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Ann Thorac Surg 1998;66:2145-2152
© 1998 The Society of Thoracic Surgeons

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Current Review

The platelet in cardiopulmonary bypass

^a Department of Cardiothoracic Surgery, Imperial College of Science, Technology and Medicine, University of London, Hammersmith Hospital, London, England, United Kingdom

Address reprint requests to Dr Taylor, Department of Cardiothoracic Surgery, Imperial College of Science, Technology and Medicine, University of London, Hammersmith Hospital, London W12 OHS, England

	Abstract

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Platelets are the smallest of the blood cells and are known to be activated during cardiopulmonary bypass. They play a role in many associated complications. Both quantitative and qualitative platelet defects have been demonstrated, resulting in microvascular hemorrhage and thromboembolism. As their interactions with endothelium and other blood cells are unraveled, the important contribution they make toward the systemic inflammatory response to operation seen in cardiopulmonary bypass is increasingly evident. In this review, we consider platelet activation during cardiopulmonary bypass, the resultant clinical effects, and potential approaches to therapy and prevention.

	Introduction

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Platelets are 1.5- to 3.5-mm diameter anucleated circulating cells derived from precursor megakaryocytes. Adult humans have 150 to 400 x 10⁹ platelets per liter of blood. Their daily turnover is around 35 x 10⁹ cells per liter of blood volume. The majority of the body’s platelets are in the circulation with 25% to 30% being sequestrated in the spleen at any one time [1]. The average survival time of human platelets in the circulation is 9 to 11 days [2]. Unactivated platelets are discoid in shape. Their cytoplasm contains organelles, a cytoskeleton consisting of microtubules and microfilaments, and granules. The surface membrane of the platelet expresses various glycoprotein molecules. Invaginations of the cell wall form a passageway between the exterior and the interior of the platelet and are known as the surface-connected canalicular system [3].

Resting platelets are discoid in shape. On activation changes occur in the internal cytoskeleton causing the platelet to become spheroid in shape. Along with this, constitutively present surface molecules are reorganized (eg, glycoprotein IIb and IIIa), which form a fibrinogen-binding complex. Simultaneously there is movement of cytoplasmic granules toward the surface of the cell. These granules fuse with the platelet surface extruding their contents. Platelet factor-4, ß-thromboglobulin, and von Willebrand factor are secreted in this manner from -granules. At the same time molecules that were an integral part of the granule membranes are now expressed on the surface of the activated platelet. P-selectin derived from -granules and CD63 derived from lysosomes [4, 5] are two such molecules. On activation platelets also generate large quantities of microparticles containing phospholipids such as phosphatidylserine.

	What does cardiopulmonary bypass do to the platelet?

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Cardiopulmonary bypass (CPB) activates platelets with resultant structural and biochemical changes. Alterations in platelet count, clot formation, and the manner in which platelets interact with other cells is seen.

Changes in platelet surface molecules
Platelets express a range of surface molecules that mediate their hemostatic and inflammatory functions. The effect of CPB on them is summarized in Table 1. GPIb levels have been shown to be decreased by CPB. Kondo and colleagues [11] showed that minimal levels of expression were at around 120 minutes after commencement of CPB when levels dropped to 64% ± 26% of the prebypass levels. Expression thereafter increased gradually, taking more than 3 hours to return to prebypass levels. Although Kondo’s group have reported that there is no significant change in GPIIb/IIIa expression throughout CPB, Holada and colleagues [7] showed a significant decrease in levels soon after CPB. The GPIV receptor is involved in thrombospondin-mediated stabilization of the platelet aggregate [12] and appears to function as a receptor for platelet–collagen adhesion [13]. Rinder and associates [8] reported a minimal increase in GPIV expression during hypothermic CPB, but noted a substantial increase at 2 to 4 hours after CPB. A similar temporal increase was noted by Rinder and colleagues [8] for the major histocompatibility complex class I molecule, human leucocyte antigen HLA-ABC, on platelets with peak values at 2 to 4 hours after CPB. The increase after CPB in the levels of these two receptors may result from the influx of a previously sequestrated pool of platelets with a higher expression of these molecules once CPB is terminated. Rinder’s group postulated that recruitment is likely to be from sources such as the spleen rather than attributable to an outpouring of new platelets from the bone marrow. CD31 (also known as platelet endothelial cell adhesion molecule-1/PECAM-1 because of its occurrence on both platelets and endothelium) is downregulated on platelets during CPB [10].

Formation of platelet conjugates
Platelets activated during CPB form conjugates both between themselves and with red cells and white cells [15]. In vitro studies have shown that platelet–monocyte and platelet–neutrophil binding is mediated through P-selectin expressed on activated platelets. Rinder and colleagues [16] showed a progressive increase in platelet–monocyte conjugates throughout CPB with levels decreasing after bypass. In comparison, platelet–neutrophil conjugates peaked by 10 minutes after commencement of CPB but then dropped off gradually. This decrease is thought to be attributable to concomitant neutrophil activation leading to the loss of their platelet-binding ligand [17]. In comparison platelet–lymphocyte conjugates decreased during CPB.

Effect on platelet count
Thrombocytopenia is well documented in association with CPB. Early hemodilution occurs from the use of crystalloid fluids for priming the extracorporeal circuit. Holloway and associates [18] found that the decrease in platelet count during CPB was in excess of that accounted for by hemodilution. Mechanical disruption as well as adhesion to the extracorporeal circuit along with sequestration in organs contributes to this true drop in circulating platelet counts.

Altered platelet force generation
Platelet-mediated clot retraction increases the strength of the nascent platelet plug and may help reapproximate damaged vascular endothelium. This platelet-mediated force development requires adhesion and aggregation as well as a contractile cytoplasm capable of generating cytoskeletal retraction [19]. Greilich and colleagues [20] demonstrated that peak platelet force development after CPB was substantially lower than before CPB. This is likely to play a role in CPB-associated microvascular hemorrhage.

	How does cardiopulmonary bypass induce these platelet changes?

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Numerous factors associated with CPB contribute toward the changes that occur in platelets. These include physical factors (such as hypothermia and shear forces), exposure to artificial surfaces, the use of exogenous drugs, and the release of endogenous chemicals (Fig 1).

View larger version (31K): [in this window] [in a new window]   Fig 1. Mechanisms of platelet activation in cardiopulmonary bypass.

Surface exposure of the synthetic materials in the extracorporeal circuit
Extracorporeal CPB circuits are manufactured from synthetic materials that activate platelets. Gemmell and associates [22], using an in vitro model, have shown that material-induced platelet activation is a calcium-dependant process involving GPIIb/IIIa receptors. Furthermore, it has been shown that platelets deficient in GPIIb/IIIa (Glanzmann’s thrombasthenia) do not bind to foreign surfaces of extracorporeal circuits [23].

Drugs used in cardiopulmonary bypass
Heparin
Heparin (used as an anticoagulant for CPB) binds to and stimulates components of the fibrinolytic system. Increased plasminogen activator function leads to generation of plasmin, which binds to the surface of platelets causing -granule release. Platelet activation by plasmin has a lag phase and is calcium and temperature dependent [24, 25].

Protamine
Protamine sulfate is used for reversal of heparin anticoagulation after conclusion of CPB. A transient thrombocytopenia occurs after the administration of protamine [26]. This is associated with activation of platelets and the formation of transient aggregates that appear to sequestrate in the lungs. Generation of complement occurs through the classic pathway when protamine is administrated and is likely to mediate this activation [27].

Endogenous chemical mediators
Thrombin
Thrombin generated during CPB stimulates platelet protein kinase-C activation, which mediates upregulation of P-selectin [28]. This action of thrombin has been considered as being mediated through GPIb receptors. Recent evidence suggests that activation of platelets by thrombin involves GTP binding protein-linked mechanisms [29, 30].

Complement
Complement activation forms part of the humoral response to CPB and includes anaphylatoxins C3a and C5a, the opsonin C3b, and the membrane attack complex C5b–9. Platelet activation leading to P-selectin expression occurs in response to C5b–9 complex [31]. An antihuman monoclonal antibody preventing generation of C5a and C5b–9 has been shown to be able to abolish the expression of platelet P-selectin expression in a model of extracorporeal circulation [32]. A further wave of complement activation through the classic pathway occurs on administration of protamine after termination of CPB [33].

Cytokines
Elevated levels of cytokines interkeukin-6 (IL-6) and IL-8 have been extensively documented during CPB [34–36]. Lumadue and colleagues [37] used various concentrations of IL-6 and IL-8 and showed in vitro platelet stimulation leading to P-selectin expression. Concentrations of IL-6 used were comparable to those seen with CPB.

Adrenaline
Elevated levels of catecholamines occur during CPB [38, 39]. Adrenaline is known to act on platelets through ₂-adrenoceptors causing their activation [40] and may contribute to the CPB-associated platelet response. However, the data on platelet -adrenergic receptors during CPB are conflicting in that Zucker and Amory [41] suggest that they are not downregulated, whereas Wachtogel and colleagues [42] suggest that they are.

Multifactorial in vivo state
The changes seen in platelets as a result of CPB represent the cumulative effects of many factors. One example of this is the overall decrease in GPIIb/IIIa alluded to previously. Plasmin (a fibrinolytic protease generated during CPB) has been shown to cleave GPIIb/IIIa in vitro. On the other hand platelet microparticles formed on platelet activation contain GPIIb/IIIa and may contribute to loss of these molecules from platelets [43].

	Complications associated with platelet dysfunction in cardiopulmonary bypass

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
These complications include thromboembolism, hemorrhage, and inflammation (Fig 2).

View larger version (31K): [in this window] [in a new window]   Fig 2. Clinical effects of cardiopulmonary bypass-induced platelet activation.

Hemorrhage
Platelet changes during CPB such as thrombocytopenia and decreased platelet force generation may lead to microvascular hemorrhage by compromising the platelets’ role in the hemostatic process. Commencement of CPB causes a decrease in platelet count due to dilution of blood in the fluid used to prime the CPB circuit. An increase in the bleeding time occurs independent of the reduction in platelet count and is attributable to impaired platelet function. The aggregation of platelets in response to adenosine diphosphate and collagen is impaired [48, 49]. Edmunds and colleagues [50] showed that the decrease in platelet aggregation, the increase in bleeding time, and postoperative bleeding were comparable with bubble and membrane oxygenators.

Inflammation
Evidence is accumulating that activated platelets attached to vascular endothelium play an important role in neutrophil adhesion and transmigration. Endothelial cells have an adhesion molecule known as CD40. Recent in vitro work has shown that activated platelets express on their surface a complementary binding molecule (ligand) known as CD40L [51]. This transmembrane ligand protein is structurally related to tumor necrosis factor- and induces endothelium to secrete chemokines and express further adhesion molecules. Substantial secretion of IL-8 (a chemoattractor for neutrophils), and MCP-1 (a chemoattractor for monocytes) was noted on platelets binding to endothelium. Thus, activated platelets bound to endothelium are able to initiate recruitment of neutrophils and monocytes. Neutrophils are able to attach to activated platelets through the neutrophil ß₂ integrin adhesion molecule Mac-1 (CD11b/CD18) [52, 53]. Both platelet P-selectin [54] and the platelet glycoprotein GPIIb/IIIa [55] are involved in this process. Research on the expression of platelet CD40L during CPB is awaited.

	How may these complications be prevented?

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Preventing the processes that activate platelets or using methods to prevent the harmful effects of activation are important measures in reducing complications associated with CPB.

By reducing platelet shear
Cardiotomy suction causes platelet damage due to aspiration of air along with blood. Intense cardiotomy suction may result in a decreased ability of platelets to aggregate [56]. Controlled gentle cardiotomy suction prevents aspiration of air, decreases shear forces, and preserves platelets. Differences between centrifugal and roller pumps were studied in an in vitro model by Moen and colleagues [57] and no difference in platelet activation as measured by soluble ß-thromboglobulin levels was seen. Similar results are presented by Yoshikai’s team [58]. In early work done using a roller pump by Taylor and associates [59], no substantial difference between pulsatile and nonpulsatile flow on platelet depletion was noted. A similar absence of a difference in platelet counts and activation as assessed by expression of platelet factor-4 and ß-thromboglobulin (-granule contents) has been shown by Goto and colleagues [60].

By reducing surface activation
Heparin coating of CPB circuits has been used to reduce activation of cellular and humoral components of blood. van der Kamp and van Oeveren [61] found no difference in platelet activation using a heparin-coated circuit, in contrast to which Moen and colleagues [62] found platelet activation to be less. Both groups used ß-thromboglobulin as their indicator of platelet activation.

By preventing platelet-related microembolism
Membrane oxygenators cause less intense platelet activation than was seen with bubble oxygenators [63]. Furthermore, the generation of particulate microemboli is lower with membrane oxygenators [56, 64]. Various types of filters have been studied and differ in their ability to prevent microembolic phenomena. Ware and associates [65] compared a Dacron (C. R. Bard, Haverhill, PA) wool cardiotomy filter with a 40-µm pore mesh filter and found the former more efficient in removing microemboli. Muraoka and colleagues [66] showed that 20-µm filters in the arterial line prevented the occurrence of postoperative computed tomographic changes suggestive of microembolism, whereas 40-µm filters were incapable of doing so.

By using inhibitors of platelet activation
Aprotinin
Aprotinin is a serine protease inhibitor. The effect of aprotinin on platelet activation in CPB has been studied extensively. Early studies showed that using a continuous infusion to maintain plasma concentrations around 4 mmol/L during CPB was able to minimize platelet activation and aggregation [67] as well as decrease the loss of surface GPIb [68]. Wahba and colleagues [69] suggest that aprotinin has no effect on platelet activation during CPB, and that its ability to reduce blood loss is mediated by its effect on fibrinolysis. Flow cytometry was used by this group to show that aprotinin had no significant effect on P-selectin and CD63 (platelet activation markers), nor on the glycoprotein receptors GPIb and GPIIb/IIIa in CPB. The findings of Wahba and associates are in contradiction to the results of Primack and colleagues [15] who make a very strong case that aprotinin does indeed decrease platelet activation in CPB. The differences between the two groups lies chiefly in that Primack’s group used whole blood analysis and not purified platelets as did Wahba’s group. Therefore, they make the point of being able to analyze maximally activated platelets that had formed conjugates with other blood cells (red and white blood cells). It was in this population of maximally activated platelets that aprotinin seemed to be effective in reducing CPB-induced activation.

Shigeta and colleagues [70] have shown that the dose of aprotinin required to inhibit plasmin (1 x 10⁶ KIU per patient) is less than that required to inhibit fibrinolysis (6 x 10⁶ KIU per patient).

Nitric oxide
Nitric oxide inhibits platelet protein kinase-C enzymes that regulate the expression of P-selectin. In turn, this decreases platelet adhesiveness [28]. The effect of nitric oxide in inhibiting attachment of whole blood platelets to the synthetic membranes of hollow fiber oxygenators has been demonstrated [71, 72]. Platelet cyclic GMP appears to be involved in mediating this effect [72]. Decreased platelet adherence to oxygenator membranes is likely to prevent deterioration in their gas exchange capabilities. Furthermore, nitric oxide decreases platelet aggregation and may have a role to play in decreasing microembolization.

Other platelet inhibitors
Reversible inhibition of platelets for the peri-CPB period has been explored as an attractive alternative research tool. Intravenous infusions of prostaglandins such as PGE₁, which activate adenylate cyclase and inhibit aggregation, showed promising results with platelet preservation. Despite this their clinical use is complicated because of the propensity to cause significant vasodilation and hypotension. More recently iloprost, a prostaglandin analog, has been combined with a GPIIb/IIIa receptor antagonist at what may prove to be a clinically safe dose, and shown to inhibit temporarily, platelet activation during in vitro extracorporeal circulation [73].

Dipyridamole is a nucleoside transport inhibitor that prevents uptake of adenosine. It has been shown to ameliorate the decrease in platelets after CPB, especially when used intravenously [74].

The platelet glycoprotein GPIIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands. This binding is the final common pathway mediating platelet aggregation. Blocking this common pathway is an attractive means of preventing many platelet-related complications of CPB. The role these receptors play in platelet adhesion to artificial surfaces was discussed previously. The synthetic tetra peptide RGDS (arginine-glycine-aspartic acid-serine) blocks GPIIb/IIIa receptors and has been shown to reduce platelet adhesion to the extracorporeal circuit [75].

By preventing exposure of platelets to cardiopulmonary bypass
Preoperative platelet pheresis, harvesting 20% or more of the total platelet population and reinfusing after CPB, physically removes a pool of platelets from the effects of CPB and has been shown to result in substantially less postoperative blood loss and decreased fluid and blood transfusion requirements [76]. The quantity of platelets transfused may explain the reason why this beneficial effect was not as apparent in some previous studies.

	Summary

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 
Our understanding of platelets as merely cells involved in hemostasis has evolved and the important role they play in inflammation is now evident. As more is known about those receptors, adhesion molecules, and activation pathways involved in platelet activation during CPB, we are likely to attempt increasingly the modulation of platelet activation at a cellular level. Blocking monoclonal antibodies against platelet adhesion molecules are already in clinical use in other fields of medicine. A Fab fragment of the mouse; human chimeric antibody 7E3 (c7E3 Fab), also known as ReoPro, has been used in unstable angina [77]. The increased risk of bleeding when combined with heparin anticoagulation is an important consideration in using blocking monoclonal antibodies. This risk may be overcome by developing methods for temporarily blocking receptors with molecules that dissociate or disintegrate with time (so-called platelet anesthesia). Many novel methods of modifying platelet behavior in CPB are likely to be developed in the future. We look forward to these with anticipation.

	References

Top Abstract Introduction What does cardiopulmonary bypass... How does cardiopulmonary bypass... Complications associated with... How may these complications... Summary References

 

1. Klonizakis I., Peters A.M., Fitzpatrick M.L., Kensett M.J., Lewis S.M., Lavender J.P. Radionuclide distribution following injection of 111Indium–labelled platelets. Br J Haematol 1980;46:595-602.[Medline]
2. Peters A.M., Lavender J.P. Platelet kinetics with indium–111 platelets: comparison with chromium–51 platelets. Semin Thromb Hemost 1983;9:100-114.[Medline]
3. Behnke O. The morphology of blood platelet membrane systems. Ser Haematol 1970;3:3-16.[Medline]
4. Nieuwenhuis H.K., van Oosterhout J.J., Rozemuller E., van Iwaarden F., Sixma J.J. Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000–molecular weight lysosome–like granule protein is exposed on the surface of activated platelets in the circulation. Blood 1987;70:838-845.[Abstract/Free Full Text]
5. Metzelaar M.J., Schuurman H.J., Heijnen H.F., Sixma J.J., Nieuwenhuis H.K. Biochemical and immunohistochemical characteristics of CD62 and CD63 monoclonal antibodies. Expression of GMP–140 and LIMP–CD63 (CD63 antigen) in human lymphoid tissues. Virchows Arch B Cell Pathol Incl Mol Pathol 1991;61:269-277.[Medline]
6. Wahba A., Black G., Koksch M., et al. Cardiopulmonary bypass leads to a preferential loss of activated platelets. A flow cytometric assay of platelet surface antigens. Eur J Cardiothorac Surg 1996;10:768-773.[Abstract]
7. Holada K., Simak J., Kucera V., Roznova L., Eckschlager T. Platelet membrane receptors during short cardiopulmonary bypass–a flow cytometric study. Perfusion 1996;11:401-406.[Abstract/Free Full Text]
8. Rinder C.S., Mathew J.P., Rinder H.M., Bonan J., Ault K.A., Smith B.R. Modulation of platelet surface adhesion receptors during cardiopulmonary bypass. Anesthesiology 1991;75:563-570.[Medline]
9. Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass [Discussion]. J Thorac Cardiovasc Surg 1990;99:788–96; 796–7.
10. Metzelaar M.J., Korteweg J., Sixma J.J., Nieuwenhuis H.K. Comparison of platelet membrane markers for the detection of platelet activation in vitro and during platelet storage and cardiopulmonary bypass surgery. J Lab Clin Med 1993;121:579-587.[Medline]
11. Kondo C., Tanaka K., Takagi K., et al. Platelet dysfunction during cardiopulmonary bypass surgery. With special reference to platelet membrane glycoproteins. ASAIO J 1993;39:M550-M553.[Medline]
12. Tuszynski G.P., Rothman V.L., Murphy A., Siegler K., Knudsen K.A. Thrombospondin promotes platelet aggregation. Blood 1988;72:109-115.[Abstract/Free Full Text]
13. Tandon N.N., Kralisz U., Jamieson G.A. Identification of glycoprotein IV (CD36) as a primary receptor for platelet–collagen adhesion. J Biol Chem 1989;264:7576-7583.[Abstract/Free Full Text]
14. Komai H., Haworth S.G. Effect of cardiopulmonary bypass on the circulating level of soluble GMP–140. Ann Thorac Surg 1994;58:478-482.[Abstract]
15. Primack C., Walenga J.M., Koza M.J., Shankey T.V., Pifarre R. Aprotinin modulation of platelet activation in patients undergoing cardiopulmonary bypass operations. Ann Thorac Surg 1996;61:1188-1193.[Abstract/Free Full Text]
16. Rinder C.S., Bonan J.L., Rinder H.M., Mathew J., Hines R., Smith B.R. Cardiopulmonary bypass induces leukocyte–platelet adhesion. Blood 1992;79:1201-1205.[Abstract/Free Full Text]
17. Rinder H.M., Tracey J.L., Rinder C.S., Leitenberg D., Smith B.R. Neutrophil but not monocyte activation inhibits P–selectin–mediated platelet adhesion. Thromb Haemost 1994;72:750-756.[Medline]
18. Holloway D.S., Summaria L., Sandesara J., Vagher J.P., Alexander J.C., Caprini J.A. Decreased platelet number and function and increased fibrinolysis contribute to postoperative bleeding in cardiopulmonary bypass patients. Thromb Haemost 1988;59:62-67.[Medline]
19. Daniel J.L. Platelet contractile proteins. In: Coleman R.W., Hirsh J., Marder V.J., Salzman E.W., eds. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: JB Lippincott, 1994:569-573.
20. Greilich P.E., Carr M.E., Jr, Carr S.L., Chang A.S. Reductions in platelet force development by cardiopulmonary bypass are associated with hemorrhage. Anesth Analg 1995;80:459-465.[Abstract]
21. Boldt J., Knothe C., Welters I., Dapper F.L., Hempelmann G. Normothermic versus hypothermic cardiopulmonary bypass: do changes in coagulation differ?. Ann Thorac Surg 1996;62:130-135.[Abstract/Free Full Text]
22. Gemmell C.H., Ramirez S.M., Yeo E.L., Sefton M.V. Platelet activation in whole blood by artificial surfaces: identification of platelet–derived microparticles and activated platelet binding to leukocytes as material–induced activation events. J Lab Clin Med 1995;125:276-287.[Medline]
23. Gluszko P., Rucinski B., Musial J., et al. Fibrinogen receptors in platelet adhesion to surfaces of extracorporeal circuit. Am J Physiol 1987;252:H615-H621.[Abstract/Free Full Text]
24. Gouin I., Lecompte T., Morel M.C., et al. In vitro effect of plasmin on human platelet function in plasma. Inhibition of aggregation caused by fibrinogenolysis. Circulation 1992;85:935-941.[Abstract/Free Full Text]
25. Lu H., Soria C., Cramer E.M., et al. Temperature dependence of plasmin–induced activation or inhibition of human platelets. Blood 1991;77:996-1005.[Abstract/Free Full Text]
26. Bjoraker D.G., Ketcham T.R. In vivo platelet response to clinical protamine sulphate infusion. Anesthesiology 1982;57:A-7 [Abstract].
27. Kirklin J.K., Chenoweth D.E., Naftel D.C., et al. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg 1986;41:193-199.[Abstract]
28. Dewanjee M.K. Molecular biology of nitric oxide synthases. Reduction of complications of cardiopulmonary bypass from platelets and neutrophils by nitric oxide generation from L–arginine and nitric oxide donors. ASAIO J 1997;43:151-159.[Medline]
29. Liu L., Freedman J., Hornstein A., Fenton J.W., II, Song Y., Ofosu F.A. Binding of thrombin to the G–protein–linked receptor, and not to glycoprotein Ib, precedes thrombin–mediated platelet activation. J Biol Chem 1997;272:1997-2004.[Abstract/Free Full Text]
30. Ozawa K., Takahashi M., Sobue K. Phase specific association of heterotrimeric GTP–binding proteins with the actin–based cytoskeleton during thrombin receptor–mediated platelet activation. FEBS Lett 1996;382:159-163.[Medline]
31. Wiedmer T., Sims P.J. Participation of protein kinases in complement C5b–9–induced shedding of platelet plasma membrane vesicles. Blood 1991;78:2880-2886.[Abstract/Free Full Text]
32. Rinder C.S., Rinder H.M., Smith B.R., et al. Blockade of C5a and C5b–9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest 1995;96:1564-1572.
33. Cavarocchi N.C., Schaff H.V., Orszulak T.A., Homburger H.A., Schnell W.A., Jr, Pluth J.R. Evidence for complement activation by protamine–heparin interaction after cardiopulmonary bypass. Surgery 1985;98:525-531.[Medline]
34. Tonnesen E., Christensen V.B., Toft P. The role of cytokines in cardiac surgery. Int J Cardiol 1996;53(Suppl):1-10.[Medline]
35. Butler J., Chong G.L., Baigrie R.J., Pillai R., Westaby S., Rocker G.M. Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygenation. Ann Thorac Surg 1992;53:833-838.[Abstract]
36. Frering B., Philip I., Dehoux M., Rolland C., Langlois J.M., Desmonts J.M. Circulating cytokines in patients undergoing normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;108:636-641.[Abstract/Free Full Text]
37. Lumadue J.A., Lanzkron S.M., Kennedy S.D., Kuhl D.T., Kickler T.S. Cytokine induction of platelet activation. Am J Clin Pathol 1996;106:795-798.[Medline]
38. Reves J.G., Buttner E., Karp R.B., Oparil S., McDaniel H.G., Smith L.R. Elevated catecholamines during cardiac surgery: consequences of reperfusion of the postarrested heart. Am J Cardiol 1984;53:722-728.[Medline]
39. Taggart D.P., Fraser W., Gray C.E., Beastall G., Shenkin A., Wheatley D.J. The effects of systemic intraoperative hypothermia on the acute–phase and endocrine response to cardiac surgery. Thorac Cardiovasc Surg 1992;40:74-78.[Medline]
40. Lanza F., Cazenave J.P., Beretz A., Sutter–Bay A., Kretz J.G., Kieny R. Potentiation by adrenaline of human platelet activation and the inhibition by the alpha–adrenergic antagonist nicergoline of platelet adhesion, secretion and aggregation. Agents Actions 1986;18:586-595.[Medline]
41. Zucker J.R., Amory D.W. Platelet alpha–adrenergic receptors are not down–regulated during cardiopulmonary bypass. Anesthesiology 1985;63:449-451.[Medline]
42. Wachtogel Y.T., Musial J., Jenkin B., Niewiarowski S., Edmunds L.H., Jr, Colman R.W. Loss of platelet alpha 2–adrenergic receptors during simulated extracorporeal circulation: prevention with prostaglandin E₁. J Lab Clin Med 1985;105:601-607.[Medline]
43. Sims P.J., Faioni E.M., Wiedmer T., Shattil S.J. Complement proteins C5b–9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988;263:18205-18212.[Abstract/Free Full Text]
44. Janes S.L., Wilson D.J., Chronos N., Goodall A.H. Evaluation of whole blood flow cytometric detection of platelet bound fibrinogen on normal subjects and patients with activated platelets. Thromb Haemost 1993;70:659-666.[Medline]
45. Altieri D.C., Edgington T.S. The saturable high affinity association of factor X to ADP–stimulated monocytes defines a novel function of the Mac–1 receptor. J Biol Chem 1988;263:7007-7015.[Abstract/Free Full Text]
46. Altieri D.C., Morrissey J.H., Edgington T.S. Adhesive receptor Mac–1 coordinates the activation of factor X on stimulated cells of monocytic and myeloid differentiation: an alternative initiation of the coagulation protease cascade. Proc Natl Acad Sci USA 1988;85:7462-7466.[Abstract/Free Full Text]
47. Celi A., Pellegrini G., Lorenzet R., et al. P–selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 1994;91:8767-8771.[Abstract/Free Full Text]
48. Harker L.A., Malpass T.W., Branson H.E., Hessel E.A., II, Slichter S.J. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha–granule release. Blood 1980;56:824-834.[Free Full Text]
49. Zilla P., Fasol R., Groscurth P., Klepetko W., Reichenspurner H., Wolner E. Blood platelets in cardiopulmonary bypass operations. Recovery occurs after initial stimulation, rather than continual activation. J Thorac Cardiovasc Surg 1989;97:379-388.[Abstract]
50. Edmunds L.H., Jr, Ellison N., Colman R.W., et al. Platelet function during cardiac operation: comparison of membrane and bubble oxygenators. J Thorac Cardiovasc Surg 1982;83:805-812.[Abstract]
51. Henn V., Slupsky J.R., Grafe M., Anagnostopoulos I., Forster R., Muller–Berghaus G., Kroczek R.A. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998;391:591-594.[Medline]
52. Diacovo T.G., Roth S.J., Buccola J.M., Bainton D.F., Springer T.A. Neutrophil rolling, arrest, and transmigration across activated, surface–adherent platelets via sequential action of P–selectin and the beta 2–integrin CD11b/CD18. Blood 1996;88:146-157.[Abstract/Free Full Text]
53. Sheikh S., Nash G.B. Continuous activation and deactivation of integrin CD11b/CD18 during de novo expression enables rolling neutrophils to immobilize on platelets. Blood 1996;87:5040-5050.[Abstract/Free Full Text]
54. Buttrum S.M., Hatto R., Nash G.B. Selectin–mediated rolling of neutrophils on immobilized platelets. Blood 1993;82:1165-1174.[Abstract/Free Full Text]
55. Weber C., Springer T.A. Neutrophil accumulation on activated, surface–adherant platelets in flow is mediated by interaction of Mac–1 with fibrinogen bound to alphaII beta3 and stimulated by platelet activating factor. J Clin Invest 1997;100:2085-2093.[Medline]
56. Boers M., van den Dungen J.J., Karliczek G.F., Brenken U., van der Heide J.N., Wildevuur C.R. Two membrane oxygenators and a bubbler: a clinical comparison. Ann Thorac Surg 1983;35:455-462.[Abstract]
57. Moen O., Fosse E., Braten J., et al. Differences in blood activation related to roller/centrifugal pumps and heparin–coated/uncoated surfaces in a cardiopulmonary bypass model circuit. Perfusion 1996;11:113-123.[Abstract/Free Full Text]
58. Yoshikai M., Hamada M., Takarabe K., Okazaki Y., Ito T. Clinical use of centrifugal pumps and the roller pump in open heart surgery: a comparative evaluation. Artif Organs 1996;20:704-706.[Medline]
59. Taylor K.M., Bain W.H., Maxted K.J., Hutton M.M., McNab W.Y., Caves P.K. Comparative studies of pulsatile and nonpulsatile flow during cardiopulmonary bypass. I. Pulsatile system employed and its hematologic effects. J Thorac Cardiovasc Surg 1978;75:569-573.[Abstract]
60. Goto M., Kudoh K., Minami S., et al. The renin–angiotensin–aldosterone system and hematologic changes during pulsatile and nonpulsatile cardiopulmonary bypass. Artif Organs 1993;17:318-322.[Medline]
61. Van der Kamp K.W., van Oeveren W. Contact, coagulation and platelet interaction with heparin treated equipment during heart surgery. Int J Artif Organs 1993;16:836-842.[Medline]
62. Moen O., Fosse E., Dregelid E., et al. Centrifugal pump and heparin coating improves cardiopulmonary bypass biocompatibility. Ann Thorac Surg 1996;62:1134-1140.[Abstract/Free Full Text]
63. Teoh K.H., Christakis G.T., Weisel R.D., et al. Blood conservation with membrane oxygenators and dipyridamole. Ann Thorac Surg 1987;44:40-47.[Abstract]
64. Solis R.T., Kennedy P.S., Beall A.C., Jr, Noon G.P., DeBakey M.E. Cardiopulmonary bypass. Microembolization and platelet aggregation. Circulation 1975;52:103-108.[Abstract/Free Full Text]
65. Ware J.A., Scott M.A., Horak J.K., Solis R.T. Platelet aggregation during and after cardiopulmonary bypass: effect of two different cardiotomy filters. Ann Thorac Surg 1982;34:204-206.[Abstract]
66. Muraoka R., Yokota M., Aoshima M., et al. Subclinical changes in brain morphology following cardiac operations as reflected by computed tomographic scans of the brain. J Thorac Cardiovasc Surg 1981;81:364-369.[Abstract]
67. Bidstrup B.P., Royston D., Sapsford R.N., Taylor K.M. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364-372.[Abstract]
68. Van Oeveren W., Eijsman L., Roozendaal K.J., Wildevuur C.R. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet 1988;1:644.[Medline]
69. Wahba A., Black G., Koksch M., et al. Aprotinin has no effect on platelet activation and adhesion during cardiopulmonary bypass. Thromb Haemost 1996;75:844-848.[Medline]
70. Shigeta O., Kojima H., Jikuya T., et al. Aprotinin inhibits plasmin–induced platelet activation during cardiopulmonary bypass. Circulation 1997;96:569-574.[Abstract/Free Full Text]
71. Konishi R., Shimizu R., Firestone L., et al. Nitric oxide prevents human platelet adhesion to fiber membranes in whole blood. ASAIO J 1996;42:M850-M853.[Medline]
72. Sly M.K., Prager M.D., Eberhart R.C., Jessen M.E., Kulkarni P.V. Inhibition of surface–induced platelet activation by nitric oxide. ASAIO J 1995;41:M394-M398.[Medline]
73. Bernabei A., Gikakis N., Kowalska M.A., Niewiarowski S., Edmunds L.H., Jr Iloprost and echistatin protect platelets during simulated extracorporeal circulation. Ann Thorac Surg 1995;59:149-153.[Abstract/Free Full Text]
74. Teoh K.H., Christakis G.T., Weisel R.D., et al. Dipyridamole preserved platelets and reduced blood loss after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1988;96:332-341.[Abstract]
75. Tatsumi E., Matsuda T., Takano H., et al. A synthetic tetrapeptide as a novel platelet–preserving agent during cardiopulmonary bypass. ASAIO Trans 1988;34:813-816.[Medline]
76. Christenson JT, Reuse J, Badel P, Simonet F, Schmuziger M. Platelet pheresis before redo CABG diminishes excessive blood transfusion. Ann Thorac Surg 1996;62:1373–8; [discussion] 1378–9.
77. Bhattacharya S., Jordan R., Machin S., et al. Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): potent dose–dependent inhibition of platelet function. Cardiovasc Drugs Ther 1995;9:665-675.[Medline]

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