Enhanced Thrombin Regulation during Warfarin Therapy in Children Compared to Adults^[*]

Summary

The intensity of warfarin therapy for prevention of primary and secondary thromboembolic complications in paediatric patients, is extrapolated from guidelines for adults, which may not be optimal. Therefore, we assessed thrombin regulation ex vivo and in vitro in plasmas from 40 children (1 to 18 years old with a median age of 13 years) and 27 adults receiving warfarin with an international normalized ratio of 2 to 3 (child: 2.5 ± 0.15; adult: 2.4 ± 0.14). Ex vivo concentrations of prothrombin fragment 1.2 were significantly lower in children (0.30 ± 0.03 nM) compared to adults (0.45 ± 0.04 nM; p <0.01). Thrombin generation in defibrinated plasmas (Arvin) was decreased and delayed for children compared to adults when activated by either activated partial thromboplastin time (child = 32 ± 1.7, adult = 45 ± 1.9 μM · s) or prothrombin time (child = 35 ± 0.7, adult = 46 ± 1.0 μM · s) reagents (p <0.01 for both). Although plasma concentrations of factors (F) II, FVII, FIX, F X, protein C and protein S were similar, more of the thrombin generated was complexed to α₂ macroglobulin (α₂M) at times close to peak thrombin activity (60 s) in plasma from children (general linear analysis of variance; p <0.03). Thus, increased α₂M levels may enhance thrombin regulation in paediatric compared to adult patients receiving warfarin, suggesting that clinical trials in children, using less intense warfarin treatment, may be required to determine optimum therapy.

^* This work was supported by a grant from the Heart and Stroke Foundation of Ontario. Dr. Massicotte is a fellow of the Heart and Stroke Foundation of Ontario, and Dr. Andrew is a Career Scientist with the Heart and Stroke Foundation of Canada.

• References

• 1 David M, Andrew M. Venous thromboembolism complications in children: A Critical Review of the Literature.. J Pediatr 1993; 123: 337-46.
• 2 Andrew M, Marzinotto V, Brooker L, Adams M, Ginsberg J, Freedom R, Williams W. Oral anticoagulant therapy in pediatric patients: A prospective study.. Thromb Haemost 1994; 71: 265-9.
• 3 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen D, Powers P. Development of the human coagulation system in the full-term infant.. Blood 1987; 70: 165-72.
• 4 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant.. Am J Pediatr Hematol Oncol 1990; 12: 95-104.
• 5 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood.. Blood 1992; 80: 1998-2005.
• 6 Johnston M, Zipursky A. Microtechnology for the study of the blood coagulation system in newborn infants.. Can J Med Tech 1980; 42: 159-64.
• 7 Schmidt B, Ofosu F, Mitchell L, Brooker L, Andrew M. Anticoagulant effects of heparin in neonatal plasma.. Pediatr Res 1989; 25: 405-8.
• 8 Andrew M, Ofosu F, Schmidt B, Brooker L, Hirsh J, Buchanan M. Heparin clearance and ex vivo recovery in newborn piglets and adult pigs.. Thromb Res 1988; 52: 517-27.
• 9 Hirsh J. Oral anticoagulant drugs. Review article.. N Engl J Med 1991; 324: 1865-75.
• 10 Poller L. Progress in standardization anticoagulation control.. Hematology Review 1987; 1: 225-41.
• 11 Loeliger E. ICSH/ICTH recommendations for reporting prothrombin time in oral anticoagulant control.. Acta Haematol 1984; 72: 405-7.
• 12 Bussey H, Force R, Bianco T, Leonard A. Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy.. Arch Intern Med 1992; 152: 278-82.
• 13 Hirsh J. Substandard monitoring of warfarin in North America: time for change.. Arch Intern Med 1992; 152: 257-8 (Editorial).
• 14 Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin.. Thromb Haemost 1990; 63: 27-30.
• 15 Ofosu F, Sie P, Modi G, Fernandez F, Buchanan M, Blajchman M, Boneu B, Hirsh J. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin.. Biochem J 1987; 243: 579-88.
• 16 Spevak P, Freed M, Castaneda A, Norwood WI, Pollack P. Valve replacement in children less than 5 years of age.. J Am Cardiol 1986; 8: 901-8.
• 17 El Makhlouf A, Friedli B, Oberhansli I, Rouge JC, Faidutti B. Prosthetic heart valve replacement in children.. J Thorac Cardiovasc Surg 1987; 93: 80-5.
• 18 Harada Y, Imai Y, Kurosawa H, Ishihara K, Kawada M, Fukuchi S. Ten-year follow-up after valve replacement with the St. Jude Medical prosthesis in children.. J Thorac Cardiovasc Surg 1990; 100: 175-80.
• 19 Stewart S, Cianciotta D, Alexson C, Manning J. The long-term risk of warfarin sodium therapy and the incidence of thromboembolism in children after prosthetic cardiac valves.. J Thorac Cardiovasc Surg 1987; 93: 551-4.
• 20 Rao S, Solymar L, Mardini M, Fawzy M, Guinn G. Anticoagulant therapy in children with prosthetic valves.. Ann Thorac Surg 1989; 47: 589-92.
• 21 Woods A, Vargas J, Berri G, Kreutzer G, Meschengieser S, Lazzari MA. Antithrombotic therapy in children and adolescents.. Thromb Res 1986; 42: 289-301.
• 22 Stein P, Alpert J, Copeland J, Dalen J, Goldman S, Turpie A. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.. Chest 1992; 102: 445S-55S.