Strategies to reduce hemostatic activation during cardiopulmonary bypass.

INTRODUCTION: We evaluated whether a modified protocol for cardiopulmonary bypass (CPB) could reduced the systemic hemostatic activation associated with this procedure. MATERIALS AND METHODS: The in vivo rates of thrombin, fibrin, plasmin and D-dimer generation were determined in each subject during CPB using measured levels of hemostatic factors combined with a computer model of the cardiovascular and hemostatic systems. A standard CPB group using uncoated circuits, standard heparin levels and direct shed blood reinfusion (n=9) was compared to a modified CPB group using heparin-coated circuits, shed blood collection, washing and reinfusion post-operatively, lower heparin levels and epsilon-amino-caproic acid (n=10). RESULTS AND CONCLUSIONS: Standard CPB increased average thrombin generation 9-fold, decreased fibrin generation 2-fold, increased plasmin generation 11-fold and increased fibrin degradation and D-dimer generation 19-fold. During CPB in the modified group thrombin generation was not increased beyond surgical levels, lower heparin concentrations allowed each thrombin to make more fibrin prior to inhibition, while fibrin degradation was suppressed by epsilon-amino-caproic acid. At baseline for every 100 fibrins formed only 1-2 were degraded to D-dimer. During standard CPB for every 100 fibrins generated on average 34 fibrins were degraded with some subjects showing a net fibrin loss. In contrast, in the modified CPB group for every 100 fibrins formed only 4 fibrins were degraded (p<0.0001 vs. standard group). Kinetic modeling of hemostasis in individual patients showed that a modified CPB protocol could reduce excessive thrombin generation during CPB and suppress fibrin degradation moving hemostatic regulation back towards normal.

Plasmin generation and D-dimer formation during cardiopulmonary bypass.

The purpose of this study was to estimate the in vivo rates of plasmin and D-dimer generation for comparison with the rate of fibrin formation during cardiopulmonary bypass (CPB), a procedure known to induce a hyperfibrinolytic state. Plasmin and D-dimer generation rates were based on measured levels of antiplasmin, plasmin-antiplasmin complex and D-dimer obtained before, during and after CPB from nine males, combined with a computer model of each patient's vascular system that continuously accounted for secretion, clearance, hemodilution, blood loss and transfusion. At baseline the average plasmin and D-dimer generation rates were 0.27 +/- 0.07 and 0.18 +/- 0.07 pmol/s, respectively. Within 5 min of CPB initiation, plasmin generation increased over 100-fold to 36 +/- 40 pmol/s while D-dimer generation increased 200-fold to 37 +/- 39 pmol/s. For the remainder of the CPB, average plasmin and D-dimer generation remained 20-fold to 30-fold above baseline levels. During CPB, the rate of D-dimer generation was similar to the rate of total fibrin formation, indicating that, in the absence of fibrinolytic inhibitors, CPB induces plasmin-mediated removal of fibrin from the vascular system at a rate similar to the rate of fibrin formation.

Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1 during cardiopulmonary bypass.

INTRODUCTION: Cardiopulmonary bypass (CPB) is associated with elevated tissue plasminogen activator (t-PA) levels during CPB and increased plasminogen activator inhibitor 1 (PAI-1) levels post-operatively. The goal of this study was to estimate the rate of t-PA and PAI-1 secretion in vivo, before, during and after CPB. MATERIALS AND METHODS: Estimated rates of t-PA and PAI-1 secretion were based on measured levels of active and total t-PA, and active and total PAI-1, obtained before, during and after CPB from nine males, combined with a computer model of each patient's vascular system that continuously accounted for secretion, clearance, hemodilution, blood loss and transfusion. RESULTS AND CONCLUSIONS: At baseline, the average t-PA and PAI-1 secretion rates were 0.74+/-0.33 and 1.28+/-0.74 pmol/s, respectively. Within 5 min of CPB initiation, t-PA secretion increased six-fold to 4.41+/-2.58 pmol/s, while PAI-1 secretion was unchanged, resulting in a six-fold increase in active t-PA levels. t-PA secretion remained elevated throughout CPB and into the early post-operative period. Average PAI-1 secretion did not start to increase until the end of CPB. By 2 h after surgery, average PAI-1 secretion had increased 15-fold to 19.60+/-17.10 pmol/s, resulting in reduced levels of active t-PA even though t-PA secretion was still elevated. We conclude that CPB induces an immediate sustained increase in t-PA secretion followed by a delayed progressive increase in PAI-1 production. Variations in the level of active t-PA are a function of the relative rates of t-PA versus PAI-1 secretion at different times during and after surgery.

Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass.

Our objective was to estimate the in vivo rates of thrombin and fibrin generation to better understand how coagulation is regulated. Studied were 9 males undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and soluble fibrin generation in vivo were based on measured levels of prothrombin activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and soluble fibrin, combined with a computer model of the patient's vascular system that accounted for marker clearance, hemodilution, blood loss, and transfusion. Prior to surgery, the average thrombin generation rate was 0.24 +/- 0.11 pmol/s. Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1% was soluble fibrin. The thrombin generation rate did not change after sternotomy or administration of heparin, then rapidly increased 20-fold to 5.60 +/- 6.65 pmol/s after 5 minutes of CPB (P =.000 05). Early in CPB each new thrombin generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin generation rate was 2.14 +/- 1.88 pmol/s during the remainder of CPB, increasing again to 5.47 +/- 4.08 pmol/s after reperfusion of the ischemic heart (P =.000 08). After heparin neutralization with protamine, thrombin generation remained high (5.34 +/- 4.01 pmol/s, P =.0002) and total fibrin generation increased, while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and fibrin generation rates were returning to baseline levels. We conclude that cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of nonhemostatic thrombin generation and dysregulated fibrin formation, not just a steady increase in thrombin generation as suggested by previous studies.

Effects of surgical trauma and cardiopulmonary bypass on active thrombin concentrations and the rate of thrombin inhibition in vivo.

The in vivo concentration of active thrombin and the second-order rate constant for the inhibition of thrombin by antithrombin (k(inh)) were estimated in patients undergoing cardiopulmonary bypass (CPB) based on measured levels of hemostatic markers in combination with a computer model of the patient's hemostatic and vascular systems. At baseline k(inh) = 0.6 +/- 0.1 microM(-1) s(-1) leaving 270 +/- 101 fM of active thrombin in the circulation. These factors were unchanged after sternotomy. Soon after heparin administration and the start of CPB, k(inh) increased 25-fold resulting in decreased active thrombin. After CPB and heparin neutralization, k(inh) decreased to 8-fold above baseline allowing active thrombin levels to rise. Both factors had returned to normal 2 h after surgery. We conclude that CPB with heparinization results in a rapid increase in thrombin inhibition leading to decreased active thrombin levels in vivo.