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Enhanced thrombin regulation during warfarin therapy in children compared to adults
P Massicotte1, M Leaker, V Marzinotto
1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Insights
Warfarin dosing for children may need adjustment. Pediatric patients show different thrombin regulation compared to adults, suggesting potentially safer, less intense warfarin therapy is possible.
Area of Science:
- Pharmacology
- Hematology
- Pediatrics
Background:
- Current warfarin dosing for pediatric thromboembolic prevention is based on adult guidelines.
- Optimal warfarin intensity in children remains uncertain, potentially leading to suboptimal treatment.
Purpose of the Study:
- To compare thrombin regulation ex vivo and in vitro in pediatric and adult patients on warfarin therapy.
- To investigate potential differences in warfarin's anticoagulant effect between age groups.
Main Methods:
- Assessed thrombin generation and prothrombin fragment 1.2 levels in plasmas from 40 children and 27 adults on warfarin (INR 2-3).
- Utilized activated partial thromboplastin time and prothrombin time reagents for thrombin generation assays.
- Measured plasma concentrations of coagulation factors (II, VII, IX, X) and anticoagulants (protein C, protein S).
Main Results:
- Children exhibited significantly lower ex vivo prothrombin fragment 1.2 concentrations compared to adults.
- Thrombin generation was decreased and delayed in children's plasma.
- Higher complexation of generated thrombin with alpha2-macroglobulin (alpha2M) was observed in children.
Conclusions:
- Differences in thrombin regulation, potentially due to increased alpha2M, suggest pediatric patients may require different warfarin dosing.
- Current warfarin therapy intensity in children might be higher than necessary.
- Clinical trials are warranted to determine optimal, potentially less intense, warfarin treatment for pediatric patients.
Abstract:
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 microM x s) or prothrombin time (child = 35 +/- 0.7, adult = 46 +/- 1.0 microM x 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 alpha2 macroglobulin (alpha2M) at times close to peak thrombin activity (60 s) in plasma from children (general linear analysis of variance; p <0.03). Thus, increased alpha2M 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.