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Ann Thorac Surg 1995;59:872-876
© 1995 The Society of Thoracic Surgeons

Aprotinin Improves Hemostasis After Cardiopulmonary Bypass Better Than Single-Donor Platelet Concentrate

Ami Shinfeld, MD, Douglas Zippel, MD, Jacob Lavee, MD, Ayala Lusky, MSc, Eilat Shinar, MD, Naphtali Savion, PhD, Rephael Mohr, MD

Department of Cardiac Surgery, Goldschleger Eye Institute, Department of Epidemiology, and National Blood Bank, The Chaim Sheba Medical Center, Tel Hashomer, Israel

Accepted for publication November 29, 1994.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Platelet transfusion and aprotinin administration improve platelet function and clinical hemostasis after extracorporeal circulation. To compare two methods of improving postoperative hemostasis, we preoperatively randomized 40 patients undergoing various open heart procedures into two groups. Group A included 20 patients who, immediately after bypass, received single-donor plateletpheresis concentrates collected from ABO-compatible donors (Baxter Autopheresis-C System). They were compared with 20 patients who received high-dose aprotinin (6 x 106 KIU) before and during cardiopulmonary bypass (group B). Group A patients showed significantly higher platelet count after single-donor plateletpheresis concentrate transfusion (157 +/- 36 x 109/L compared with 118 +/- 42 x 109/L (p < 0.05). However, platelet aggregation on extracellular matrix was better in group B (3.4 +/- 0.7 versus 2.8 +/- 0.9; p < 0.05). Total 24-hour blood loss and exposure to homologous blood products were significantly less in group B (396 +/- 125 mL and 1.1 +/- 1.6 units compared with 617 +/- 233 mL and 5.4 +/- 3.4 units; p < 0.01). Despite higher platelet count in patients after single-donor plateletpheresis concentrates transfusion, hemostasis in patients receiving aprotinin is better due to improved platelet function.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The impaired hemostasis observed after cardiac operations mainly is due to acute acquired platelet dysfunction and decrease in platelet count [1–3]. Administration of the protease inhibitor aprotinin improves postoperative hemostasis by its protective effect on platelet adhesiveness and aggregation [4, 5]. Another means to improve postoperative platelet function is administration of fresh plateletpheresis concentrates. Transfusion of single-donor plateletpheresis concentrate (SDPC) collected on the morning of operation from an ABO-compatible donor can minimize exposure to homologous blood products while providing the patient with a relatively large amount of platelets.

The purpose of the present study was to compare the effect of high-dose aprotinin with that of SDPC transfusion on clinical hemostasis and platelet function after cardiopulmonary bypass (CPB).


   Patients and Methods
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 Footnotes
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Forty patients undergoing various CPB procedures were randomized preoperatively into two groups.

Group A included 20 patients who, immediately after CPB, received fresh SDPC collected from an ABO-compatible donor on the morning of operation. Platelet collection was done using the Autopheresis-C system (Baxter Apheresis Instrument Model A-201 with the Plateletcell Separator; Baxter Healthcare Corp, Irvine, CA) [6]. This system allows continuous uninterrupted processing of donor blood to provide 600 to 700 mL of platelet-rich plasma, with red cells returned to the donor. Platelets are concentrated to a volume of approximately 200 mL by using a spinning membrane plasma separation device, which is part of the processing unit. The 200 mL of platelet concentrates contained 3.4 +/- 1.2 x 1011 platelets, with a mean platelet volume of 8.2 fL. White blood cell and red blood cell contamination were low (3 x 109 and 5 x 108 concentrate, respectively). Collecting time was 70 minutes, with no side effects to the donors.

Group B included 20 patients who received high-dose aprotinin during CPB. A loading dose of 2 x 106 KIU aprotinin (Trasylol; Bayer, Leverkusen, Germany) was given before sternotomy. An additional dose of 2 x 106 KIU was added to the priming solution of the bubble oxygenator, and continuous infusion of 0.5 x 106 KIU/hour was given until skin closure or until a total dose of 6 x 106 KIU aprotinin was achieved. Clinical and surgical data of the patients are presented in Table 1Go.


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  		Table 1. . Characteristics of Patients in the Two Study Groups
 
For all patients a Sarns pump (Sarns Inc, Ann Arbor, MI) and bubble oxygenator (Bentley Laboratories, Inc, Irvine, CA) were used. The oxygenators were primed with 1,500 mL of Hartmann's solution and 500 mL of dextrose 5% solution. All pump blood was returned to the patient through the aortic cannula or intravenously by infusion bags without hemoconcentration.

Platelet count and function were evaluated preoperatively, immediately after CPB, and after SDPC transfusion (group A). All postoperative blood samples for platelet function were collected before protamine administration. Platelet function was assessed by their reactivity with extracellular matrix using scanning electron microscopy [7]. Four distinct grades of aggregation on ECM were defined. In grade 1, the platelets are discoid and lack any pseudopodia. In this grade the platelets do not adhere to each other, and each platelet can be seen individually. In grade 2, the platelets display the first signs of activation, and they appear with slender dendritelike pseudopodia, still separated from each other. In grade 3, the aggregation process is more advanced; the platelets start to cluster. In this immature aggregate, each platelet still can be identified separately. Grade 4 consists of a mature aggregate in which individual platelets are difficult to define. The final grade of aggregation of each sample was defined after examination of 40 scanning electron microscopic fields by observers who were not aware of the group to which the sample belonged.

Clinical hemostasis was evaluated by measurement of 24-hour blood loss, blood requirement, and total number of homologous blood products transfused. Red blood cell units were transfused to keep hemoglobin level greater than 10 mg/100 mL. Platelet concentrate transfusions were administered only to patients with active bleeding and a platelet count less than 100 x 109/L. Intensive care nurses and physicians were blinded regarding the groups to which the patients belonged.

The {chi}2 test was used to compare discrete (categoric) variables, and the t test was used to compare continuous variables. The significance of improvement within each of the two groups was assessed by McNemar's test and Kappa statistic. Data are expressed as mean +/- standard deviation, and statistical significance was accepted at p less than 0.05.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
The two groups were similar regarding age, sex, bypass time, and lowest body temperature. There were more reoperative open heart procedures in group B (aprotinin) (see Table 1Go).

Group A had a significantly greater platelet count after SDPC transfusion (157 +/- 36 x 109/L compared with 118 +/- 42 x 109/L; p < 0.05) (Fig 1Go). Postoperative platelet aggregation grade on extracellular matrix was better in group B (aprotinin) (3.4 +/- 0.7 versus 2.8 +/- 0.9; p < 0.05) (Fig 2Go). Only 12 of the 20 patients (60%) in group A reached grade 3 or 4 aggregation after SDPC transfusion. Eighteen of the 20 patients (90%) who received aprotinin (group B) remained in grades 3 or 4 (p < 0.05). The only 2 patients in group B who had grade 2 aggregation postoperatively had grade 2 aggregation before operation (Fig 3Go). Scanning electron micrographs of patients from each group are shown in Figures 4 and 5GoGo.



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  		Fig 1. . Platelet count. (CPB = cardiopulmonary bypass; SDPC = single-donor plateletpheresis concentrate.)

 


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  		Fig 2. . Platelet aggregation (Agg) on extracellular matrix. (CPB = cardiopulmonary bypass; SDPC = single-donor plateletpheresis concentrate.)

 



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  		Fig 3. . Changes in individual platelet aggregation grades in the two groups from before operation to after cardiopulmonary bypass (CPB). Numbers indicate number of patients. (A) Single-donor plateletpheresis concentrate. (B) Aprotinin.

 



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  		Fig 4. . Scanning electron micrographs of a patient from the aprotinin group: (A) preoperative (grade 4); (B) after cardiopulmonary bypass (grade 4).

 




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  		Fig 5. . Scanning electron micrographs of a patient from the placebo group: (A) preoperative (grade 4); (B) after cardiopulmonary bypass (grade 1); (B) after cardiopulmonary bypass (grade 1); (C) after transfusion of single-donor plateletpheresis concentrate (grade 2-3).

 
Twenty-four--hour blood loss was significantly less in the aprotinin-treated group (396 +/- 125 mL versus 617 +/- 233 mL; p < 0.01). This group (group B) also consumed fewer homologous red blood cell units (Table 2Go) and were exposed to a significantly lower number of homologous blood product units (Table 3Go).


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  		Table 2. . Number of Red Blood Cell Units Transfused
 

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  		Table 3. . Homologous Blood Products Transfusion
 
Ten (50%) of the patients in the aprotinin-treated group were never exposed to homologous transfusion compared with none (0%) of the patients in group A (p < 0.01) (see Table 3Go).


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
This study, like previously published studies [4, 5, 8–11], showed improved clinical hemostasis with administration of high-dose aprotinin (6 x 106 KIU) to patients undergoing open heart procedures with bubble oxygenators.

The improved hemostasis is related to protection of platelets from the damaging effect of CPB [4, 12–14]. The superior platelet function was demonstrated by the better aggregate formed on the extracellular matrix at the end of CPB in patients treated with aprotinin (group B) compared with those treated with SDPC (group A).

High-dose aprotinin, including administration of a loading dose before bypass and continuous drip during bypass, achieved complete preservation of platelet aggregation grade in 90% of the patients (18 of 20). All patients in the SDPC group showed a decrease in aggregation grade at the end of CPB, (all were grades 1 or 2 on extracellular matrix aggregation), and only 12 of the 20 in this group (60%) could form mature aggregates (grades 3 or 4) after SDPC transfusion.

Despite the significantly greater postoperative platelet count in the patients who received SDPC transfusion (157 +/- 36 x 109/L compared with 118 +/- 42 x 109/L in the aprotinin group), clinical hemostasis was better in the aprotinin-treated group.

Twenty-four--hour blood loss in the aprotinin group was less (396 +/- 125 versus 617 +/- 233 mL/24 hours), and these patients required fewer red blood cell units (0.8 versus 3.4) and were exposed to fewer homologous blood products (1.1 versus 5.4 units) (Fig 6Go). All patients in the SDPC group were exposed to homologous blood products compared with only 50% of the patients in the aprotinin group.



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  		Fig 6. . Red blood cells (RBC) transfusion requirement and exposure to homologous blood products in the single-donor plateletpheresis concentrate (SDPC) and aprotinin-treated groups.

 
This study supports the concept that the main cause of bleeding after open heart procedures is platelet dysfunction, which is even more important than the absolute decrease in platelet count [2, 15, 16]. Moreover, it also shows that preservation of platelet function is a more efficient means to improve postoperative hemostasis than increasing platelet count by platelet transfusion.

The improved hemostasis observed in the group of patients treated with aprotinin also may be related to effects of aprotinin on the hemostatic process other than its protective effect on platelet function. Extracorporeal circulation with its artificial surfaces causes contact activation of the intrinsic coagulation pathway, fibrinolysis, and complement activation [17, 18]. Heparin treatment cannot inhibit thrombin already bound to fibrin. Thus fibrin formation, thrombin generation, and fibrinolysis continue throughout bypass despite the antithrombin effect of heparin on plasma thrombin [11, 17, 18]. Aprotinin inhibits lysis of both fibrinogen and fibrin [11, 12]. Aprotinin also inhibits kallikrein, and thus decelerates activation of the intrinsic coagulation pathway [19] and formation of plasmin and thrombin, which are the most powerful platelet stimulators [17, 20, 21].

Transfusion of SDPC increases platelet count and provides potentially active unstimulated platelets. However, it does not have any effect on fibrinolysis and platelet stimulation by thrombin and plasmin.

Plateletpheresis technique allows selective collection of large quantities of platelets with a very low rate of red blood cell and white blood cell contamination. The average yield of platelets was 3.4 +/- 1.2 x 1011, which is the equivalent of six homologous platelet units [6]. Infusion of homologous [22] and autologous [23] SDPC has been shown in the past to be an effective means of elevating platelet count and reducing postoperative bleeding, with minimal exposure to homologous blood products and decreased risk of disease transmission by transfusion [6].

The average immediate increment in platelet count ranges between 30,000 and 40,000/mL. However, the new generation PlateletCell Separators enable collection of a larger amount of platelets for patients with increased risk of bleeding [24], or when the patient is thrombocytopenic and has very few compatible donors.

We conclude that hemostasis in patients receiving high-dose aprotinin is better due to improved platelet function. Administration of SDPC causes a more significant increase in platelet count, and we therefore recommend its use in thrombocytopenic patients. Single-donor plateletpheresis concentrate also is recommended for patients with rare blood types (such as Rh negative) to reduce exposure to homologous blood products.

In view of the excellent aggregation achieved with high-dose aprotinin, and recent reports suggesting vein graft thrombosis with this drug [17], a word of caution should be added regarding its use in coronary bypass operations. Clinical experience and longer follow-up are required for complete evaluation of this risk.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 
Presented at the Sixty-sixth Scientific Session of the American Heart Association, Atlanta, GA, Nov 8--11, 1993.

Address reprint requests to Dr Mohr, Department of Cardiac Surgery, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.


   References
Top
 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Mohr R, Golan M, Martinowitz U, Rosner E, Goor DA. Effect of cardiac operation on platelets. J Thorac Cardiovasc Surg 1986;92:434–41.[Abstract]
  2. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990;76:1680–97.[Abstract/Free Full Text]
  3. Harker LA, Malpass TW, Branson HE, Hessel EA II, Slighter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha granules release. Blood 1980;56:824–34.[Free Full Text]
  4. Mohr R, Goor DA, Lusky A, Lavee J. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction. Circulation 1992;86(Suppl 2):405–9.
  5. Blauhut B, Gross C, Necek S, Doran JE, Spath P, Hansen PL. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958–67.[Abstract]
  6. Simon T, Lee EJ, Heaton CA, et al. Storage and transfusion of platelets collected by an automated two-stage apheresis procedure. Transfusion 1992;32:624–8.[Medline]
  7. Lavee J, Martinowitz U, Mohr R, et al. The effect of transfusion of fresh whole blood versus platelet concentrates after cardiac operations: a scanning electron microscope study of platelet aggregation on extracellular matrix. J Thorac Cardiovasc Surg 1989;97:204–12.[Abstract]
  8. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119–26.[Medline]
  9. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364–72.[Abstract]
  10. Edmunds LH. Invited letter concerning: aprotinin use in pediatric cardiac operations. J Thorac Cardiovasc Surg 1993;105:757–60.[Medline]
  11. Haven M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991;101:968–73.[Abstract]
  12. Lavee J, Savion N, Smolinsky A, Goor DA, Mohr R. Platelet protection by aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1992;53:477–81.[Abstract]
  13. Wildevuur CRH, Eijsman L, Roozendaal KJ, Jarder MP, Chang M, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989;3:533–8.[Abstract]
  14. Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993;55:1033–41.[Abstract]
  15. Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991;175:388–93.
  16. Lu H, Soria C, Cramer EM, et al. Temperature dependence of plasmin-induced activation or inhibition of human platelets. Blood 1991;77:996–1005.[Abstract/Free Full Text]
  17. Dietrich W, Mossinger H, Spannagl M. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993;105:712–20.[Abstract]
  18. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57.[Abstract]
  19. Weitz J, Hudoba M, Massel D, Maraganore J, Hirsch J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990;86:385–91.[Medline]
  20. Hanson S, Harker L. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-arginyl chloromethylketone. Proc Natl Acad Sci USA 1988;85:3184–8.[Abstract/Free Full Text]
  21. Winters K, Santoro S, Miletich J, Eisenberg P. Relative importance of thrombin compared with plasmin-mediated platelet activation in response to plasminogen activation with streptokinase. Circulation 1991;84:1552–60.[Abstract/Free Full Text]
  22. Umeki Y, Yoshitake J, Inaba S, Todoroki H, Okochi K. Transfusion of platelets harvested by CEU separator in open heart surgery. Fukoaka Igaku Zasshi 1984;75:496–500.
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