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Ann Thorac Surg 2006;81:1720-1727
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Protamine Enhances Fibrinolysis by Decreasing Clot Strength: Role of Tissue Factor-Initiated Thrombin Generation

Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama

Accepted for publication December 7, 2005.

^_* Address correspondence to Dr Nielsen, Department of Anesthesiology, The University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35249-6810 (Email: vnielsen{at}uab.edu).

BACKGROUND: Excessive protamine administration to neutralize heparin after cardiopulmonary bypass has been implicated as a cause of postoperative hemorrhage. Protamine directly inhibits thrombin and tissue factor (TF)-mediated activation of factor VII. However, the half-life of protamine is only 4.5 minutes; thus the purpose of this study was to determine if protamine could enhance fibrinolysis, explaining the delayed, protamine-associated hemorrhage observed in the postoperative period.

METHODS: Human plasma containing 0, 6.25, 12.5, or 25 µg/mL of protamine (n = 6 per condition) was exposed to 0.01% tissue factor and tissue-type plasminogen activator (tPA, 100 U/mL) for 30 minutes, with clot growth and disintegration measured by Thromboelastograph (Haemoscope Corp, Skokie, IL). The TF was increased to 0.1% in additional experiments with plasma containing protamine (25 µg/mL) and tPA.

RESULTS: Protamine significantly (p < 0.05) delayed the time to clot initiation, decreased the speed of clot propagation, and diminished clot strength in a concentration-dependent fashion. The onset of fibrinolysis was significantly (p < 0.05) increased only in samples with 25 µg/mL of protamine, and the rate of clot lysis was not different among the conditions. The clot duration time (from initiation to disintegration) was significantly (p < 0.05) decreased in a concentration-dependent manner by protamine. Increased TF concentration (0.1%) significantly improved clot growth kinetics and prolonged clot duration in samples with 25 µg/mL of protamine compared with samples activated with 0.01% TF.

CONCLUSIONS: Protamine enhanced fibrinolysis by decreasing clot strength by diminishing TF-initiated thrombin generation. Additional, clinical investigation is warranted to mechanistically implicate protamine-mediated enhancement of fibrinolysis to delayed bleeding after cardiopulmonary bypass.

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