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Ann Thorac Surg 2009;88:318-325. doi:10.1016/j.athoracsur.2008.12.097
© 2009 The Society of Thoracic Surgeons
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Reviews

Thrombin in Myocardial Ischemia-Reperfusion During Cardiac Surgery

Peter Raivio, MD, PhDa,*, Riitta Lassila, MD, PhDb,c, Jari Petäjä, MD, PhDd

a Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland
b Department of Coagulation Disorders, Helsinki University Central Hospital, Helsinki, Finland
c Laboratory Division (HUSLAB), Helsinki University Central Hospital, Helsinki, Finland
d Department of Pediatrics, Helsinki University Central Hospital, Helsinki, Finland

* Address correspondence to Dr Raivio, Department of Cardiothoracic Surgery, Helsinki University Central Hospital, PO Box 340, Helsinki, FI-00029 HUS, Finland (Email: peter.raivio{at}hus.fi).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 
Thrombin is a multifunctional protease with procoagulant, pro-inflammatory, and pro-apoptotic effects. Thrombin has direct potentially adverse effects on the endothelium and on cardiomyocytes, which are independent of its procoagulant effects, and it has emerged as a possible mediator of ischemia-reperfusion injury. Several lines of experimental evidence specifically implicate thrombin to be involved in myocardial ischemia-reperfusion injury. Cardiopulmonary bypass increases thrombin generation progressively, but reperfusion after myocardial ischemia induces an additional distinct and rapid increase in thrombin generation. Clinical studies have shown that thrombin formation during cardiac surgery, especially during myocardial reperfusion, is involved with myocardial damage and impaired hemodynamic recovery. Therefore, strategies to improve thrombin control during cardiopulmonary bypass might be beneficial.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 
Thrombin is a multifunctional protease with functions that extend from activation of coagulation and inhibition of fibrinolysis to many aspects of cellular regulation (Fig 1). In addition to being the final enzyme of the coagulation pathway, which leads to fibrin formation and clot stability, it is the most potent known stimulator of platelet aggregation and de-granulation [1]. Importantly, thrombin also has significant pro-inflammatory and pro-apoptotic effects [2, 3].


Figure 1
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  		Fig 1. Multiple functions of thrombin. (See reviews [1, 2, 9] and text for further references.)

 
During cardiopulmonary bypass (CPB) the generation of thrombin, fibrin formation, and fibrinolysis are significantly increased [4]. This activation of coagulation during cardiac surgery has detrimental consequences that include blood loss and the formation of microemboli [5–7]. The former is multifactorial, but partly the result of a consumptive coagulopathy and thrombin-induced platelet activation [4]. Reperfusion after myocardial ischemia during cardiac surgery is known to further significantly propagate thrombin generation [8]. In light of this reperfusion-induced thrombin burst and the multiple potentially adverse effects of thrombin, including its direct effects on the endothelium and on cardiomyocytes, the possible role of thrombin as a mediator of myocardial ischemia-reperfusion injury has become most interesting. Recently, both experimental and clinical studies suggest that thrombin generation during cardiac surgery associates with myocardial injury and that more effective control of thrombin, especially during reperfusion after myocardial ischemia might be beneficial. This review focuses on the actual or potential consequences of circulating thrombin during CPB and temporary myocardial ischemia and reperfusion.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 
More than a decade of related basic, experimental, and clinical research by the authors forms the basis of this review. In addition, Medline searches with the key words thrombin, blood coagulation, cardiopulmonary bypass, and myocardial reperfusion injury were performed and the reference lists of related review articles were manually searched to find additional references.


   Adverse Effects of Thrombin
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 
Pro-Inflammatory Effects of Thrombin
Thrombin is an important link between coagulation and inflammation. The pro-inflammatory effects of thrombin are mediated through activation of endothelial cells, smooth muscle cells, and platelets, as well as release of cellular mediators. In contrast, its anti-inflammatory effects are mediated through activation of natural anticoagulant mechanisms. Interestingly many of the pro-inflammatory effects of thrombin also have implications for the promotion of atherosclerosis [9]. On the other hand, inflammation shifts the hemostatic balance toward coagulation by enhancing thrombopoiesis and platelet reactivity, by downregulating natural anticoagulant mechanisms, by initiating and propagating thrombin generation, and by impairing fibrinolysis [2].

Thrombin exerts significant pro-inflammatory effects on endothelial cells [10], smooth muscle cells, and platelets. Thrombin induces the proliferation of endothelial cells and activates endothelial cells by cleaving protease-activated receptor-1 and protease-activated receptor-2, which results in the expression of several adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin) and in the secretion of inflammatory chemokines (interleukin-6, interleukin-8, monocyte chemotactic protein-1, platelet-derived growth factor, and macrophage migration inhibitory factor). Interleukin-6, on the other hand, is also pro-thrombotic and increases the levels of circulating fibrinogen and plasminogen activator inhibitor-1 [2, 9]. Thrombin stimulates the proliferation and migration of vascular smooth muscle cells and the synthesis of collagen, the generation of reactive oxygen species, and the secretion of chemokines (interleukin-6 and monocyte chemotactic protein-1) by smooth muscle cells [11]. Thrombin also induces the proliferation and migration of fibroblasts [12] and is involved in wound healing. Thrombin-mediated activation of platelets results in the secretion of chemokines (platelet-derived growth factor among others) and the expression of CD40 ligand, which also induces the secretion of chemokines and the expression of adhesion molecules by endothelial cells, smooth muscle cells, and macrophages [2, 9].

Thrombin and Apoptosis
Programmed cell death, or apoptosis, is a sequence of events, which is characterized by biochemical and morphologic changes in the nucleus, mitochondria, cytoplasm, and cell membrane of cells, and leads to their removal by phagocytosis [13]. Apoptosis is now considered to constitute a significant component of cell death after myocardial ischemia [13]. Recent evidence shows that the activation of protease-activated receptor-1 by thrombin modulates apoptosis. High concentrations of thrombin have pro-apoptotic effects on cultured vascular smooth muscle cells [3]. High concentrations or prolonged exposure to thrombin also induce apoptosis and cell death of neurons, whereas moderate concentrations of thrombin protect neurons from toxic insults [14]. A similar dual effect of thrombin has been observed in several human tumor cell lines [15]. In addition to its apoptotic effects on nucleated cells, the platelet activator thrombin has been shown to induce membrane changes in platelets that are associated with apoptosis in nucleated cells, such as aberrant exposure of phosphatidylserine [16]. The phosphatidylserine exposure on platelets, on the other hand, provides a membrane surface for sustained assembly and activation of coagulation factors [17]. Interestingly, both the anti-apoptotic and pro-apoptotic effects of thrombin have been shown to be protease-activated receptor-1-mediated. Whereas thrombin is pro-apoptotic in high concentrations, activated protein C (APC) has been shown to have anti-apoptotic effects on hypoxic cultured brain endothelial cells [18].

Thrombin and Coronary Thrombosis
Thrombosis is the pivotal event in the acute presentation of coronary artery disease. Physical disruption of the coronary atherosclerotic plaque, either rupture of the fibrous cap of the plaque or superficial erosion of the endothelial monolayer, exposes the pro-coagulant lipid-rich core of the plaque. Expression of tissue factor by exposed plaque macrophages then provokes thrombosis through thrombin generation and platelet activation. Inflammation not only controls the susceptibility of the plaque to rupture, but inflammatory mediators in the plaque can also enhance the thrombogenicity of the plaque by inducing tissue factor expression by plaque macrophages [19]. There is evidence to suggest that subclinical plaque progression is also a thrombotic phenomenon. Autopsy studies have shown that recurrent episodes of subclinical plaque disruption and minor thrombosis without arterial occlusion contribute to the stable progression of the underlying coronary artery disease [20, 21]. In these studies, multiple healed plaque rupture sites with layering causing stenosis have been identified in the majority of coronary lesions of subjects who died of sudden coronary death.


   Evidence Linking Thrombin and Myocardial Ischemia-Reperfusion Injury
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 
Thrombin and Ischemia-Reperfusion: Experimental Evidence
A number of biochemical and metabolic changes occur during ischemia-reperfusion that lead to cell death. During ischemia, adenosine triphosphate is progressively depleted, and the cytosolic Ca2+ concentration increases. Reperfusion results in the generation of reactive oxygen species, further uptake of intracellular Ca2+, and rapid restoration of physiological pH. These changes lead to the opening of the mitochondrial permeability transition pore and result in activation of apoptotic pathways and depletion of adenosine triphosphate, which in turn causes cell death. An inflammatory response is present several hours after the onset of reperfusion. Inflammation mediates further cardiomyocyte death by causing vascular plugging, release of degradative enzymes, and the further generation of reactive oxygen species [22, 23].

Several experimental models of ischemia-reperfusion suggest that thrombin has a role as a mediator of myocardial ischemia-reperfusion injury (Table 1). Thrombin increased cell death in a dose-dependent manner, when cultured cardiomyocytes were subjected to simulated ischemia-reperfusion, and this effect was reversed by the direct thrombin inhibitor lepirudin [24]. In these experiments, thrombin enhanced the cytosolic Ca2+ overload caused by simulated ischemia-reperfusion. In a rabbit model of myocardial ischemia-reperfusion, direct thrombin inhibition with recombinant hirudin reduced myocardial infarction size and the polymorphonuclear leukocyte infiltration in the endothelium and subendothelium of reperfused myocardium [25]. An inhibitor of the thrombin receptor protease-activated receptor-1, as well as the direct thrombin inhibitor, lepirudin, reduced myocardial infarct size in rat models of myocardial ischemia-reperfusion injury [26]. Furthermore, human recombinant active site-blocked factor VII, which inhibits tissue factor-dependent thrombin generation, reduced myocardial infarct size and the myocardial no-reflow area in a rabbit model of myocardial ischemia-reperfusion [27]. In a porcine model of CPB with aortic cross clamping and cardioplegia, thrombin inhibition with hirudin, added to standard heparin anticoagulation, improved immediate hemodynamic recovery after ischemia-reperfusion and reduced cardiomyocyte apoptosis [28, 29]. Also APC attenuated myocardial ischemia-reperfusion in a porcine model [30]. Infusion of a monoclonal antibody that prevents protein C activation led to slower and incomplete recovery of left ventricular function after left anterior descending coronary artery occlusion, whereas infusion of APC led to almost immediate recovery of left ventricular function.


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  		Table 1 Evidence Suggesting That Thrombin is a Mediator of Myocardial Ischemia-Reperfusion Injury
 
Substances that inhibit thrombin or thrombin generation also attenuated ischemia-reperfusion injury in other animal models of ischemia-reperfusion. In experimental models of intestinal ischemia-reperfusion, antithrombin reduced neutrophil rolling and adhesion during reperfusion [31], and antithrombin and APC reduced intestinal histologic injury and dysfunction and inhibited systemic inflammation [32]. In rat models of liver ischemia-reperfusion, pretreatment with either a selective factor Xa inhibitor or APC reduced neutrophil sequestration [33] and treatment with tissue factor pathway inhibitor (TFPI) reduced liver necrosis and tissue factor expression [34]. Tissue factor pathway inhibitor also protected the spinal cord from ischemia-reperfusion injury [35]. Activated protein C protected tissue in models of ischemia-reperfusion of the brain [36, 37], spinal cord [38], and kidney [39]. The protective effects of APC in ischemia-reperfusion injury seem to be distinct from its anticoagulant effects and are either anti-inflammatory [36, 38, 39] or directly anti-apoptotic, which is the case after ischemia-reperfusion of the brain [37].

Thrombin Generation During Cardiopulmonary Bypass
Thrombin generation and activity during CPB have been well characterized with measurements of markers of thrombin generation (prothrombin fragment F1+2 [F1+2]), inhibition of free thrombin by antithrombin (thrombin-anti-thrombin complex), and the fibrinogen-cleaving activity of thrombin (fibrinopeptide A) [8, 40–46]. These studies have demonstrated that CPB causes a progressive increase in thrombin generation, the mechanism of which has been recently reviewed [4]. However, reperfusion after myocardial ischemia has been shown to induce an additional distinct and very rapid increase in thrombin generation during CPB [8, 43, 46]. Indeed, a computer model of the vascular system that accounted for marker clearance, hemodilution, and blood loss, showed that instead of a steady continuous increase in thrombin generation, CPB results in the generation of bursts of nonhemostatic thrombin and soluble fibrin, especially soon after the initiation of CPB and during early reperfusion after myocardial ischemia [47].

During CPB, the surgical wound is the primary source of thrombin formation [48]. Microparticle-bound tissue factor in wound blood stimulates thrombin formation, but activated wound monocytes, together with wound soluble tissue factor, activate factors VII and X more efficiently to generate thrombin [48]. However, the source of the massively upregulated systemic generation of thrombin during reperfusion is unknown. The reperfusion-induced burst of thrombin is explained only partly by local tissue factor expression in the reperfused post-ischemic myocardium, as transcoronary gradients of thrombin markers during reperfusion are modest [46, 49]. Also, the relative contribution of the various forms of tissue factor remains unclear. Redistribution of activated monocytes or release of prothrombotic microparticles might explain the very rapid increase in thrombin generation. Also, recruitment of parts of the pulmonary and splanchnic circulations or systemic vasodilation related to rewarming after the release of the aortic clamp might contribute to reperfusion-induced generation of thrombin.

The concentrations of circulating thrombin during CPB are below thrombin concentrations needed for clot formation in various plasma assays. However, thrombin generation during clinical CPB causes fibrin production, as evidenced by elevated levels of circulating soluble fibrin monomers [45, 50]. Also, microemboli from many sources are circulating during CPB [51]. Microemboli that might be related to thrombin generation include platelet, leukocyte, and platelet-leukocyte aggregates, fibrin, and platelet-fibrin emboli [4–7].

Thrombin Associates With Myocardial Damage After Coronary Artery Bypass Grafting
In our recent clinical study thrombin generation during reperfusion after coronary artery bypass grafting (CABG) associated with postoperative myocardial damage and postoperative pulmonary vascular resistance [8]. Patients with increased postoperative cardiac biomarker levels and those with new pathological Q-waves had higher thrombin marker F1+2 levels during reperfusion than comparison patients [8]. Also, multivariable logistic regression analysis identified thrombin generation during reperfusion to be independently associated with postoperative myocardial damage. In addition, patients with increased F1+2 levels during reperfusion had higher postoperative pulmonary vascular resistance than comparison patients. Remarkably, this thrombin formation occurred under very extensive anticoagulation with heparin (targeted activated clotting time greater than 600 seconds). Another clinical study also supports the notion that the thrombin burst observed during reperfusion might be harmful after CABG. Dixon and coworkers [52] demonstrated that a marker of thrombin generation (F1+2) correlated with measurements of organ dysfunction after CABG, including left ventricular stroke work index, Pa02 fraction of inspired oxygen ratio, and serum creatinine.


   Control of Thrombin Effects During Cardiopulmonary Bypass
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
Comment
 Acknowledgments
 References
 
Anticoagulant Function of Thrombin
Low levels of thrombin are believed to generate markedly increased levels of the endogenous circulating anticoagulant, APC, exerting, therefore causing a net anticoagulant effect [53]. This "thrombin paradox" has been characterized in a primate model in which systemic infusions of low doses of thrombin (75 to 150 pM) were anti-thrombotic and increased APC levels [54]. The competitive binding of the cofactors, fibrin, and thrombomodulin, plays a crucial role in redirecting thrombin activity from procoagulant to anticoagulant in areas of intact endothelium. Once thrombin binds to thrombomodulin, it is no longer capable of cleaving its procoagulant substrates, but thrombomodulin-bound thrombin activates protein C on the endothelial surface. Activated protein C binds to its cofactor, protein S, and downregulates thrombin generation by proteolytically inactivating factors Va and VIIIa [1, 55].

Impact of Natural Anticoagulants During Cardiopulmonary Bypass
The role of the natural anticoagulants APC, TFPI, antithrombin, and heparin cofactor II (HCII) during CPB is incompletely understood. Only a few studies have addressed protein C activation during CPB. Plasma APC levels have been shown to increase rapidly during reperfusion after myocardial ischemia [46, 50]. Recently, we showed that patients with high circulating APC levels during reperfusion after CABG had a higher postoperative cardiac output and a lower systemic vascular resistance than comparison patients [50]. Surprisingly, preoperative levels of APC and APC levels measured after heparin neutralization correlated with an unfavorable hemodynamic profile postoperatively. Also, protein C activation during CPB was clearly delayed in relation to both thrombin generation and fibrin formation. In fact, throughout the study a dominance of thrombin generation over protein C activation was demonstrated by the APC/F1+2 ratio, which remained below the preoperative level throughout the observation period. Therefore, in the setting of CPB and cardiac surgery, our results did not support the hypothesis that low levels of thrombin preferentially generate APC instead of fibrin [56]. Rather, it can be speculated that the dynamic association of APC levels with postoperative hemodynamics might reflect an insufficient and delayed APC response to an underlying thrombin challenge. Previous clinical studies support the notion that APC might protect the myocardium during reperfusion. Patients with higher increases in coronary sinus blood APC levels during reperfusion tended to have a more favorable postoperative hemodynamic profile after CABG [46]. Also, protein C activation during reperfusion after CABG had an inverse correlation with neutrophil sequestration in the human myocardium and with L-selectin expression of circulating neutrophils, implicating APC as a possible regulator of myocardial ischemia-reperfusion injury [57].

Tissue factor pathway inhibitor is the major physiological inhibitor of the tissue factor-factor VIIa complex. Tissue factor pathway inhibitor inhibits factor Xa and the TFPI-factor Xa complex in turn inactivates the tissue factor-factor VIIa complex. Heparin causes TFPI to be released from endothelial cells [58]. There is significant variability in the TFPI response to heparinization in patients undergoing CPB, and evidently some patients fail to respond to heparin with an increase in TFPI levels [59]. On average, CPB with heparin anticoagulation causes a very significant increase in both total and free TFPI levels [60, 61]. When heparin is neutralized with protamine after CPB, TFPI levels decrease but remain higher than preoperatively [60, 62]. However, TFPI undergoes proteolytic degradation during CPB and this nonfunctional form of TFPI circulates in plasma after heparin neutralization, and may produce a decrease in endothelium-associated TFPI after CPB [60].

Antithrombin and HCII are serine protease inhibitors that inhibit thrombin directly. Quantitatively anti-thrombin is the main circulating inhibitor of coagulation proteases and physiologically HCII has at best only a secondary role in the inhibition of thrombin [1, 55]. Effective heparin anticoagulation requires sufficient levels of plasma antithrombin. As a result of hemodilution and consumption, anti-thrombin levels decrease during CPB [63–65], which might lead to ineffective anticoagulation. Furthermore, preoperative heparin treatment decreases anti-thrombin levels in cardiac surgical patients [66]. Heparin cofactor II levels decrease during CPB [67], but the significance of this finding is uncertain because the role of HCII in hemostasis is believed to be clinically less important [55]. However, dermatan sulfate, which augments the inhibition of thrombin by HCII, has been used as an anticoagulant in experimental CPB in pigs [68].

Regulation of Thrombin During Cardiopulmonary Bypass
Several thrombophilic factors associated with increased basal thrombin generation [69, 70], and therefore we recently hypothesized that thrombophilic factors might enhance CPB-related activation of coagulation [45]. However, we showed that a preoperative thrombophilic state did not associate with perioperative generation of thrombin or its procoagulant activity. This suggests that other mechanisms that enhance thrombin generation during CPB overwhelm any possible effect of thrombophilia on activation of coagulation during CPB [45].

In light of the evidence suggesting that activation of coagulation during cardiac surgery is detrimental, efficient control of thrombin during CPB and the various phases of surgery are important. There is both indirect and direct evidence suggesting that maintaining high heparin concentrations during CPB might be beneficial. Plasma fibrinopeptide A correlated inversely with heparin levels during CPB [64, 71]. High-dose heparin anticoagulation for patients undergoing aortic surgery under deep hypothermic circulatory arrest resulted in reduced levels of thrombin-antithrombin complex and D-dimer [72]. Also, in randomized settings, higher heparin doses during CPB associated with reduced thrombin formation and fibrin turnover [73, 74], reduced consumption of coagulation factors [74], and fewer transfusions [75]. We measured heparin effects at various relevant time points during CPB and found that the lowest heparin levels during CPB associated with higher subsequent F1+2 levels were after heparin reversal [76]. We also demonstrated that patients with high heparin levels during CPB received the fewest transfusions [76]. This potentially clinically important finding might contribute to a reduction of consumption coagulopathy and is in agreement with the findings of a previous randomized study [75].

Other strategies to diminish CPB-induced thrombin generation include the elimination of cardiotomy suction and the use of heparin-coated circuits for CPB. Blood in the surgical wound has been shown to be highly procoagulant [4] and a number of studies suggest that the elimination of cardiotomy suction attenuates the activation of coagulation during CPB [77–80]. Cardiopulmonary bypass-induced thrombin generation can also be reduced by processing the aspirated blood with a cell saver; the aspirated plasma is discarded and only the resulting packed red blood cells are reinfused [81].

Some studies suggest that coating of extracorporeal circuits with heparin reduces the inflammatory response associated with CPB, as evidenced by reduced complement and granulocyte activation [82]. The effect of heparin coating of the extracorporeal circuit on activation of coagulation is less convincing. Most studies have not demonstrated an effect on levels of markers of activation of coagulation [83–88], whereas others have shown reduced thrombin formation [79, 89]. One study reported similar levels of markers of thrombin generation in patients who were treated with either full or reduced heparin doses and closed heparin-coated circuits [90]. However, there are reports of increases in markers of coagulation activation with reduced systemic heparin doses [91, 92]. Therefore, the evidence does not support lowering systemic heparin doses when heparin-coated circuits are used.

Finally, the introduction of direct thrombin inhibitors as anticoagulants for CPB may result in more effective suppression of thrombin generation. Preliminary data suggest that the direct thrombin inhibitor, bivalirudin, very efficiently suppresses thrombin generation during CPB [93].


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
Acknowledgments
 References
 
Both experimental and indirect clinical evidence suggest that activation of coagulation after cardiac surgery, especially during reperfusion after myocardial ischemia, might exacerbate ischemia-reperfusion-induced myocardial damage (Table 1). Experimental studies imply that thrombin is a mediator of myocardial ischemia-reperfusion injury. Clinical studies have shown that thrombin formation during cardiac surgery is associated with myocardial damage and hemodynamic recovery after CABG. Furthermore, during reperfusion after myocardial ischemia, the thrombin-dependent activation of the protein C pathway associates with a more favorable hemodynamic recovery after CABG and with downregulation of myocardial inflammation. Effective control of thrombin generation, especially during myocardial reperfusion, therefore seems prudent. Maintaining high heparin concentrations during CPB results in reduced coagulation activation and might correlate with reduced transfusion requirements. Elimination of re-transfusion of suctioned mediastinal blood might be another strategy to reduce thrombin generation during CPB.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
References
 
This work was supported by Finnish governmental special grants for health sciences research (Helsinki University Central Hospital grants) and a grant from The Päivikki and Sakari Sohlberg Foundation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Adverse Effects of Thrombin
 Evidence Linking Thrombin and...
 Control of Thrombin Effects...
 Comment
 Acknowledgments
 References
 

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R. M. Sniecinski and W. L. Chandler
Review Articles: Activation of the Hemostatic System During Cardiopulmonary Bypass
Anesth. Analg., December 1, 2011; 113(6): 1319 - 1333.
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