Aprotinin is a serine protease inhibitor with antithrombotic, antifibrinolytic, and antiinflammatory effects. It is effective in reducing bleeding and the need for blood transfusions after cardiac surgery with cardiopulmonary bypass. Additional benefits, such as cerebral protection, are hypothesized but not yet thoroughly substantiated. The safety of aprotinin has been questioned based on a phase IV analysis of large data sets, including patients undergoing cardiac surgery. Potential risks including increased occurrences of stroke, myocardial infarction, renal failure, and death are implied by these analyses; however, adequate study group matching is lacking from these nonrandomized, retrospective studies. In October 2007, a large randomized controlled trial comparing antifibrinolytics in patients undergoing cardiac surgery was stopped after a preliminary analysis suggested a trend toward an increase in all-cause 30-day mortality associated with aprotinin. Subsequently, the manufacturer of aprotinin temporarily suspended marketing and halted all shipment of aprotinin on a worldwide basis. Pending a complete analysis of this study, the use of aprotinin could be considered as one component of a blood conservation strategy. After contemplating the benefits and risks of this controversial drug, clinicians should reserve its use for patients at high risk for postoperative blood loss.

Benefits and risks of aprotinin use during cardiac surgery.

Cardiopulmonary bypass (CPB) has been routinely used in cardiac surgery for over 50 years. Depending on the definitions used, as many as 20% of cardiac surgical patients experience excessive bleeding in the perioperative period, and 2% to 6% of patients require re-exploration of the mediastinum. About half of these bleeding episodes are due to an identifiable surgical bleeding source, whereas the other 50% are presumably due to a coagulopathy. Hemostatic changes may result from both CPB and non–CPB-related variables, as well as pharmacologic modulation of the hemostatic system in the perioperative period. Despite improvements in the construction of CPB circuits and advances in both surgical and blood conservation techniques, there is still a substantial demand for perioperative blood product transfusion. This may be due to the changing demographics of the cardiac surgical population. More complex operations are being performed on older, sicker patients. Due to the complexities of the coagulation system, of the cardiac surgical procedures, the materials used in the CPB circuits, and a number of uncontrollable variables, we do not yet have a complete understanding of what causes the coagulopathy of bypass. Many of the studies looking at the effects of CPB on coagulation use in vitro models, and the results may or may not be applicable to the in vivo system. Spiess noted that what is being studied in one part of the system may not accurately reflect what is occurring in other parts of the system. He proposed that the complexity of the system requires a new paradigm, and a more comprehensive approach to research to garner a greater understanding of what truly controls hemostasis. This chapter will review the pathophysiologic effects of CPB on hemostasis and the effects of pharmacologic agents used to modulate the coagulation process. To appreciate these changes, a basic understanding of normal hemostasis is necessary.

Cardiopulmonary Bypass-associated Coagulopathies and Prophylactic Therapy

https://www.semthorcardiovascsurg.com/article/S1043-0679(04)00119-4/pdf

Antifibrinolytic agents in cardiac surgery: Current controversies

OBJECTIVES 
To assess the effects of ultra-low dose one million kallikrein inhibitor units (KIU) of aprotinin on bleeding and the need for transfusion after cardiac surgery.
 METHODS 
We carried out this randomized clinical trial on 162 cardiac surgery patients in Shahid Madani Hospital, Tabriz, Iran from April 2004 to December 2005. The patients were randomly divided into 2 groups of 81 individuals. In the aprotinin group, 0.5 million KIU infused before and 0.5 million KIU during cardiopulmonary bypass. In the placebo group, 100 ml normal saline was infused as above. The need to use fresh frozen plasma (FFP), packed red blood cells (PRBCs) transfusion during, after operation, the rate of chest tubes drainage at 6, 12 and 24 hours after surgery were measured in 2 groups.
 RESULTS 
Chest tubes drainage at 6 hours after surgery was 190 +/- 24 ml in the aprotinin group and 266 +/- 33 ml in the placebo group (p=0.066). The amount of bleeding at 12 and 24 hours was significantly different between 2 groups (p=0.048, p=0.009). The frequency of blood products transfusion in the aprotinin group was 68% and in the placebo group was 75% (p=0.02). The number of PRBCs and FFP units transfused were significantly lower in the aprotinin group (p=0.000, p=0.005). Total amount of blood and products transfusion in the aprotinin group was 2.56 +/- 0.27 units and in placebo group it was 4.37 +/- 0.27 units (p=0.0001).
 CONCLUSIONS 
Results indicate that the use of one million KIU of aprotinin in cardiac surgery is effective in reducing postoperative bleeding and transfusion requirements.

https://smj.org.sa/content/smj/28/1/49.full.pdf

Ultra-low dose aprotinin effects on reducing the need for blood transfusion in cardiac surgery.

This report describes two patients who underwent cardiac surgery utilizing cardiopulmonary bypass (CPB). Both patients were fully heparinized during the bypass period; however, both of them developed massive intravascular thrombosis and thromboembolism after initiation of heparin reversal with protamine. The surgeries were prolonged extensive procedures but and heparinization was carefully monitored throughout. The potential etiologies of this devastating, and very rare occurrence are explored. A less severe similar complication has been reported on one occasion previously from this institution.1 It is of interest that both patients described in these reports received prophylactic antifibrinolytic therapy, as did the patient in the previousearlier case report. The safety of administrating prophylactic antifibrinolytic therapy given routinely to patients undergoing on-pump cardiac surgery is examined.

/pdf/massive-intravascular-thrombosis-and-thromboembolism-after-3gvamlfsej.pdf

Massive Intravascular Thrombosis and Thromboembolism after Cardiopulmonary Bypass

BACKGROUND AND AIM OF THE STUDY Aprotinin is effective in promoting hemostasis, notably in cardiac surgery with cardiopulmonary bypass. Its efficacy has been shown in coronary bypass graft operations. However, few reports exist of aprotinin use in valve operations, and in those studies only the full dose was used. Thus, our aim was to evaluate the effects of low-dose aprotinin in patients undergoing heart valve reoperation. METHODS Eighteen patients having reoperative valve surgery received 10(6) KIU aprotinin after induction of anesthesia, and a further 10(6) KIU in the pump prime. A group of 18 similar patients who were operated on but did not receive aprotinin were used as controls. RESULTS A significant reduction in postoperative blood loss (approximately 470 ml) occurred in patients receiving aprotinin. These patients also presented less postoperative bleeding than untreated patients in 70.4% of cases. No adverse effects of the drug were noted, except for one case of allergic reaction. CONCLUSION The systematic use of low-dose aprotinin should be considered in valve reoperation, except in cases of re-exposure to the drug, or allergic reaction.

Gonçalves

Papers

Low-dose aprotinin in heart valve reoperations.