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Ann Thorac Surg 1995;60:1008-1014
© 1995 The Society of Thoracic Surgeons
Department of Surgery, Brockton/West Roxbury Veterans Affairs Medical Center; Brigham and Women's Hospital; Harvard Medical School; and the Naval Blood Research Laboratory, Whitaker Cardiovascular Institute, and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
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Abstract |
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Methods. Sampling was performed in 55 patients undergoing cardiac operations before and 5 minutes after the routine administration of heparin, before the institution of cardiopulmonary bypass.
Results. Heparin administration resulted in a significant prolongation of the bleeding time (from 6.3 ± 2.1 to 12.6 ± 4.9 minutes; p < 0.00001), a significant reduction in the level of shed blood thromboxane B2 (from 1,152 ± 669 to 538 ± 187 pg/0.1 mL; p = 0.00002), and an increase in the plasma levels of plasmin (from 11.8 ± 9.7 to 125.4 ± 34.8 U/L; p < 0.0001) and D-dimer (from 571.3 ± 297.1 to 698.5 ± 358.6 µg/mL; p = 0.05). There were no significant differences before and after heparin administration in the plasma levels of fibrinogen, plasminogen, tissue plasminogen activator, antiplasmin, antithrombin III, and von Willebrand factor.
Conclusions. Heparin, independent of cardiopulmonary bypass, causes both platelet dysfunction and increased fibrinolysis. The use of an alternative anticoagulant or a lower dose of heparin in conjunction with heparin-coated surfaces might improve the hemostatic balance during open heart operations.
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Introduction |
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The institution of cardiopulmonary bypass alters hemostasis and results in increased postoperative bleeding [1]. Platelet dysfunction and increased fibrinolysis are two mechanisms that are primarily responsible for the hemostatic dysfunction induced by cardiopulmonary bypass [1]. Although contact with the extracorporeal circuit results in platelet loss secondary to platelet activation, secretion, and degranulation, the resultant thrombocytopenia encountered in the majority of patients undergoing cardiopulmonary bypass is not severe enough to account for the platelet dysfunction observed in these patients, which is manifested by a marked prolongation of the postoperative bleeding time [2]. It was postulated that cardiopulmonary bypass induced platelet dysfunction by altering the platelet membrane receptors GP1b and GPIIb/IIIa. A recent collaborative study from our institution demonstrated that the membrane receptors were intact in platelets circulating during cardiopulmonary bypass [3]. It suggested that factors extrinsic to the platelet might be important determinants of the platelet dysfunction observed during and after cardiopulmonary bypass. Hypothermia, for example, has been clearly shown to prolong the bleeding time and to reduce the platelet production of thromboxane A2 in patients undergoing cardiopulmonary bypass [4]. Heparin, which is universally used in patients undergoing cardiopulmonary bypass, is another extrinsic factor that may influence platelet function in these patients. Heparin has also been shown to have profibrinolytic activity [5]. Hence, heparin may contribute to the hemostatic abnormality of cardiopulmonary bypass not only by its inhibition of thrombin, but also by inducing platelet dysfunction and by promoting fibrinolysis. This investigation was carried out to elucidate the effect of the administration of heparin before the institution of cardiopulmonary bypass on platelet function and fibrinolytic activity in patients undergoing cardiac operations.
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Material and Methods |
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Blood Samples and Assays
After opening of the chest and before cannulation for cardiopulmonary bypass, two arterial blood samples were obtained, one before and one 5 minutes after the administration of heparin. Blood was collected for the measurement of hematocrit and platelet count employing a Coulter JT Counter (Coulter Electronics, Hialeah, FL). Von Willebrand factor (vWF) antigen concentration was measured with enzyme-linked immunosorbent assay [6]. The vWF multimer distribution was assessed by separating plasma proteins electrophoretically on a sodium dodecyl sulfate-1% agarose gel using a continuous buffer [7]. The vWF antigen was identified by incubating the gel with 125I--anti-vWF antibody followed by autoradiography. Each sample was tested at least twice on separate gels to ensure reproducibility. Multimer distribution was assessed by visual inspection of the autoradiograph. Plasminogen and plasmin activity in plasma were measured employing the same substrate [2]. Measurements of tissue plasminogen activator were made using enzyme-linked immunosorbent assay. Samples for measurement of fibrinogen were collected in 3.8% sodium citrate tubes and centrifuged at 1,200 g for 10 minutes. After neutralization with protamine, fibrinogen was measured using a Coag-a-Mate X2 photo optical instrument (General Diagnostics, Organon Teknika Corp, Durham, NC). Heparin levels were measured with a chromogenic substrate. D-Dimer, a breakdown product of fibrin, was measured by an enzyme-linked immunsorbent assay with a monoclonal antibody [2]. Chromogenic assays were used for the measurement of antithrombin III and antiplasmin.
Measurement of Bleeding Time and Shed Blood Thromboxane B2
The bleeding time was measured from the lateral aspect of the volar surface of the forearm according to the method of Babson and Babson [8] with the Simplate II bleeding time device (General Diagnostics). With every bleeding time measurement, local skin temperature was recorded by placing a surface skin thermistor (Skin Temperature sensor; Mon-A-Therm, Inc, St. Louis, MO) within a few millimeters of the bleeding time site. Concomitant with bleeding time and temperature measurements, shed blood obtained from the bleeding time site every 30 seconds was aspirated through a blunt needle into a tuberculin syringe coated with heparin (1,000 U/mL) and containing 20 µL of ibuprofen for 1 mL of blood (1.9 mg/mL). Each template produced two skin incisions, and two templates were used at each period, one for measurement of the duplicate bleeding times and the recording of the mean value, and the other for collection of the shed blood from the skin incision. A volume of 0.6 mL of blood was collected from the bleeding time site for these measurements. The blood samples were kept on ice until they were centrifuged at 1,650 g (3,000 rpm) in a Sorvall RC-3 centrifuge (DuPont Company, Wilmington, DE) for 10 minutes. The plasma was removed and frozen at -80°C until assays for thromboxane B2 levels were done. Assays were performed with thromboxane B2 (iodine 125) radioimmunoassay kits (New England Nuclear Corp, Boston, MA).
Data Analysis
The bleeding time was corrected for temperature by applying the factor described by Valeri and associates [9]. The plasma proteins were corrected for hemodilution as described previously [1]. Comparisons were made between data obtained before and after the administration of heparin using the paired Student's t test. Statistical significance was set at p less than or equal to 0.05. Correlations were performed employing linear regression analysis. Analyses were done using SAS Statistical Software (SAS Institute Inc, Cary, NC). The mean values in the narrative and the tables are shown ± their standard deviation; in the figures, they are shown ± their standard error.
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Results |
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). This drift was ascribed to progressive cooling of the skin secondary to a low ambient temperature in the operating room and to the opening of the chest. In the 55 patients it averaged 29.7° ± 1.3°C before and 28.7° ± 1.7°C after heparin administration. This difference, although small, was highly significant (p = 0.0004). The hematocrit before the administration of heparin was 34.31% ± 5.04%. After heparin it was 32.52% ± 4.89% (p = 0.163). The platelet count before heparin administration in 55 patients ranged from 64,000 to 399,000/µL. It averaged 212,833 ± 66,569/µL. Five minutes after heparin administration it averaged 198,040 ± 56,451/µL (p = 0.24).
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Platelet Function
Platelet function parameters before and 5 minutes after heparin administration are shown in Table 1. The bleeding time before heparin administration ranged from 3.5 to 10.5 minutes and averaged 6.3 minutes. After the administration of heparin, the bleeding time increased in all but 2 patients (Fig 2); it averaged 12.6 minutes. This was a marked and a significant increase compared with the preheparin level (p < 0.00001). The administration of heparin also resulted in a marked fall in the level of thromboxane B2 in the blood shed from the site of the bleeding time determination. Paired data were obtained in 32 patients; their results are shown in Table 1 and Figure 2. The mean shed blood thromboxane B2 level before heparin administration was 11.5 ng/mL. After heparin administration, it fell to 5.5 ng/mL (p = 0.00002). There was a moderate but significant negative correlation between the bleeding time and the shed blood thromboxane B2 (r = -0.43; p < 0.0005). There were no significant negative correlations between the skin temperature and the changes in the corrected bleeding time and the shed blood thromboxane B2 level. Therefore, the changes in the bleeding time and thromboxane B2 were not due to the slight fall in skin temperature that was observed between the preheparin and postheparin time points.
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, the vWF antigen concentration before and after heparin were not significantly different. The vWF multimer distribution was not altered in patients after infusion of heparin, as measured by visual inspection of vWF antigen on autoradiographs (Fig 3).
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displays the results of fibrinolytic and related parameters before and after the administration of heparin. Plasmin was measured in 19 patients. As shown in Figure 4, heparin administration resulted in a tenfold increase in plasmin from a preheparin average of 11.8 U/L to a postheparin average of 125.4 U/L (p < 0.0001). In these patients, the preheparin and postheparin administration levels of plasmin correlated significantly with the preheparin and postheparin bleeding times (r = 0.75; p = 0.005) (Fig 5). In 51 patients in whom D-dimer measurements were made, the administration of heparin elicited an increase in D-dimer level in 43 (77%) and no change or a decrease in 12 (23%) (see Fig 4). On the average, there was a modest but significant increase in the D-dimer level from a preheparin mean of 571.3 µg/mL to a postheparin mean of 698.5 µg/mL (p = 0.05). As shown in Table 2, the administration of heparin elicited no significant changes in the plasma levels of fibrinogen, tissue plasminogen activator, plasminogen, antiplasmin, and antithrombin III.
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Comment |
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Platelet Dysfunction in Open Heart Operations and the Effect of Heparin
It has long been recognized that patients undergoing cardiac operations have increased postoperative bleeding. This has been attributed to a cardiopulmonary bypass--induced hemostatic defect, which was thought to be due mostly to platelet dysfunction and, to a lesser extent, increased fibrinolysis [1, 10]. Because the magnitude of thrombocytopenia encountered in the course of a cardiac operation is not severe enough to account for the marked extension of the bleeding time observed during and after cardiopulmonary bypass [2], investigations in this field have focused on specific platelet abnormalities that might be induced by cardiopulmonary bypass. The platelet defect of cardiopulmonary bypass has been postulated to be due to a loss of the platelet membrane receptors responsible for platelet adhesion and aggregation. Loss of platelet membrane receptors for both the vWF and fibrinogen were reported during and after cardiopulmonary bypass [11–13]. However, the methods with which the platelets were prepared in these studies involved centrifugation and gel filtration of the platelets before assay, thereby introducing the possibility of an artifactual in vitro decrease in platelet surface GPIb-IX complex (the vWF receptor) and GPIIb-IIIa complex (the fibrinogen receptor) as a result of proteolysis or activation. In a study of 20 patients undergoing cardiac operations, we used a flow cytometric method that allowed us to study the platelet GPIb-IX and GPIIb/IIIa in whole blood, thereby avoiding potential artefactual reductions in platelet surface glycoprotein receptors. With this method, we demonstrated that cardiopulmonary bypass did not result in a decrease in the platelet surface expression of either the GPIb-IX complex or the GPIIb-IIIa complex [3]. This study underscored the possibility of factors extrinsic to the platelet itself that might contribute to the platelet dysfunction observed in patients undergoing cardiac operations. Two such factors are hypothermia and heparin. In a study of 37 patients undergoing cardiopulmonary bypass, we confirmed the adverse effect of hypothermia on platelet function by demonstrating that hypothermia resulted in a significant prolongation of the bleeding time and a significant reduction in the ability of the platelet to produce thromboxane A2 [4].
Platelet function in the present study was assessed by the measurement of the bleeding time and the level of thromboxane B2 in the blood shed from the skin at the site of the bleeding time determination. Despite its limitations, the bleeding time continues to be a reliable indicator of platelet function and platelet--vessel wall interaction [1]. The measurement of the shed blood thromboxane B2 has also been shown to be a reliable indicator of platelet function [2, 14]. It has the distinct advantage of reflecting in vivo platelet function, making it an ideal measurement for use in patients undergoing cardiopulmonary bypass [2–4]. Both measurements indicated a marked reduction in platelet function after the administration of heparin. Although it has been long recognized that heparin caused a prolongation of the bleeding time [15], its recognition as an etiologic factor in postbypass hemorrhage is only recent [1, 16].
The mechanism with which heparin might cause platelet dysfunction was partially addressed in our previous study in which whole blood flow cytometry was employed in the characterization of the platelet membrane glycoproteins Ib and IIb-IIIa and platelet activation before and after cardiopulmonary bypass [3]. That study provided evidence that heparin suppressed platelet activation in vivo via inhibition of endogenous thrombin, the latter being the most important platelet agonist in vivo.
Another possible mechanism for the inhibition of platelet function by heparin is through an inhibition of vWF activity. Ristocetin is a cationic antibiotic that induces in vitro binding of vWF to its receptor on platelet GP1b. Sobel and associates [17] demonstrated that the intravenous administration of heparin to patients before open heart operations reduced ristocetin cofactor activity by 58%. This impairment of vWF-dependent platelet function was closely related to plasma heparin levels but not to plasma vWF levels. It appeared to be caused by direct binding of heparin to vWF in solution, but may also be a consequence of heparin binding directly to the platelet surface [18]. In the present study, we have demonstrated that the concentration and multimer distribution of the vWF were unaffected by the administration of heparin. Hence our data are consistent with the hypothesis that heparin reduces platelet function by preventing the vWF from binding to its receptor on the GPIb on the platelet.
The third mechanism by which heparin can induce platelet dysfunction is through its effect on plasmin. This is explained in the section below.
Fibrinolysis During Cardiopulmonary Bypass and the Effect of Heparin
There are a number of pathways that could lead to increased fibrinolysis during cardiopulmonary bypass operations, including the activation of kallikrein and the release of tissue plasminogen activator from the endothelial cell [1]. Fibrin(ogen) degradation products and D-dimer levels increase during and following cardiopulmonary bypass [1, 19]. Administration of aprotinin during cardiopulmonary bypass prevents the formation of fibrin degradation products and the reduction in 
2-antiplasmin activity [20]. It also reduces the bleeding time [21]. These observations, the mechanism of action of aprotinin [22], and the clinical effectiveness of aprotinin in decreasing blood loss [21], strongly suggest that fibrinolysis is important in the hemorrhagic diathesis associated with cardiopulmonary bypass operations. The present study demonstrates that, in patients before the institution of cardiopulmonary bypass, the administration of heparin increases fibrinolysis as evidenced by a uniform increase in plasmin and a partial but significant increase in D-dimer level. Heparin and its fractions, however, have been known to possess profibrinolytic activities for more than a decade [5]. Fareed and associates [5] reported an increase in tissue plasminogen activator levels in human volunteers after the institution of intravenous and subcutaneous heparin over a period of 10 days (daily dose of 7,500 units). They postulated a number of profibrinolytic actions of heparin and its fractions. Several recent studies have shown that heparin and heparin-like compounds stimulated cell surface plasminogen activation by 10- to 17-fold [23]. Because this interaction occurred at the cell surface level, it would be unlikely that the profibrinolytic effect of heparin would be reflected by the levels of plasminogen in the plasma. Hence, in our study, we did not show any change in the plasma levels of plasminogen with the administration of heparin. The lack of a significant increase in tissue plasminogen activator after the administration of heparin did not denote a lack of profibrinolytic activity because the plasma level tissue plasminogen activator antigen may not correlate with the functional activity of the molecule in patients undergoing cardiopulmonary bypass. The rise in plasmin and D-dimer levels after the administration of heparin indicated an increase in profibrinolytic activity. It is of note that plasmin, fibrin degradation products, and D-dimer have all been shown to interfere with platelet aggregation, presumably through a proteolytic effect on the platelet GPIIIa in the case of plasmin [24] and by competing with fibrinogen for GPIIb/IIIa binding in the case of the degradation products. Hence the generation of plasmin, stimulated by heparin, provides another possible mechanism by which heparin impairs platelet function as well. A confirmatory finding of this mechanism is the significant correlation that was observed in this study between the bleeding time and the plasma levels of plasmin.
Clinical Implications
The hemostatic defect observed in patients undergoing cardiac operations is not fully reversed with the administration of protamine and the discontinuation of cardiopulmonary bypass. In fact, D-dimer levels increase after the administration of protamine, and the bleeding time continues to be significantly elevated in the hours after the discontinuation of cardiopulmonary bypass [1, 2]. The bleeding time at 2 hours after cardiopulmonary bypass was shown to be an important determinant of postoperative blood loss [2]. Interventions aimed at reducing postoperative platelet dysfunction and fibrinolysis are likely to reduce postoperative blood loss in patients undergoing cardiac operations. Because a variety of complex factors could contribute to the hemostatic defect observed in the initial postoperative hours in these patients, it is very difficult to appreciate the specific contribution of the administration of heparin per se to this defect. Nevertheless, the present study raises questions as to whether an alternative anticoagulant or a lower dose of heparin might improve the hemostatic balance during open heart operations. In the present study, the ACT was kept on the high side to achieve full suppression of thrombin. Significantly lower ACT levels have been employed in conjunction with heparin-coated surfaces. It remains to be determined whether combining low-dose heparin with heparin-coated surfaces would suppress thrombin adequately and, at the same time, reduce the adverse effect of heparin on platelet function and fibrinolysis. It also remains to be determined whether an alternative anticoagulant that would not interfere with either the platelet function or the fibrinolytic process can improve postoperative hemostasis in the cardiac surgical patient.
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Supported by the US Navy (Office of Naval Research Contract N00014-94-C-0149 with funds provided by the Naval Medical Research and Development Command), and by the Richard Warren Surgical Research and Educational Fund, Westwood, Massachusetts.
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The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or Naval Service at large.
Address reprint requests to Dr Khuri, VA Medical Center, 1400 VFW Parkway, West Roxbury, MA 02132.
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Y. J. Gu, M. A. Mariani, W. van Oeveren, J. G. Grandjean, and P. W. Boonstra Reduction of the Inflammatory Response in Patients Undergoing Minimally Invasive Coronary Artery Bypass Grafting Ann. Thorac. Surg., February 1, 1998; 65(2): 420 - 424. [Abstract] [Full Text] [PDF]
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 G. J. Despotis, J. H. Joist, and L. T. Goodnough Monitoring of hemostasis in cardiac surgical patients: impact of point-of-care testing on blood loss and transfusion outcomes Clin. Chem., September 1, 1997; 43(9): 1684 - 1696. [Abstract] [Full Text] [PDF]
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 G. R. Upchurch Jr, G. N. Welch, J. E. Freedman, A. J. Fabian, A. Pigazzi, A. M. Scribner, C. S. Alpert, J. F. Keaney Jr, and J. Loscalzo High-Dose Heparin Decreases Nitric Oxide Production by Cultured Bovine Endothelial Cells Circulation, April 15, 1997; 95(8): 2115 - 2121. [Abstract] [Full Text]
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S. Bannan, A. Danby, D. Cowan, S. Ashraf, and P. G. Martin Low Heparinization With Heparin-Bonded Bypass Circuits: Is It a Safe Strategy? Ann. Thorac. Surg., March 1, 1997; 63(3): 663 - 668. [Abstract] [Full Text]
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Y. Hiramatsu, N. Gikakis, H. L. Anderson III, J. H. Gorman III, C. Marcinkiewicz, R. J. Gould, S. Niewiarowski, and L. H. Edmunds Jr. TIROFIBAN PROVIDES ""PLATELET ANESTHESIA"" DURING CARDIOPULMONARY BYPASS IN BABOONS J. Thorac. Cardiovasc. Surg., January 1, 1997; 113(1): 182 - 193. [Abstract] [Full Text]
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E. Ovrum, E. A. Holen, G. Tangen, and M.-A. L. Ringdal Heparinized Cardiopulmonary Bypass and Full Heparin Dose Marginally Improve Clinical Performance Ann. Thorac. Surg., October 1, 1996; 62(4): 1128 - 1133. [Abstract] [Full Text]
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G. S. Aldea, M. Doursounian, P. O'Gara, P. Treanor, O. M. Shapira, H. L. Lazar, and R. J. Shemin Heparin-Bonded Circuits With a Reduced Anticoagulation Protocol in Primary CABG: A Prospective, Randomized Study Ann. Thorac. Surg., August 1, 1996; 62(2): 410 - 418. [Abstract] [Full Text]
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A. Wahba, G. Rothe, G. Schmitz, D. E. Birnbaum, S. F. Khuri, C. R. Valeri, J. Loscalzo, and A. D. Michelson Heparin Effect on Platelets and Fibrinolysis Ann. Thorac. Surg., May 1, 1996; 61(5): 1590 - 1591. [Full Text]
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