patients ages five to twenty-one years old with a history of Kawasaki disease were enrolled. Each patient had an UCT of the heart. There were four patients with calcifications noted. All of the four patients had: a previous history of an aneurysm, were at least five years from their acute illness, and had the calcification correlate to the previous site of aneursym formation. A calcium score was determined by the Agaston method for each calcification. The Mayo clinic guidelines for adult atherosclerosis were then used to correlate these scores with the risk of future coronary artery disease. All four patients were at moderate or greater risk of future coronary disease.Conclusion: This study indicates that UCT can be used as an effective non-invasive methodology in Kawasaki patients to successfully identify the high-risk patients predisposed to developing potential early atherosclerotic coronary artery disease.