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Ann Thorac Surg 1996;62:1549-1557
© 1996 The Society of Thoracic Surgeons
Divisions of Cardiothoracic Surgery and Anesthesia, University of Washington, Seattle, Washington
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Abstract |
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 TopFootnotes Abstract IntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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Introduction |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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Recent discoveries in the field of vascular biology have led to an expanded understanding of the pathogenesis of many of the immediate and long-term complications of patients undergoing cardiovascular operations and interventional cardiologic procedures. In particular, the vascular endothelium has emerged as the central focus of many of the biologic events that affect the preoperative, operative, and postoperative course of nearly all heart surgery patients. A recurring theme in the study of endothelial cell biology is the crucial role that endothelial cell injury plays in the difficulties that our patients encounter. The deleterious effects of endothelial cell injury are most evident in the acute syndromes of vasospasm, coagulopathy, ischemia/reperfusion injury, and the systemic inflammatory response to cardiopulmonary bypass. In addition, chronic endothelial cell injury contributes to the development of anastomotic narrowing and the progression of atherosclerosis, both of which limit the long-term success of coronary artery bypass grafting. Because of the increasingly recognized role of the endothelium in cardiovascular function there is a tremendous amount of basic science information accumulating detailing the response of the endothelium to injury. This is the third in a series of seven reviews intended as an introduction to the major topics of endothelial cell biology that are of importance to the practicing cardiothoracic surgeon. In particular, the authors have focused on the role that the endothelium has on the development of vasomotor dysfunction, bleeding and thrombosis, neutrophil-endothelial cell interaction, and obstructive arteriopathy. The aim of these reviews is to provide a concise reference point for cardiothoracic surgeons as they evaluate the ever-accumulating research findings and new therapies that stem from the study of the endothelium in response to the insults encountered in cardiothoracic surgery.Edward D. Verrier, MD
Postoperative bleeding complications and thrombosis are potentially life-threatening in patients who undergo cardiopulmonary bypass (CPB). Difficult surgical hemostasis, extracorporeal circulation, hemodilution, systemic heparinization, hypothermia, and various coagulopathies are predisposing factors for both hemorrhagic and thrombotic complications [1–6]. Currently cardiac-related surgical procedures account for approximately 10% of all red blood cell transfusions in the United States, and in some institutions more than 25% of all blood products are dedicated to CPB patients [5, 7]. Some types of patients and patients undergoing certain procedures have an increased propensity to bleed, which explains why 20% of patients account for more than 80% of the total blood product transfusions required in patients undergoing cardiac procedures [7]. Combined valvular and coronary procedures, reoperations, aortic root replacement, history of dialysis, steroid use, cardiogenic shock, and extremes of age create particular risks for bleeding after CPB [5, 8].
Although bleeding after CPB is quite common, reexploration for bleeding is required in only 3% to 5% of patients in most series. Of patients returned to the operating room for bleeding, an isolated site of bleeding is identified in little more than half. In the remaining patients, in whom bleeding is the result of disorders of coagulation, transfusion (with the attendant morbidity and costs) is required. Reexploration for bleeding is a significant predictor of increased mortality and morbidity. Patients reexplored for bleeding have been found to have an operative mortality 4.8 times that of patients without difficulties with bleeding [8]. This is perhaps due to the increased need for prolonged ventilation, renal failure, septicemia, adult respiratory distress syndrome, stroke, deep sternal infection, and atrial fibrillation noted in patients reoperated on for bleeding after CPB [8]. In contrast to the coagulopathy that is frequently associated with CPB, acute thrombosis can play a role in early coronary artery bypass graft closure, mechanical valvular failure, and some cerebrovascular events.
Although there are likely many causes of abnormal coagulation in patients undergoing CPB, the tendency to bleed is, for the most part, secondary to several features [4, 5, 9, 10]. First, there is a decrease of circulating coagulation factors. Although hemodilution plays a role, this is most likely caused when tissue factor, as a result of numerous inflammatory stimuli, is expressed throughout the intravascular space resulting in the initiation of coagulation via the extrinsic pathway of coagulation. Important clotting factors, notably prothrombin and fibrinogen, are consumed in this process [10]. Second, there is a CPB-related qualitative platelet defect that is exacerbated by thrombocytopenia as platelets are consumed from the circulation secondary to adherence to the conduits of the CPB circuit. Thrombin production may further activate platelets, resulting in aggregation and loss from the circulating pool. Finally, CPB results in a dysregulation of the complex system of fibrinolysis, which results from an imbalance between endothelial-derived circulating plasminogen activators and plasminogen-activator inhibitors, resulting at first in fibrinolysis and later in a propensity to thrombose [4, 11]. Although one cannot characterize the tissue factor response, platelet dysfunction, or fibrinolysis as being most important, the expression of intravascular thrombin, induced by diffuse intravascular tissue factor expression, appears to be a critical event in all of these causes. Thrombin has broad biological properties including, most notably, the conversion of fibrinogen to fibrin, but also the activation of platelet aggregation and the release of endothelial cell tissue plasminogen activator (t-PA), which probably mediates a majority of the fibrinolytic picture (Fig 1
). Furthermore, coagulation factors are consumed in the process of thrombin generation. Because the vascular endothelium contributes to the production of thrombin through the inducible ability to express tissue factor, it is of critical importance in the development of coagulopathy after CPB.
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Normal Coagulation |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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In response to tissue injury there is a loss of many of the aforementioned natural anticoagulant mechanisms and a procoagulant response (Fig 2). The procoagulant response is characterized by two principal mechanisms that function to stop blood loss as a result of vascular injury [14]. First, platelets adhere and become activated, releasing von Willebrand's factor and other molecules that increase platelet adhesiveness and accelerate coagulation. Second, a series of reactions are triggered that result in the formation of insoluble fibrin, which binds avidly to platelet surfaces, forming solid clot.
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). This division resulted from observations that coagulation could be initiated by contact with negatively charged artificial substances in vitro or by exposure to the subendothelial elements, simulated by exposing blood to tissue thromboplastin, obtained from purified rabbit brain extract [15]. The former was termed the intrinsic pathway of coagulation, so named because all of the components were present in the blood [16]. The intrinsic pathway requires activation of factor XII in association with high-molecular-weight kininogen and prekallikrein [14]. This division of coagulation into the intrinsic and extrinsic pathways of coagulation is reflected in the two most commonly performed studies of coagulation, the activated partial thromboplastin time and the partial thromboplastin time, where the two pathways are simulated in vitro by either exposing plasma to cephalin and kaolin (negatively charged substances) or tissue factor and timing how long it takes blood to clot [17, 18]. Although the division of coagulation into an intrinsic and extrinsic pathway of coagulation may have been useful in initiation of coagulation in vitro, there is very little evidence that intrinsic pathway activation occurs in vivo. This is evident in observations of patients with congenital deficiencies in factor XI (hemophilia C), XII, prekallikrein, or high-molecular-weight kinogen, who do not appear to have marked abnormalities in clotting [15]. In contrast, patients with genetic deficiencies in factor VII, VIII (hemophiilia A), and IX (hemophilia B), the factors involved in extrinsic pathway activation, have severe bleeding abnormalities [16]. These observations coupled with the growing basic science findings detailing the importance of the tissue factor pathway have led to the speculation that the extrinsic pathway is responsible for the initiation of coagulation and the intrinsic factors are required for growth and maintenance of clot formation once coagulation has been initiated.
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Coagulation is also affected by the degree of plasminogen activation. Plasminogen is a circulating plasma protein that can converted to plasmin by tPA. Plasmin cleaves fibrin into the fibrin split products characteristic of states of fibrinolysis. Plasminogen-activator inhibitors (PAIs), such as PAI-1, which prevent fibrinolysis by binding with and deactivating tPA, are upregulated when endothelial cells are activated by cytokines. When these procoagulant surface changes are enhanced, many of the anticoagulant mechanisms are concurrently down-regulated (such as thrombomodulin and proteins C and S), promoting an overall procoagulant surface. In states of inflammation, such as seen after CPB, endothelial cells initially promote fibrinolysis by releasing tPA stores and later thrombosis by the loss of the constitutive antithrombin mechanisms, the inducible expression of tissue factor and the release of PAI-1.
The complexity of activators and inhibitors within coagulation makes it quite difficult to reach conclusions about the overall effect of any single event. What is important is that there are checks and balances within the systems of inflammation and coagulation that promote either a quiescent anticoagulant surface, an inflamed procoagulant state, or a state of fibrinolysis. Although these checks and balances were likely designed by evolution to prevent hemorrhage or thrombosis on a local level, they seem less well adapted on a systemic level, such as that seen after CPB. Efforts to understand the critical control points in this process may lead to novel therapeutic approaches to prevent bleeding or thrombosis in the cardiovascular surgery patient.
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Tissue Factor Pathway Activation After Cardiopulmonary Bypass |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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Exposure to tissue factor is required for the activation of the extrinsic pathway of coagulation; however, until recently it did not make sense that there would be widespread tissue factor exposure just from opening the chest and performing a cardiac operation. Unlike most other human cells, endothelial cells and the circulating blood components do not normally express tissue factor, assuring that blood in the vascular tree remains in the fluid phase. Experimental observations that inflammatory mediators widely circulating in cardiac surgery patients, such as tumor necrosis factor and interleukin-1, as well as lipopolysaccharide, induce the expression of tissue factor on endothelial cells and monocytes in culture may explain why there is an extensive activation of the extrinsic pathway of coagulation in CPB patients [26–28]. This assertion is further supported by the observation that many of the features of CPB-induced coagulopathy can be induced in animal models or normal human subjects infused with cytokines [29, 30]. The intravascular expression of tissue factor has been quantified by Altieri and colleagues [31], who demonstrated that at rest monocytes express no detectable tissue factor; however, when stimulated with lipopolysaccharide or cytokines they express approximately 17,000 molecules of tissue factor on each cell surface, suggesting that monocytes also play a major role in the intravascular activation of the extrinsic pathway of coagulation in states of systemic inflammation. The potential for massive expression of tissue factor throughout the entire intravascular space is appreciated when one realizes that all endothelial cells and monocytes could be activated in the whole-body inflammatory response during CPB. If left unchecked, this would result in intravascular coagulation and deposition of fibrin in the microvascular circulation. Although this may be of phylogenetic benefit in preventing the spread of infection or controlling blood loss when it occurs locally, when it occurs systemically secondary to CPB, sepsis, or shock, the result is a potential consumptive coagulopathy that can be life threatening.
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Endothelial-Platelet Interactions |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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Platelet activation is closely regulated by endothelial cell activation in response to inflammation and injury, especially in the form of thrombin. Thrombin is an extremely potent stimulant for platelet activation, resulting in the release of the contents of platelet and endothelial cell storage vesicles, known as Wiebel-Palade bodies. Wiebel-Palade granules contain von Willebrand's factor, which increases platelet adhesive function; P-selectin, an endothelial cell adherence molecule that mediates leukocyte attachment to vascular surfaces; and thrombospondin, which participates in plasminogen activation. Von Willebrand's factor forms the glue by which platelets adhere to each other and to the activated endothelium. Von Willebrand's factor is likely an important element in consumption of platelets by the circuit and membranes of the CPB pump and oxygenator. Once activated by thrombin, platelets express glycoprotein binding sites, which facilitate platelet-platelet adhesion as well as platelet incorporation into the fibrin clot. Glycoprotein IA, the binding site for von Willebrand's factor, mediates the initial stickiness of platelets. Fibrin has six binding sites of a specific amino acid sequence for platelets (glycoprotein IIB/IIIA), and therefore each molecule can link a number of platelets into the cement-like solid clot. Because this process occurs diffusely when endothelial cells and monocytes are activated throughout the body during CPB, platelets become activated and some adhere to fibrin, neutrophils, the CPB circuit, and the activated endothelium. When this occurs circulating platelet levels drop and many of the remaining platelets are often incompetent to promote coagulation. Glycoprotein IIB/IIIA, the platelet binding site for fibrin, is often destroyed or made dysfunctional by CPB [32]. Furthermore, plasmin, which is generated secondary to endothelial cell tPA release, directly inactivates platelet membrane receptors [33]. The exact reason for thrombin-induced platelet dysfunction is unknown; however, this likely contributes significantly to the platelet abnormalities encountered after CPB.
Another component of endothelial cell and platelet activation is Wiebel-Palade release of P-selectin (GMP-140; CD 62) [34]. Thrombin is a potent agonist of P-selectin release, promoting leukocyte adherence and the initiation of intravascular inflammation, thus demonstrating that the expression of tissue factor represents a conversion of the proinflammatory and procoagulant pathways following CPB [35, 36]. P-selectin creates an active site for binding of platelets to monocytes and neutrophils [37, 38]. Platelet-monocyte and neutrophil-platelet interactions occur fairly rapidly after CPB is begun. The net effect appears to be pulmonary sequestration of platelet-leukocyte combinations that may contribute to localized vascular reactivity and capillary leak. In addition, P-selectin has been investigated as an important mediator of ischemia/reperfusion injury. The expression of P-selectin on the surface of endothelial cells and platelets may be important in an inflammatory process contributing to the "no reflow" phenomenon. This theory proposes that activated platelets and leukocytes together aggregate on the endothelium in the circulation, causing capillary obstruction. Blockage of P-selectin in a number of animal studies has reduced the degree of myocardial injury seen upon reperfusion [37–39]. Much work is yet to be done, but the presence of these cell surface receptors that bind neutrophils, platelets, and coagulation proteins strengthens the hypothesis that ischemia-reperfusion injury not only involves inflammatory mediators but involves coagulation as well.
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Hyperfibrinolysis and Inflammation |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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The fibrinolytic system is a complex cascade of serine proteases and their inhibitors, which regulate the conversion of plasminogen to the protease plasmin [40] (Fig 4). Plasmin controls the runaway reaction of clot acceleration by degrading fibrinogen and fibrin. Over-expression of plasmin is an important component of the accelerated fibrinolysis that occurs during and after CPB [2, 41]. Plasmin, which is produced when tPA interacts with circulating plasminogen, is the active agent of fibrinolysis. Furthermore, CPB-induced contact activation leads to the production of kallikrein and bradykinin. These are potent stimulators of serum urokinase plasminogen activator, which in turn potentates tPA production. Plasmin itself is a platelet inhibitor at normothermia, but at hypothermic temperatures (<32°C) it is a profound platelet activator [4, 42]. Therefore the stimulation of the fibrinolytic system can decrease platelet function profoundly.
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The degree of plasmin formation is regulated by the interplay of plasminogen activators, such as tPA and serum urokinase plasminogen activator, and plasminogen-activator inhibitors, such as PAI-1 [40] (see Fig 4
). In the early postoperative period tPA levels begin to decrease. When this occurs the fibrinolytic activity is partially reduced by increased endothelial cell surface expression of PAI-1 and by binding to circulating PAI, which counteract the effects of tPA [26, 43, 45, 46]. Plasminogen-activator inhibitor-1 is produced by activated endothelial cells and is released from platelets [34]. Interleukin-1, tumor necrosis factor, and lipopolysaccharide decrease the overall fibrinolytic function by increasing the release of PAI-1 from endothelium and the liver, which in part explains why microthrombosis is a prominent feature of some forms of sepsis. Tissue plasminogen activator is cleared from the blood by hepatic clearance and by the active binding to PAI-1. After CPB, for t-PA to have its effects it must overcome circulating levels of PAI-1. The ability of t-PA to overpower the effects of PAI-1 is mediated, in part, by the protein thrombospondin. Thrombospondin is a component of endothelial cell and platelet alpha granules, released when platelets and endothelial cells are activated by thrombin. Thrombospondin forms a trimolecular complex with plasminogen and t-PA, dramatically increasing the catalytic activity of t-PA to form plasmin [40]. When thrombospondin binds with t-PA it prevents its inactivation by competitively inhibiting the action of PAI-1. Postoperatively, once the stimulus for tPA is over, PAI-1 production far exceeds tPA and the balance is shifted toward a hyperocoaguable state where thrombosis is promoted.
Why some patients are prone to excessive fibrinolysis and others to thrombosis is not clearly known. Clinical measurements have documented that t-PA and PAI production in response to stimuli such as thrombin production is quite variable from patient to patient. Chandler and colleagues [47] found that t-PA release has at least a 400-fold variability in the human population. Furthermore, expression of PAI-1 has more than a 50-fold variability. This may explain why some patients have a greater propensity to bleed and others to thrombosis after CPB. Because the controllers of the fibrinolytic system respond to both thrombin production and inflammatory mediators it is difficult at this time to determine what makes an individual patient a large or small risk for bleeding or thrombosis secondary to these factors. Clearly the length of bypass and the complexity of the procedure, which are known to be associated with a greater inflammatory response and risk for bleeding or thrombosis, likely contribute to the degree of penetrance of these genetic traits.
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Current and Future Therapeutic Options |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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Even though some of the untoward effects of intravascular coagulation can be attenuated with heparin, thrombin generation increases after the neutralization of the heparin with protamine sulfate, and continues to be elevated significantly 24 hours postoperatively [48]. Furthermore, high-dose heparin does not prevent thrombin generation during CPB, consistent with previous experimental studies demonstrating that thrombin bound to fibrin or other surfaces (eg, the CPB conduit) is resistant to antithrombin III/heparin inhibition [48]. Therefore, although heparin is a useful adjunct in preventing widespread thrombosis during CPB, it does not prevent the formation of thrombin, which drives many of the procoagulant, proinflammatory, and fibrinolytic complications associated with cardiovascular operations [10].
Recently there has been a great deal of interest in the use of protease inhibitors to attenuate the generalized fibrinolysis seen during and immediately after CPB. Aprotinin is a naturally occurring serine protease inhibitor isolated from bovine lung tissue that inhibits kallikrein and plasmin [49]. High-dose aprotinin administered during CPB has been shown to reduce postoperative bleeding substantially [50]. A reduction in fibrinolytic activity by inhibition of plasmin generated during CPB appears to be one of its primary modes of action [2]. It may also block some of the inflammatory pathways; however, these mechanisms have yet to be defined. Platelet function is definitely preserved if aprotinin is given prophylactically [51].
Other agents, such as the lysine analogues (tranexaminic acid and 
-aminocaproic acid), demonstrate decreased bleeding after CPB if given before and during CPB. However, aprotinin may be more effective in patients at high risk for coagulopathy. The lysine analogues only partially block the conversion of plasminogen to plasmin and plasmin binding to fibrin. Recently, there is enthusiasm about the use of c7E3 (REOPRO), a monoclonal antibody introduced into clinical study that binds the glycoprotein IIb/IIIa receptors on platelets, thereby blocking the ligands that bind fibrinogen. Early studies suggest that it decreases some of the ischemic complications associated with catheter-directed coronary interventions, and it may in fact decrease early coronary restenosis after angioplasty; however, a benefit after CPB has yet to be demonstrated [52].
Like heparin, however, serine protease and platelet inhibitors focus on inhibiting coagulation distal in the cascade, once endothelial cells have been activated, tissue factor has been expressed, and thrombin has been diffusely generated. An improved understanding of the role of endothelial cell activation in promoting diffuse thrombin generation is currently allowing the design of laboratory experiments to prevent the initial formation of thrombin in response to inflammatory mediators. For example, specific inhibitors of factor VII and IX are currently being evaluated. In addition, the predictable manner in which tissue factor is expressed after endothelial cell activation provides a particularly focused point of therapeutic control. Insights into the molecular mechanisms that regulate tissue factor expression are of interest in the pursuit of novel therapies to attenuate the coagulopathy seen after cardiac operations. The expression of tissue factor on endothelial cell and monocyte surfaces requires transcriptional activation of the tissue factor gene, translation of tissue factor specific messenger RNA transcripts into protein that is transported to the plasma membrane [53]. In our laboratory we have focused on the transcriptional activation of the tissue factor gene because manipulation of tissue factor expression may be accomplished more precisely at a transcriptional level [54]. The tissue factor promoter region, which controls the expression of the tissue factor gene, contains the transcriptional regulatory element nuclear factor kB [19]. We are currently evaluating therapies aimed at blocking nuclear factor kB activation in several laboratory models. Because nuclear factor kB is involved in a variety of inflammatory genes, this line of investigation may allow us to attenuate the overall degree of inflammatory activation, thus affecting the generation of thrombin on a much broader scale. Efforts to further characterize the molecular events that result in tissue factor expression may allow the development of more precise techniques to preserve the anticoagulant properties of the endothelium and thereby prevent some of the coagulopathic or thrombotic events that can complicate cardiothoracic operations.
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Footnotes |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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References |
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TopFootnotesAbstractIntroductionNormal CoagulationTissue Factor Pathway Activation...Endothelial-Platelet...Hyperfibrinolysis and...Current and Future Therapeutic...References |
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