Coagulation disorders of cardiopulmonary bypass: a review ...

Intensive Care Med (2004) 30:1873–1881 DOI 10.1007/s00134-004-2388-0

Domenico Paparella Stephanie J. Brister Michael R. Buchanan

Received: 21 November 2003 Accepted: 24 June 2004 Published online: 24 July 2004
Springer-Verlag 2004 D. Paparella ()) Division of Cardiac Surgery, Dipartimento di Emergenza e Trapianti di Organo, University of Bari, Piazza Giulio Cesare 11, 70100 Bari, Italy e-mail: [email protected] Tel.: +39-080-5478844 Fax: +39-080-5478816 S. J. Brister Department of Surgery, University of Toronto, University Health Network, Department of Cardiovascular Surgery, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada M. R. Buchanan Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

REVIEW

Coagulation disorders of cardiopulmonary bypass: a review

Abstract Background: Postoperative bleeding is one of the most common complications of cardiac surgery. Discussion: Extensive surgical trauma, prolonged blood contact with the artificial surface of the cardiopulmonary bypass (CPB) circuit, high doses of heparin, and hypothermia are all possible triggers of a coagulopathy leading to excessive bleeding. Platelet activation and dysfunction also occur and are caused mainly by heparin, hypothermia, and inadequate protamine administration. Heparin and protamine administration based on heparin concentrations as opposed to fixed doses may reduce coagulopathy and postoperative blood loss. Conclusions: A better comprehension of the multifactorial mechanisms of activation of coagulation, inflammation, and fibrinolytic pathways during CPB may enable a more effective use of the technical and pharmaceutical options which are currently available.

Introduction Postoperative bleeding is one of the most common complications of cardiac surgery. Approximately 20% of patients bleed significantly after cardiac surgery, and 5% require reexploration [1, 2]. Predictive factors for hemorrhage and reexploration following cardiac surgery include: age, renal insufficiency, cardiopulmonary bypass (CPB) time and intracardiac repair. Reexploration for bleeding is a strong independent risk factor for adverse outcome following cardiac surgery. Specifically, opera-

Keywords Cardiac surgery · Cardiopulmonary bypass · Coagulation cascade · High-dose heparin · Hypothermia · Postoperative bleeding

tive mortality, prolonged mechanical ventilation, acute respiratory distress syndrome, sepsis, and atrial arrhythmias are increased in these patients [3, 4]. In addition, postoperative bleeding requiring multiple transfusions and surgical reexploration are associated with increased sternal wound infection [5] and transfusion-related infection. A surgical cause of bleeding is found in 50% of patients undergoing reoperation for bleeding. In the remainder of patients the cause is “multifactorial” and is probably related to the unique circumstances of the surgical procedure. Extensive surgical trauma, prolonged

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Fig. 1 The underlying causes of bleeding following cardiac surgery performed either on- or off-pump related to both the exogenous mechanical/physical properties of the procedure itself and to endogenous hemostatic, coagulant, and inflammatory responses to the invasive procedures

blood contact with the artificial surface of CPB, high doses of heparin, and hypothermia contribute to dysfunction of the coagulation and inflammatory systems that lead to a postoperative coagulopathy. It is often difficult to delineate the specific factors contributing to the coagulopathy in any given patient in the operating room or in the intensive care unit since the coagulopathy is not necessarily defined by routine assays [activated clotting time (ACT), activated partial thromboplastin time, prothrombin time international normalized ratio). As a result, empirical treatment is often instituted. This review focuses on the pathophysiology for the coagulopathy that occurs during cardiac surgery. The complexity of this problem is summarized in Fig. 1, and each component is discussed in detail under separate headings below.

The coagulation cascade CPB requires anticoagulation to prevent immediate blood clotting within the circuit. Heparin, a glycosaminoglycan that catalyzes the inhibition of thrombin via antithrombin III (ATIII) is the drug most commonly used. Heparin effectively inhibits systemic thrombin but is not able to inhibit surface-bound thrombin. During CPB both fibrinogen and fibrin are deposited onto the CPB circuitry, creating a surface to which thrombin avidly adheres. When thrombin binds to fibrinogen/fibrin, thrombin undergoes a conformational change that renders it resistant to inhibition by heparin/ATIII [6, 7, 8]. Thus the surface-bound thrombin remains active and continues to generate more circulating thrombin. Thrombin also activates platelets,

which adhere to specific binding sites on the fibrinand fibrinogen-coated surfaces (Fig. 1). In addition, the membrane surface of activated platelets provides a phospholipid platform upon which the prothrombinase complex is assembled [9]. The prothrombinase complexes express full enzymatic activity, thereby allowing for the activation of more prothrombin to thrombin. As a result high-dose heparin is required to prevent the formation of a fibrin-rich thrombus during CPB. However, high-dose heparin does not prevent the generation of thrombin per se. Thrombin levels, measured as thrombin-antithrombin complex (TAT) and by prothrombin fragment F1+2 (F1+2), increase within minutes of the initiation of CPB, increase further following the discontinuation of CPB and the administration of protamine and remain elevated for periods of time up to 60 days after surgery [8, 10, 11, 12]. Neither heparin concentrations, ATIII levels, nor ACT values appears to be correlated with thrombin generation [13]. Activation of the coagulation system is triggered predominantly by the blood contact with the foreign surfaces such as the CPB circuitry, leading to the activation of the contact system and the intrinsic coagulation pathway (Fig. 1). The contact system is activated when factor XII (FXII, or Hageman factor) binds to negatively charged surfaces becoming activated FXII (FXIIa). FXIIa activates factor XI (FXIa) of the intrinsic pathway that eventually leads to thrombin formation. FXIIa also activates prekallikrein to kallikrein, which in turn induces high-molecularweight kininogen to form bradykinin [14]. While the kallikrein/kinin system is activated, its activation is selflimiting since it results in a marked consumption and subsequent decrease in circulating kallikrein levels [15]. Recent studies suggest that the contact system and the intrinsic coagulation pathway are not the only trigger for thrombin generation. Heparin coating of the CPB conduits has been shown to reduce the activation of the contact system; however, this reduction is not associated with a significant decrease in thrombin generation. These results imply that other thrombogenic mechanisms also are involved [16]. Boisclair et al. [17] measured FXIIa as a marker of the activation of the contact system in eight patients undergoing CPB. They observed that FXIIa increased only slightly in response to the surgery before CPB, and there was no further increase once CPB was initiated. Moreover, there was no correlation between FXIIa and F1+2 levels [17]. The same group also reported similar results in a 12-year-old girl with severe FXII deficiency who underwent cardiac surgery with CPB to repair an atrial septal defect and a patent ductus arteriosus. Despite her severe FXII deficiency thrombin generation (measured as TAT and F1+2) occurred to the same extent as seen in cardiac patients with normal FXIIa levels [18]. These data indicated that prothrombin activation can occur independently of the intrinsic pathway. It is now recognized that prothrombin activation via the extrinsic pathway plays an important role in systemic

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thrombin generation and subsequent thrombus formation. For example, circulating levels of mononuclear cell tissue factor (TF) expression and plasma factor VIIa concentrations are high in cardiac surgical patients following surgical trauma and CPB. High levels are seen in the pericardial sac and may impact significantly on the coagulation system [19]. For example, de Haan and colleagues [20] found that when retransfusion of blood lost into the thoracic cavity is avoided, there are significant decreases in systemic TAT complexes, tissue plasminogen activator (t-PA) antigen, fibrin degradation products, and free plasma hemoglobin. These data indicate that activation of the systemic coagulation system, fibrinolysis, and hemolysis are due in part to the retransfusion of blood lost into the thoracic cavity and exposed to air and thrombogenic surfaces. These investigators also found that there is a significant decrease in postoperative blood loss; however, there was no difference in the amount of blood products transfused [20]. Their findings have been recently confirmed by Aldea et al. [21] who demonstrated that thrombin generation, measured as TAT and F1+2, platelet activation and inflammation are reduced in patients when reinfusion of blood aspirated from the pericardium and pleural space is avoided. Blood contact with TF within the pericardial and pleural cavities represents a significant trigger for the activation of the coagulation system.

Anticoagulation During the early development of cardiac surgery the dose of heparin used to prevent blood clotting in the CPB circuits was established empirically. The heparin dose chosen was the minimum dose at which clotting within the CPB circuit did not occur. Traditionally, the ACT is used to monitor adequate anticoagulation during CPB. Bull and colleagues [22] established a heparin dose-response curve during CPB to optimize the dose of heparin based on each patient’s ACT response. In the majority of cardiac centers the heparin dose administered prior to CPB is 300–400 U/kg, with additional bolus doses being given as required to maintain the ACT values above 400 s. However, the ACT value gives only general information regarding the blood clotting state without giving any insight into the mechanisms of coagulation (in)activation. The ACT value is also not correlated with the plasma heparin concentration and is influenced by hemodilution, hypothermia and aprotinin administration [23, 24, 25]. Whether the heparin dose per se and postoperative bleeding are related is still unclear. In a randomized trial of 254 patients undergoing CPB patients were given heparin based either on the prolongation of ACT or on the maintenance of a specific plasma heparin concentration. Those patients who received heparin based on maintaining a specific plasma heparin concentration received 32%

more heparin during CPB than those patients who received heparin based on the prolongation of the ACT, but the need for blood product transfusion in the former group was significantly less [26]. In a subgroup of patients enrolled in this trial other parameters also were analyzed. The plasma heparin concentration-based treated patients (n=15) received a mean heparin dose of 678 U/kg compared to 479 U/kg in the ACT-based treatment group (n=16). As a result there was a better suppression of thrombin activation and fibrinolysis, higher levels of factors FV, FVIII, fibrinogen, and ATIII, and as a consequences less postoperative bleeding [27]. Similar results were observed in another study in which an ex vivo heparin response predicting test was compared to the standard ACT management. There was a significant reduction in blood loss in the patients who received higher heparin doses than in the patients in the ACT-monitored group who received less heparin [28]. In contrast, increased blood loss associated with higher heparin doses during CPB has been reported. Gravlee and colleagues [29] studied the effects of three different heparin doses (250, 300, and 350–400 U/kg) on blood loss in three groups of patients undergoing CPB (n=6, 10, and 5 respectively). They found that there was a positive correlation between the plasma heparin concentration during CPB and blood loss. However, in a larger study of 63 patients the same investigators were unable to confirm any difference in blood loss when heparin doses of 200 and 400 U/kg were compared [30]. Boldt and colleagues [31] also found an increased blood loss in a small number of patients (n=15) receiving high-dose heparin (600 U/kg) compared to another 15 patients receiving 300 U heparin/ kg. Bleeding in the high heparin dose group was reduced with the administration of aprotinin. In a prospective study of 487 patients logistic and linear regression analysis showed that a lower heparin dose prior to CPB to be an independent predictor of chest tube drainage and blood products transfusion [32]. Thus the optimal heparin dose to be used during CPB remains debatable. It is possible that a heparin concentration-based management that is associated with higher heparin doses results in a better suppression of both coagulation and postoperative bleeding, provided that its anticoagulant effect is neutralized appropriately following CPB. It also should be recognized that lower doses of heparin may allow for more thrombin generation, which in turn can render platelets hemostatically dysfunctional, thereby creating a bleeding risk following CPB. Overall, it appears that blood loss following CPB is related to heparin concentration. However, because individual patient responses to heparin vary, a wider use of heparin concentration monitoring devices to achieve optimal anticoagulation may be warranted. Protamine sulfate obtained from fish sperm is the most common agent used to reverse heparin-induced anticoagulation at the end of CPB. Other alternative heparin antagonists have been tested, such as heparinase [33] and

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platelet factor 4 [34], but their use is extremely limited. Protamine sulfate forms a 1:1 complex with heparin, and has a short half life (approximately 5 min) [35]. Thus, heparin anticoagulation can be reversed rapidly. However, protamine sulfate has a number of limitations. Systemic arterial hypotension, pulmonary artery hypertension, decreased cardiac output and anaphylaxis can occur. It also can contribute to the hemostatic defect associated with cardiac surgery. Platelet reactivity and aggregation induced by thrombin are markedly inhibited by protamine sulfate [36, 37]. Protamine sulfate also alters the interactions between platelet glycoprotein Ib (GPIb) and von Willebrand factor, particularly when the protamine sulfate levels are in excess of heparin [38]. Thus optimization of the dose of protamine sulfate is essential to minimize its potential adverse side effects. Alternate methods for the administration of protamine sulfate following CPB include (a) fixed dose, 1.0–1.5 mg protamine sulfate/100 U heparin, (b) ACT/heparin dose response curve, (c) heparin levels, and (d) protamine titration [39]. The simplest technique is administration of a fixed dose of protamine sulfate based on the total heparin dose given during CPB. Mochizuki et al. [40] reported that heparin anticoagulation is maximally reversed at a protamine sulfate:heparin ratio of 1.3:1. Each increment in protamine sulfate concentration results in a longer ACT and impaired platelet aggregation. However, this technique does not take into account heparin elimination, thereby resulting in excessive protamine sulfate administration. A protamine sulfate administration protocol based on heparin concentration measured at the end of CPB has been shown to reduce postoperative bleeding [26, 28]. This method is more time consuming and requires equipment that may not be readily available in the operating room. However, the disadvantage of the additional time requirements and expense immediately after CPB may be offset by fewer bleeding complications and better patient care. Shigeta et al. [41] also have shown that a protamine sulfate-heparin titration method is effective. The titration group resulted in higher mean heparin doses given intraoperatively, higher heparin concentration levels measured at the end of CPB, but lower mean protamine sulfate doses were needed to reverse heparin anticoagulant effect, for example, 1.0 mg protamine sulfate/ 100 U of residual heparin. The lower dose of protamine sulfate was associated with better platelet aggregation, decreased platelet a-granule degranulation, and normal ACT values [41]. The reappearance of heparin anticoagulant activity, i.e., a heparin-rebound effect, has been observed up to 6 h after protamine administration following CPB [42]. Nevertheless its frequency and clinical significance are unclear [43]. Adjunctive protamine doses should not be administered when prolonged ACTs are measured following CPB unless there is evidence that there is currently a high heparin plasma level since the “prolonged”

ACT could reflect heparin-independent coagulopathy. In addition, a higher protamine dose may prolong the ACT and further impair hemostasis.

Inflammation CPB induces an intensive activation of the inflammatory system [44] leading to leukocyte activation and secretion of their granule contents. The link between the activation of the coagulation and inflammatory systems during the course of CPB is complex and is related in part to the generation of acute-phase reactions similar to those seen in sepsis [45]. For example, leukocyte activation results in the marked release of inflammatory mediators that activate monocytes, which in turn leads to TF expression, thrombin generation, and paradoxical activation and impairment of the coagulation system in many patients during and following CPB (Fig. 1). TF is produced by monocytes and is expressed constitutively on subendothelium. TF expression is enhanced following stimulation by proinflammatory mediators such as interleukin 1, tumor necrosis factor, and endotoxin [46]. Another link between the inflammatory and coagulation systems may be nuclear factor kB (NF-kB). NF-kB is an ubiquitous inducible transcription factor involved in the regulation of transcription of many proinflammatory genes. It is activated by stimuli such as interleukin 1, tumor necrosis factor a, lipopolysaccharide, ultraviolet irradiation, multiple growth factors, oxygen-free radicals, oxidative stress, and viral infection. Normally NF-kB is bound to the inhibitory protein IkB in the cytoplasm of a variety of cells, including endothelial cells and leukocytes. When stimulated, the NF-kB–IkB complex is phosphorylated, and the IkB protein becomes dissociated and inactivated. The NF-kB translocates to the nucleus where it binds to DNA, inducing the expression of several inflammatory mediators including proinflammatory cytokines, inducible nitric oxide synthase, and associated adhesion molecules [47, 48]. Recently Morgan et al. [49] demonstrated that TF activation and consequent thrombin release are regulated by NF-kB using a human blood model of CPB. The inhibition of NF-kB results in the preservation of the monocyte TF expression, reduces thrombin generation, and procoagulant activity of blood in the CPB circuit [49]. An important inhibitor of TF coagulant activity is tissue factor pathway inhibitor (TFPI). TFPI is a highly positively charged serine protease inhibitor with high affinity for negatively charged glycosaminoglycans such as heparin [50]. Heparin stimulates TFPI release, suggesting that part of the antithrombotic effect of heparin is associated with a TFPI-induced inhibition of TF [51]. Thus, heparin-induced TFPI also may contribute to bleeding complications following CPB. In support of this possibility, the standard heparin dose generally used

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during CPB is associated with a two- to four-fold increase in TFPI antigen or TFPI activity before beginning CPB [52]. The plasma level of TF generated during CPB is inversely correlated with the level of TFPI [53]. This suggests that TFPI plays a protective role against thrombin formation during CPB by reducing TF release.

Fibrinolysis The fibrinolytic system limits thrombus growth. Thrombolysis begins when plasminogen is cleaved to form plasmin. As with thrombin generation, either the intrinsic or the extrinsic pathway can initiate it. Thrombin induces the polymerization of fibrinogen, and it causes a conformational change such that other regulatory proteins become attached to fibrin, including FXIII, a2-plasminogen inhibitor, and t-PA [54]. Fibrin stimulates t-PA synthesis by endothelial cells and urokinase plasminogen activator (u-PA) synthesis by monocytes, macrophages, and fibroblasts. Both t-PA and u-PA activate plasminogen via the extrinsic pathway. In the intrinsic pathway plasminogen is activated by FXIIa formed during the contact phase of coagulation. Plasmin is an endopeptidase that cleaves both fibrinogen and fibrin, disrupting them into fragments without clotting ability. One of these fragments, D-dimer, is used as a specific marker of fibrin degradation. Plasmin also interacts with the inflammatory system stimulating the complement system and kallikrein [55]. Plasminogen activator inhibitor (PAI-1) is released after t-PA and u-PA release as a natural endogenous inhibitor of fibrinolysis Activation of fibrinolysis at the onset of CPB is mainly limited to the intrinsic coagulation pathway due to blood contact with the foreign CPB surface. Fibrinolysis then becomes extrinsically activated in nature, caused by the release of t-PA from the vascular walls throughout CPB [56]. Valen and colleagues [57] found that CPB is associated with increases in t-PA, D-dimer, t-PA–PAI-1 complexes, and a decrease in PAI-1 levels. These data indicate an activation of the fibrinolytic system and the consumption of its natural inhibitors. The levels of t-PA and D-dimer are higher in patients undergoing CPB surgery than in those undergoing other major thoracic operations without CPB [58]. D-dimer levels are still higher than preoperative levels 2 months after the operation [12]. Valve surgery, as opposed to coronary artery bypass graft, and longer cross-clamp times have also been found to be associated with enhanced activation of t-PA during CPB. Thrombin and fibrin also are likely to be important stimuli for activation of the fibrinolytic pathway. There is significant correlation between thrombin levels (measured as TAT complexes) at the end of the operation and fibrinolytic markers (measured as plasmin–a2-antiplasmin complexes and cross-linked fibrin degradation products) measured 1 h postoperatively. This suggests that the degree of activation of the coagulation system is an

important trigger for fibrinolysis [59]. In addition to thrombin, inflammatory markers such as cytokines and endotoxin also are able to induce the activation of plasminogen and its inhibitors [43, 60, 61, 62]. Nonetheless, it is difficult to demonstrate a clear association between fibrinolysis and excessive bleeding following CPB. Some studies have shown a correlation between markers of fibrinolysis and postoperative bleeding [63, 64]. Notwithstanding, numerous studies have demonstrated that the administration of an antifibrinolytic compounds (e.g., aprotinin, tranexamic acid, -aminocaproic acid) during CPB decreases the activation of the fibrinolytic and inflammatory systems. Moreover, there is less postoperative blood loss and less use of blood products. An exhaustive meta-analysis suggests that treatment with aprotinin decreases mortality almost twofold and decreases the proportion of patients requiring blood products and/or surgical reexploration without increasing the risk of perioperative myocardial infarction [65]. Other evidence that suggests a link between pathological fibrinolysis and bleeding complications following CPB is as follows. Both plasmin and t-PA are known to impair platelet function. Thrombolytic agents such as t-PA are widely used to induce reperfusion of coronary arteries occluded by thrombi following acute myocardial infarction. These agents exert their effect not only by digesting fibrin but also by degrading von Willebrand factor and the platelet surface glycoproteins GPIb and GPIIb/IIIa [66, 67, 68, 69]. There is evidence that similar effects occur during and after CPB, thereby contributing to a systemic platelet defect. As a result the administration of antifibrinolytic agents such as aprotinin that reduce the activation of fibrinolytic enzymes may attenuate the fibrinolytic-induced platelet defect. In support of this possibility Huang and colleagues [70] found that administration of aprotinin results in normal levels of a2-antiplasmin, preservation of GP1b platelet receptors, improved platelet agglutination, and a reduction in blood loss in patients undergoing CPB compared to patients undergoing CPB but not receiving aprotinin treatment. Similar findings with aprotinin use have been confirmed by others [71, 72, 73]. Other antifibrinolytic agents such as tranexamic acid and -aminocaproic acid have similar effects, but these compounds are less effective than aprotinin in preventing platelet dysfunction and membrane receptor lysis [74, 75], presumably because they bind to different sites on the plasmin molecule [73].

Platelet dysfunction Platelet dysfunction is considered by many to be the main cause of hemorrhage associated with CPB. Functional tests such as bleeding time [76] and platelet contractile force [77] are altered following CPB. There is a marked but temporary drop in platelet count caused by hemodi-

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lution observed soon after the beginning of CPB, which does not per se contribute to the platelet function defect. Historically, platelet dysfunction during and following cardiac surgery has been attributed to CPB-induced platelet activation with subsequent loss of receptors for von Willebrand factor (GP1b) and fibrinogen (GPIIb/IIIa) and the release of their granule content (e.g., platelet factor 4, b-thromboglobulin, adenine nucleotides, guanosine nucleotides) [78, 79, 80]. Other studies suggest that the CPB-associated platelet dysfunction can also be provoked by external factors. Kestin and colleagues [76] found that platelets obtained from patients undergoing CPB are less reactive in vivo but are normally reactive in vitro. In addition, they found that platelet surface GPIb/IX and GPIIb/ IIIa complexes analyzed by whole-blood flow cytometry are unchanged following CPB. These findings suggest that factors other than trauma per se are responsible for platelet activation. Both heparin and hypothermia have been considered the most likely candidates in this regard. Platelet activation by heparin is well established. Unfractionated heparin given at therapeutic concentrations in medical patients induces platelet activation, measured as platelet surface expression of P-selectin and GPIIb/IIIa [81]. Similar findings are seen during cardiac surgery. The administration of heparin before the institution of CPB causes platelet dysfunction, measured both as a prolongation of the bleeding time and a reduction in the ability of the platelet to produce thromboxane A2 in vivo [82]. Muriithi et al. [83] also found that platelet macroaggregation is impaired in vivo after heparin administration but before starting CPB. Moreover, when platelet poor plasma from these patients was used to dilute the blood of AB0-compatible volunteers, there was a marked reduction in the macroaggregatory response in the volunteers’ blood. They hypothesized that a plasma factor exists, the release of which is induced by heparin and inhibits platelet function. Lipolytic enzymes released from endothelial cells into the plasma following heparinization may play that role [84]. Interestingly, there appears to be little dose relationship to this effect. Muriithi et al. [83] studied the effects of 30 and 300 U/kg heparin on platelet function of patients prior to CPB and found no difference in the heparin-induced platelet macroaggregatory defect between the groups. Similarly, Nakajima et al. [85] did not observe any difference in PF4 and b-thromboglobulin release between patients receiving 200 and those receiving 300 U/kg heparin when undergoing CPB. High-dose heparin given during CPB may protect platelets due to its ability to better reduce thrombin formation during CPB, thereby decreasing platelet activation and protecting platelet function. Several studies suggest that hypothermia has a detrimental effect on platelet function [86, 87, 88, 89, 90, 91, 92, 93]. The bleeding time, which reflects overall platelet function, is affected by temperature in patients undergo-

ing CPB [88]. In a randomized trial (n=15) hypothermia (34C) [89]. These investigators also found that hypothermia was associated not only with increased postoperative blood loss and decreased platelet aggregation but also with decreased protein C and S levels and increased thrombin and thrombomodulin release, suggesting an overall coagulopathy [90]. In support of these findings Mazer et al. [91] randomized patients (n=11) to undergo normothermic (37C) or hypothermic (28–30C) CPB. They also found that there was a trend, albeit statistically nonsignificant, toward increased postoperative blood loss in the hypothermic group (786 vs. 547 ml) and a trend toward increased platelet activation in the hypothermic group. It should be noted, however, that the numbers in these studies, were small. In contrast, a larger study, that of the Warm Heart Investigators [92], found that the rates of chest reopening for bleeding in patients undergoing warm (33–37C, n=860) vs. cold CPB (25–30C, n=872) were similar. However, postoperative blood loss per se was not measured as one of the selected outcomes of their study. Similarly, when Birdi et al. [93] studied three groups of patients (100 patients/group) undergoing hypothermic (28C), moderately hypothermic (32C) or normothermic CPB (37C), they found that blood loss was similar among the three groups, but that the use of blood products in the normothermic group was significantly lower. Thus the extent to which hypothermia affects platelet dysfunction and subsequent blood loss remains to be clarified, and further studies may be warranted. Nonetheless, more weight should be given to the studies with the larger patient group size; thus hypothermia is likely to contribute to bleeding complications.

Conclusions CPB is a traumatic procedure that is associated with platelet and coagulation defects, inflammation, and increased fibrinolysis. In most patients these multifactorial events are well tolerated. However, a significant minority experience severe complications. These include poor postoperative outcomes that lead to temporary or permanent disabilities and increased health care system costs. There are a number of complex sequences of events that can lead to the coagulopathy, excessive postoperative bleeding, excessive use of blood product transfusion, need for chest reopening, and infection. In most cardiac surgical units these events are treated empirically since the diagnostic tests necessary to identify the underlying specific causes of the pathologies are difficult to perform, not readily accessible, and poorly understood. An understanding of the underlying mecha-

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nisms and cause of the activation of coagulation, inflammation, platelet dysfunction, and fibrinolysis during CPB may provide further insight by cardiac surgeons, anesthetists, intensivists, and other involved health care

workers to utilize effectively the technical and pharmaceutical options which are currently available, thereby decreasing the risk of complications associated with postoperative bleeding.

References 1. Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M (1996) Re-exploration for bleeding is a risk factor for adverse outcome after cardiac operations. J Thorac Cardiovasc Surg 111:1037–1046 2. Parr KG, Patel MA, Dekker R, Levin R, Glynn R, Avorn J, Morse SE (2003) Multivariate predictors of blood product use in cardiac surgery. J Cardiothorac Vasc Anesth 17:176–181 3. Sellman M, Intonti MA, Ivert T (1997) Reoperations for bleeding after coronary artery bypass procedures during 25 years. Eur J Cardiothorac Surg 11:521– 527 4. Ottino G, De Paulis R, Pansini S, Rocca G, Tallone MV, Comoglio C, Costa P, Orzan F, Morea F (1987) Major sternal wound infection after open heart surgery: a multivariate analysis of risk factors in 2,579 consecutive operative procedures. Ann Thorac Surg 44:173– 179 5. Zacharias A, Habib RH (1996) Factors predisposing to median sternotomy complications. Deep vs superficial infection. Chest 110:1173–1178 6. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J (1990) Clotbound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86:385–391 7. Liaw PC, Becker DL, Stafford AL, Fredenburgh JC, Weitz JI (2001) Molecular basis for the susceptibility of fibrin-bound thrombin to inactivation by heparin cofactor II in the presence of dermatan sulfate but not heparin. J Biol Chem 276:20958–20964 8. Brister SJ, Ofosu FA, Heigenhauser GJ, Gianese F, Buchanan MR (1994) Is heparin the ideal anticoagulant for cardiopulmonary bypass? Dermatan sulphate may be an alternate choice. Thromb Haemost 71:1–6 9. Esmon CT (2001) Role of coagulation inhibitors in inflammation. Thromb Haemost 86:51–56 10. Brister SJ, Ofosu FA, Buchanan MR (1993) Thrombin generation during cardiac surgery: is heparin the ideal anticoagulant? Thromb Haemost 70:259–262

11. Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B (1993) Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1+2. Thromb Haemost 70:253–258 12. Parolari A, Colli S, Mussoni L, Eligini S, Naliato M Wang X, Gandini S, Tremoli E, Biglioli P, Alamanni F (2003) Coagulation and fibrinolytic markers in a two month follow-up of coronary bypass surgery. J Thorac Cardiovasc Surg 125:336–343 13. Knudsen L, Hasenkam MJ, Kure HH, Hughes P, Bellaiche L, Ahlburg P, Djurhuus C (1996) Monitoring thrombin generation with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery. Thromb Res 84:45–54 14. Kaplan AP, Silverberg M (1987) The coagulation-kinin pathway of human plasma. Blood 70:1–15 15. Campbell DJ, Dixon B, Kladis A, Kemme M, Santamaria JD (2001) Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans. Am J Physiol Regul Integr Comp Physiol 281:R1059–R1070 16. Velthius H te, Baufreton C, Jansen PG, Thijs CM, Hack CE, Sturk A, Wildevuur CR, Loisance DY (1997) Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations. J Thorac Cardiovasc Surg 114:117–122 17. Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ (1993) Mechanism of thrombin generation during surgery and cardiopulmonary bypass. Blood 82:3350– 3357 18. Burman JF, Chung HI, Lane DA, Philippou H, Adami A, Lincoln JC (1994) Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 344:1192–1193 19. Chung JH, Gikakis N, Rao AK, Drake TA, Colman RW, Edmunds LH Jr (1996) Pericardial blood activated the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 93:2014–20118

20. Haan J de, Boonstra PW, Monnink SH, Ebels T, van Oeveren W (1995) Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 59:901–907 21. Aldea GS, Soltow LO, Chandler WL, Triggs CM, Vocelka CR, Crocket CI, Shin YI, Curtis WE, Verrier ED (2002) Limitation of thrombin generation, platelet activation and inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with heparinbonded circuits. J Thorac Cardiovasc Surg 123:742–755 22. Bull MH, Huse WM, Bull BS (1975) Evaluation of tests used to monitor heparin therapy during extracorporeal circulation. Anesthesiology 43:346–353 23. Cohen JA (1984) Activated coagulation time method for control of heparin is reliable during cardiopulmonary bypass. Anesthesiology 60:121–124 24. Despotis GJ, Summerfeld AL, Joist JH, Goodnough LT, Santoro SA, Spitznagel E, Cox JL, Lappas DG (1994) Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 108:1076–1082 25. Culliford AT, Gitel SN, Starr N, Thomas ST, Baumann FG, Wessler S, Spencer FC (1981) Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass. Ann Surg 193:105–111 26. Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG (1995) The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 110:46–54 27. Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Joiner-Maier D, Santoro SA, Spitznagel E, Weitz JI, Goodnough LT (1996) More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 76:902–908

1880

28. Jobes DR, Aitken GL, Shaffer GW (1995) Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 110:36–45 29. Gravlee GP, Haddon WS, Rothberger HK, Mills SA, Rogers AT, Bean VE, Buss DH, Prough DS, Cordell AR (1990) Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 99:518–527 30. Gravlee GP, Rogers AT, Dudas LM, Taylor R, Roy RC, Case LD, Triscott M, Brown CW, Mark LJ, Cordell AR (1992) Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding. Anesthesiology 76:393–401 31. Boldt J, Schindler E, Welters I, Wittstock M, Stertmann WA, Hempelmann G (1995) The effect of the anticoagulation regimen on endothelial-related coagulation in cardiac surgery patients. Anaesthesia 50:954–960 32. Despotis GJ, Filos KS, Zoys TN, Hogue CW Jr, Spitznagel E, Lappas DG (1996) Factors associated with excessive postoperative blood loss and hemostatic transfusion requirements: a multivariate analysis in cardiac surgical patients. Anesth Analg 82:13–21 33. Heres EK, Horrow JC, Gravlee GP, Tardiff BE, Luber J Jr, Schneider J, Barragry T, Broughton R (2001) A dose-determining trial of heparinase-I (Neutralase) for heparin neutralization in coronary artery surgery. Anesth Analg 93:1446–1452 34. Levy JH, Cormack JG, Morales A (1995) Heparin neutralization by recombinant platelet factor 4 and protamine. Anesth Analg 81:35–37 35. Butterworth J, Lin YA, Prielipp RC, Bennett J, Hammon JW, James RL (2002) Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg 74:1589–1595 36. Ammar T, Fisher CF (1997) The effects of heparinase 1 and protamine on platelet reactivity. Anesthesiology 86:1382–1386 37. Lindblad B, Wakefield TW, Whitehouse WM Jr, Stanley JC (1988) The effects of protamine sulfate on platelet function. Scand J Thorac Cardiovasc Surg 22:55–59 38. Barstad RM, Stephens RW, Hamers MJ, Sakariassen KS (2000) Protamine sulphate inhibits platelet membrane glycoprotein Ib-von Willebrand factor activity. Thromb Haemost 83:334–337

39. Moorman RM, Zapol WM, Lowenstein E (1993) Neutralization of heparin anticoagulation. In: GP Graelee, RF Davis, RJ Utley (eds) Cardiopulmonary bypass: principles and practice. Williams and Wilkins, Baltimore 40. Mochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH (1998) Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 87:781–785 41. Shigeta O, Kojima H, Hiramatsu Y, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T (1999) Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg 118:354–360 42. Teoh KH, Young E, Bradley CA, Hirsh J (1993) Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass. Circulation 88:420–425 43. Martin P, Horkay F, Gupta NK, Gebitekin C, Walker DR (1992) Heparin rebound phenomenon–much ado about nothing. Blood Coagul Fibrinolysis 3:187–191 44. Paparella D, Yau TM, Young E (2002) Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 21:232–244 45. Cate JW ten, van der Poll T, Levi M, ten Cate H, van Deventer SJ (1997) Cytokine: triggers of clinical thrombotic disease. Thromb Haemost 78:415–419 46. Nemerson Y (1988) Tissue factor and haemostasis. Blood 71:1–8 47. Christman JW, Lancaster LH, Blackwell TS (1998) Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med 24:1131–1138 48. Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683 49. Morgan EN, Pohlman TH, Vocelka C, Farr A, Lindley G, Chandler W, Griscavage-Ennis JM, Verrier ED (2003) Nuclear factor kappaB mediated a procoagulant response in monocytes during extracorporeal circulation. J Thorac Cardiovasc Surg 125:165–171 50. Lindahl AK (1997) Tissue factor pathway inhibitor: from unknown coagulation inhibitor to major antithrombotic principle. Cardiovasc Res 33:286–291

51. Gori AM, Pepe G, Attanasio M, Falciani M, Abbate R, Prisco D, Fedi S, Giusti B, Brunelli T, Comeglio P, Gensini GF, Neri Serneri GG (1999) Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration. Thromb Haemost 81:589–593 52. Adams MJ, Cardigan RA, Marchant WA, Grocott MP, Mythen MG, Mutch M, Purdy G, Mackie IJ, Machin SJ (2002) Tissue factor pathway inhibitor antigen and activity in 96 patients receiving heparin for cardiopulmonary bypass. J Cardiothorac Vasc Anesth 16:59–63 53. Kojima T, Gandos S, Kemmotsu O, Mashio H, Goda Y, Kawahigashi H, Watanabe N (2001) Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 15:60–64 54. Spiess BD (1991) The contribution of fibrinolysis to post bypass bleeding. J Cardiothorac Vasc Anesth 5:13–17 55. Chang SP, Stennet R (1988) Hemostasis and cardiopulmonary bypass. In: Krieger KH, Isom OW (eds) Blood conservation in cardiac surgery. Springer, New York Heidelberg Berlin, pp 213–66 56. Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K (1989) Alteration in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Vasc Anesth 3:181–189 57. Valen G, Eriksson E, Risberg B, Vaage J (1994) Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 8:324– 230 58. Hunt BJ, Parrat RN, Segal HC, Sheikh S, Kallis P, Yacoub M (1998) Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 65:712–718 59. Teufelsbauer H, Proidl S, Havel M, Vukovich T (1992) Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost 68:250–252 60. Poll T van der, Levi M, Buller HR, van Deventer SJ, de Boer JP, Hack CE, ten Cate JW (1991) Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 174:729–732

1881

61. Chia S, Qadan M, Newton R, Ludlam CA, Fox KA, Newby DE (2003) Intraarterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arterioscler Thromb Vasc Biol 23:695– 701 62. Chia S, Ludlam CA, Fox KA, Newby DE (2003) Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men. J Am Coll Cardiol 41:333–339 63. Gram J, Janetzko T, Jespersen J, Bruhn HD (1990) Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 63:241–245 64. Kuepper F, Dangas G, Mueller-Chorus A, Kulka PM, Zenz M, Wiebalck A (2003) Fibrinolytic activity and bleeding after cardiac surgery with cardiopulmonary bypass and low-dose aprotinin therapy. Blood Coagul Fibrinolysis 14:147–153 65. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJM, Briet E, Buller HR (1999) Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 354:1940–1947 66. Federici AB, Berkowitz SD, Zimmerman TS, Mannucci PM (1992) Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. Blood 79:38–44 67. Hamilton KK, Fretto LJ, Grierson DS, McKee PA (1985) Effects of plasmin on von Willebrand factor multimers: degradation in vitro and stimulation of release in vivo. J Clin Invest 76:261– 270 68. Stricker RB, Wong D, Shiu DT, Reyes PT, Shuman MA (1986) Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: effects on surface proteins and platelet aggregation. Blood 68:275–280 69. Kamat SG, Michelsen AD, Benoit SE, Moake JL, Rajasekhar D, Hellums JD, Kroll MH, Shafer AI (1995) Fibrinolysis inhibits shear stress-induced platelet aggregation. Circulation 92:1399–1407 70. Huang H, Ding W, Su Z, Zhang W (1993) Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 106:11–18 71. Kallis P, Tooze JA, Talbot S, Cowans D, Bevan DH, Treasure T (1994) Aprotinin inhibits fibrinolysis, improves platelet adhesion and reduce blood loss. Results of a double-blind randomized clinical trial. Eur J Cardiothorac Surg 8:315–322

72. Shigeta O, Kojima H, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T (1997) Aprotinin inhibits plasmin-induced platelet activation during cardiopulmonary bypass. Circulation 96:569–574 73. Haan J de, van Oeveren W (1998) Platelets and soluble fibrin promote plasminogen activation causing downregulation of platelet glycoprotein Ib/IX complexes: protection by aprotinin. Thromb Res 92:171–179 74. Karski JM, Teasdale SJ, Norman P, Carroll J, Van Kessel K, Wong P, Glynn MF (1995) Prevention of bleeding after cardiopulmonary bypass with high dose tranexamic acid. Double blind, randomized clinical trial. J Thorac Cardiovasc Surg 110:835–842 75. Vander Salm TJ, Kaur S, Lancey RA, Okike ON, Pezzella AT, Stahl RF, Leone L, Li JM, Valeri CR, Michelson AD (1996) Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid. J Thorac Cardiovasc Surg 112:1098– 1107 76. Kestin AS, Valeri CR, Khuri SF, Loscalzo J, Ellis PA, MacGregor H, Birjiniuk V, Ouimet H, Pasche B, Nelson MJ (1993) The platelet function defect of cardiopulmonary bypass. Blood 82:107–117 77. Greilich PE, Brouse CF, Beckman J, Jessen ME, Martin EJ, Carr ME (2002) Reductions in platelet contractile force correlate with duration of cardiopulmonary bypass and blood loss in patients undergoing cardiac surgery. Thromb Res 105:523–529 78. Zilla P, Fasol R, Groscurth P, Klepetko W, Reichenspurner H, Wolner E (1989) Blood platelets in cardiopulmonary bypass. Recovery occurs after initial stimulation, rather than continual activation. J Thorac Cardiovasc Surg 97:379–388 79. Cella G, Vitadello O, Gallucci V, Girolami A (1981) The release of betab thromboglobulin and platelet factor 4 during extracorporeal circulation for open heart surgery. Eur J Clin Invest 11:165–169 80. Wahba A, Rothe G, Lodes H, Barlage S, Schmitz G, Birnbaum DE (2000) Effects of extracorporeal circulation and heparin on the phenotype of platelet surface antigens following heart surgery. Thromb Res 97:379–386 81. Xiao Z, Theroux P (1998) Platelet activation with unfractionated heparin at therapeutic concentrations and comparison with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 97:251–256

82. Khuri SF, Valeri RC, Loscalzo J, Weinstein MJ, Birjiniuk V, Healey NA, MacGregor H, Doursounian M, Zolkevitz MA (1995) Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 60:1008–1014 83. Muriithi EW, Belcher PR, Day SP, Menys VC, Wheatley DJ (2000) Heparin induced platelet dysfunction and cardiopulmonary bypass. Ann Thorac Surg 69:1827–1832 84. Muriithi EW, Belcher PR, Day SP, Chaudhry MA, Caslake MJ, Wheatley DJ (2002) Lypolisis generates platelets dysfunction after in vivo heparin administration. Clin Sci (Colch) 103:433– 440 85. Nakajima T, Kawazoe K, Ishibashi K, Kubota Y, Sasaki T, Izumoto H, Nitatori T (2000) Reduction of heparin dose is not beneficial to platelet function. Ann Thorac Surg 70:186–190 86. Valeri CR, Feingold H, Cassidy G, Ragno G, Khuri S, Altschule MD (1987) Hypothermia-induced reversible platelet dysfunction. Ann Surg 205:175–181 87. Michelson AD, MacGregor H, Barnard MR, Kestin AS, Rohrer MJ, Valeri CR (1994) Reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. Thromb Haemost 71:633–640 88. Valeri CR, Khabbaz K, Khuri SF, Marquardt C, Ragno G, Feingold H, Gray AD, Axford T (1992) Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass. J Thorac Cardiovasc Surg 104:108–116 89. Boldt J, Knothe C, Zickmann B, Bill S, Dapper F, Hempelmann G (1993) Platelet function in cardiac surgery: influence of temperature and aprotinin. Ann Thorac Surg 55:652–658 90. Boldt J, Knothe C, Welters I, Dapper F, Hempelmann G (1996) Normothermic versus hypothermic cardiopulmonary bypass: do changes in coagulation differ? Ann Thorac Surg 62:130–135 91. Mazer CD, Hornstein A, Freedman J (1995) Platelet activation in warm and cold heart surgery. Ann Thorac Surg 59:1481–1486 92. Warm Heart Investigators (1994) Randomised trial of normothermic versus hypothermic coronary bypass surgery. Lancet 343:559–563 93. Birdi I, Regragui I, Izzat MB, Bryan AJ, Angelini GD (1997) Influence of normothermic systemic perfusion during coronary artery bypass operations: a randomized prospective study. J Thorac Cardiovasc Surg 114:475–481