Ann Thorac Surg 1998;65:S56-S59
© 1998 The Society of Thoracic Surgeons
Endothelial-Related Coagulation in Pediatric Surgery
Joachim Boldt, MDa
a Department of Anesthesia, Klinikum Ludwigshafen, Ludwigshafen, Germany
Address reprint requests to Dr Boldt, Klinikum Ludwigshafen, Klinik für Anaesthesiologie, Bremserstr 79, Ludwigshafen 67063, Germany
Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.
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Abstract
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Background. The endothelium plays a pivotal role in the regulation of anticoagulant and procoagulant pathways and imbalance can produce disturbances in coagulation. Serine protease inhibitors are also important controllers of the coagulation system. Aprotinin can reduce postoperative bleeding, although the mechanism of action is not clearly defined. This article focuses on a study in children with congenital heart disease scheduled for cardiac operations to determine the influence of aprotinin on plasmatic or endothelial-related natural inhibitors.
Methods. Thirty children were randomly allocated either to an aprotinin-treated group or to a control group. Levels of thrombomodulin, protein C, free protein S, and thrombin/antithrombin complex were measured before, during, and after cardiopulmonary bypass until the first postoperative day.
Results. Levels of antithrombin III, protein C and protein S, and fibrinogen, platelet count, and activated partial thromboplastin time were without differences between the two groups. Thrombin/antithrombin plasma concentrations increased significantly during cardiopulmonary bypass, without showing any differences between aprotinin-treated and nontreated children. Thrombomodulin plasma concentrations during cardiopulmonary bypass and until 5 hours after cardiopulmonary bypass were significantly lower in the aprotinin-treated children than in the control group. By the first postoperative day, the levels in the aprotinin-treated patients had returned to baseline.
Conclusions. The results suggest a direct or indirect effect of aprotinin on endothelial cell thrombomodulin expression and release in a soluble form into the circulation. Whether the lower plasma concentrations with aprotinin are related to suppression of proinflammatory mediators and preservation of endothelial cell function or whether aprotinin has a direct action on thrombomodulin expression by the endothelium can only be speculated.
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Introduction
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Bleeding remains a problem in children undergoing surgical correction of congenital heart disease [1]. A number of factors contribute to this deranged coagulation, the major one being contact of blood with the foreign, nonendothelialized surface of the cardiopulmonary bypass (CPB) circuit. In addition, an immature hemostatic system and the underlying disease in very young children result in lower concentrations of many of the coagulation factors when compared with the adult population [2]. The more profound hemodilution that occurs with pediatric CPB will further reduce the levels of the factors necessary for normal hemostasis. However, this dilutional coagulopathy may not be a major factor, as it has been suggested that factor concentrations can be reduced to 30% to 40% of normal with the maintenance of normal hemostasis [3].
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Role of the endothelium
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In recent years, it has become apparent that in addition to plasmatic- and platelet-associated hemostasis, the endothelium plays a pivotal role in the regulation of anticoagulant and procoagulant pathways [4]. Table 1 summarizes the major prothrombotic and antithrombotic substances released by endothelium.
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Actions of thrombomodulin
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The procoagulant tissue factor can initiate thrombin formation; by contrast, the endothelial cell produces the anticoagulant cofactor thrombomodulin (TM). Thrombin binds to TM, and this endothelial-activated thrombin-thrombomodulin complex activates protein C (protein Ca), which together with protein S inactivates cofactors Va and VIlla. Additionally, protein C enhances fibrinolysis by proteolyzing a plasminogen activator inhibitor, and accelerates the inactivation of thrombin by antithrombin III. These factors are responsible for inhibiting the perpetuation of thrombin generation. Furthermore, TM also possesses direct antithrombin properties. Thus, the TM/protein C system is the primary mechanism for inactivating cofactors of the coagulation cascade. Imbalance between procoagulants and physiologic anticoagulants could produce disturbances in coagulation.
Thrombomodulin is expressed by and normally remains bound to the endothelial cell. However, a soluble form of TM can be found in circulating blood and may be a marker of endothelial activation or damage [5]. Elevated plasma levels may reflect an increased expression of membrane-bound TM and subsequent release into the circulation caused by endothelial damage or an increase in proteolytic cleavage of the membrane-bound TM. The soluble TM appears to be biologically active and is capable of catalyzing protein C activation by thrombin [6], and may play a role in the development of coagulation disorders in the critically ill [7].
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Action of aprotinin on endothelial-related coagulation
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The serine protease inhibitor aprotinin can significantly reduce perioperative bleeding and the need for homologous blood and blood-product transfusions in the adult surgical patient [8, 9], although the mechanism of action has not been clearly elucidated.
A study of the use of aprotinin in children undergoing cardiac operations with CPB has highlighted the action of the drug on certain parameters involved in endothelial-regulated coagulation [10]. Thirty children with congenital heart disease scheduled for cardiac operations were randomly divided into two groups, with one group (n = 15) receiving aprotinin and the second group (n = 15) receiving no aprotinin. The aprotinin-treated group received 30,000 U/kg (4.2 mg/kg) after induction of anesthesia; 30,000 U/kg (4.2 mg/kg) was added to the prime of the CPB system, followed by an additional 30,000 U · kg-1 · h-1 (4.2 mg · kg-1 · h-1) until the end of CPB. Levels of TM, protein C, free protein S, and thrombin/antithrombin complex were measured after induction of anesthesia, and before, during, and after CPB until the morning of the first postoperative day.
Levels of antithrombin III, protein C and protein S, and fibrinogen, platelet count, and activated partial thromboplastin time were without differences between the two groups. Thrombin/antithrombin plasma concentrations increased significantly during CPB, without showing any differences between aprotinin-treated and nontreated children. Thrombomodulin plasma concentrations were within the normal range (<40 ng/mL) and were similar in both groups at baseline. However, during CPB and until 5 hours after CPB, TM plasma levels were significantly lower in the aprotinin-treated children than in the control group (Fig 1). By the first postoperative day, the levels in the aprotinin-treated patients had returned to baseline and were not significantly different from those of the control group. Hemodilution caused a significant reduction in TM level in both groups during CPB, which was rapidly reversed to baseline levels by the end of the operation in the control group. However, the TM plasma levels remained suppressed in the aprotinin-treated patients, suggesting a direct or indirect effect of aprotinin on endothelial cell TM expression and release in a soluble form into the circulation. Whether the reduction in TM plasma concentrations by aprotinin may explain the often-reported reduction in bleeding tendency is uncertain. Nevertheless, increased TM plasma levels, as seen in the patients who did not receive aprotinin, may possibly result in a less thrombogenic endothelial surface.
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Fig 1. Thrombomodulin plasma levels in the two groups (normal range, 30 to 40 ng/mL). (CPB = cardiopulmonary bypass; PO = postoperative.) (Reprinted with permission from Boldt J, Zickmann B, Schindler E, Welters A, Dapper F, Hempelmann G. Influence of aprotinin on the thrombomodulin/protein C system in pediatric cardiac operations. J Thorac Cardiovasc Surg 1994;107:1215–21.)
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Aprotinin as an antiinflammatory agent: myth or reality?
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It is widely accepted that CPB results in an increase in proinflammatory mediators. The interactions between these mediators and the maintenance of normal hemostasis are not completely understood, but the endothelium is clearly an important link between inflammation and coagulation. Cytokines such as tumor necrosis factor and interleukin-1 may induce procoagulant activity by downregulation of TM expression [11, 12], reduced release of tissue plasminogen activator, and stimulation of release of plasminogen activator inhibitor-1 [13, 14]. This, together with hypercoagulability resulting from cytokine-induced expression of tissue factor [13], may predispose the patient toward a thrombotic state.
Studies in humans have shown that aprotinin reduces tumor necrosis factor [15] and interleukin-6 release [16], although a recent study reported that low-dose aprotinin had little effect on the inflammatory response induced by CPB in a selected pediatric population at low operative risk [17]. Increased production of tumor necrosis factor was not observed in patients treated with or without aprotinin. Interleukin-6 plasma levels did increase significantly after CPB, although the lower levels in the aprotinin-treated children 4 hours postoperatively did not achieve a statistically significant difference (Fig 2).
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Fig 2. Course of interleukin-6 before, during, and after cardiopulmonary bypass (CPB) in children receiving aprotinin (n = 8) or not (n = 9). Results are mean ± standard error of the mean. (PO = postoperative; *Significant difference versus baseline values in both groups; p < 0.001.) (Reprinted with permission from Seghaye MC, Duchateau J, Grabitz RG, et al. Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children. Ann Thorac Surg 1996;61:1205–11.)
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Endothelial–leukocyte interactions
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An important component of the inflammatory process is the interaction between white cells and the microvascular endothelium resulting in the binding and subsequent migration of neutrophils through the vascular endothelium. Specific adhesion molecules, such as endothelial leukocyte adhesion molecule, vascular cell adhesion molecule, and intracellular adhesion molecule, are expressed on the surface of the endothelium. These molecules can be detected in soluble form in circulating plasma under certain conditions and are believed to be markers of endothelial activation or damage as a result of inflammatory action [18, 19]. Sessler and associates [20] reported a fourfold increase in circulating levels of intracellular adhesion molecule as septic patients deteriorated into septic shock, demonstrating that these soluble adhesion molecules may also be markers of the extent of inflammation.
In adult patients undergoing cardiac procedures with CPB, circulating levels of adhesion molecules were not significantly elevated, indicating only limited endothelial damage or inflammation [21]. However, it has recently been shown that levels of soluble endothelial leukocyte adhesion molecule are markedly elevated in children with congenital heart disease before their operation (Fig 3) [22]. The initial fall in concentration observed during bypass in the children is related to a greater degree of hemodilution, but the data show a significantly elevated level of this soluble adhesion molecule in the pediatric population compared with adults throughout the procedure up until the second postoperative day (see Fig 3). There are several postulated reasons for these elevated plasma levels of circulating adhesion molecules, including (1) influence of hypoxia secondary to microcirculatory abnormalities, (2) release of proteases from activated white cells, (3) activation of the inflammatory mediator cascade (eg, complement, tumor necrosis factor), and (4) platelet damage or coagulation abnormalities.
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Fig 3. Plasma level of circulating endothelial leukocyte adhesion molecule-1 (sELAM-1) (normal range, 30 to 60 ng/mL). (CPB = cardiopulmonary bypass; PO = postoperative; *p < 0.05, significantly different from the adult group;  p < 0.05, significantly different from baseline data.) (Reprinted with permission from Boldt J, Osmer CH, Linke LC, Dapper F, Hempelmann G. Circulating adhesion molecules in pediatric cardiac surgery. Anesth Analg 1995;81:1129–35.)
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The role of aprotinin in ameliorating the CPB-induced endothelial damage in the pediatric cardiac surgical population still needs clarification. Questions regarding when the drug should be given, how much and for how long, and which patients may benefit the most still need answers.
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References
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Abstract
Introduction
