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Thrombin regulation in congenital heart disease after cardiopulmonary bypass operations
S O Turner-Gomes1, L Mitchell, W G Williams
1Department of Pediatrics, McMaster University, Hamilton, Ontario, Toronto, Canada.
Insights
Children undergoing heart surgery with cardiopulmonary bypass experience altered thrombin regulation. Post-surgery, thrombin generation capacity decreases due to hemodilution, increasing bleeding risk over clotting risk.
Area of Science:
- Cardiovascular Surgery
- Hematology
- Pediatric Cardiology
Background:
- Children with cyanotic congenital heart disease face high risks of bleeding or clotting after cardiopulmonary bypass.
- Thrombin, a critical coagulation enzyme, plays a vital role in managing these complications.
Purpose of the Study:
- To investigate thrombin generation and inhibition in pediatric patients with cyanotic congenital heart disease before and after cardiopulmonary bypass.
- To assess in vivo thrombin generation and levels of key thrombin inhibitors.
Main Methods:
- Analyzed plasma from 15 children with cyanotic congenital heart disease.
- Measured in vitro thrombin generation and 125I-thrombin inhibition.
- Assayed fibrinogen, thrombin-antithrombin III complexes, D-dimer, antithrombin III, alpha-2-macroglobulin, and heparin cofactor II levels.
Main Results:
- Post-cardiopulmonary bypass, in vitro thrombin generation capacity decreased by 50%, mainly due to hemodilution.
- Levels of thrombin inhibitors (antithrombin III, heparin cofactor II, alpha-2-macroglobulin) decreased by 26-45%.
- Despite reduced inhibitor levels, total in vitro thrombin inhibitory capacity decreased by only 13%.
- Increased thrombin-antithrombin III and D-dimer levels indicated in vivo thrombin generation.
- No thromboembolic events occurred, but six patients experienced significant bleeding.
Conclusions:
- Thrombin regulation is significantly altered after cardiopulmonary bypass in children with cyanotic congenital heart disease.
- Hemodilution impairs post-bypass thrombin generation capacity, elevating hemorrhagic risk.
- The relative preservation of thrombin inhibition capacity suggests a greater susceptibility to bleeding complications.
Abstract:
Children with cyanotic congenital heart disease who undergo operation with cardiopulmonary bypass are at increased risk of thromboembolic or hemorrhagic complications, or both. Regulation of thrombin, a key enzyme in coagulation, is essential in preventing these complications. We therefore examined the in vitro capacity of plasma from 15 children with cyanotic congenital heart disease to generate thrombin and to inhibit 125I-thrombin before and after cardiopulmonary bypass. We also assessed whether thrombin had been generated in vivo by assaying levels of fibrinogen, thrombin-antithrombin III complexes, and D-dimer. Plasma levels of the thrombin inhibitors, antithrombin III, alpha-2-macroglobulin, and heparin cofactor II were also measured. Thrombin regulation was normal before operation. After cardiopulmonary bypass, the in vitro capacity to generate thrombin decreased by 50%, and this was primarily a result of hemodilution (31%). Similar postoperative decreases were noted in the levels of antithrombin III, heparin cofactor II, and alpha-2-macroglobulin (26% to 45%). However, the total in vitro plasma thrombin inhibitory capacity decreased by only 13%. Levels of thrombin-antithrombin III and D-dimer increased after operation, indicating that thrombin had been generated and inhibited in vivo. Clinically, there were no thromboembolic complications although six patients required replacement therapy for excessive small-vessel bleeding. In conclusion, thrombin regulation is significantly altered after cardiopulmonary bypass. Although thrombin is generated in vivo, the total residual capacity to do so is impaired because of hemodilution. Despite a concomitant decrease in thrombin inhibitor levels, the total residual in vitro capacity of plasma to inhibit thrombin is relatively spared. This suggests that after cardiopulmonary bypass the risk of hemorrhagic complications after an additional hemostatic challenge is relatively greater than the risk of thrombotic complications. This might be reflected in the predominance of hemorrhagic complications in our patients.