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Ann Thorac Surg 2001;72:S1821-S1831
© 2001 The Society of Thoracic Surgeons

Supplement: Mechanisms and attenuation of abnormalities in hemostasis/inflammation and neurologic injury: implications for patient outcomes

Mechanisms and attenuation of hemostatic activation during extracorporeal circulation

George J. Despotis, MD*a, Michael S. Avidan, MDa, Charles W. Hogue, Jr, MDa

a Departments of Anesthesiology, Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

* Address reprint requests to Dr Despotis, Departments of Anesthesiology, Pathology and Immunology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
e-mail: despotig{at}notes.wustl.edu

Presented at Mechanisms and Attenuation of Abnormalities in Hemostasis/Inflammation and Neurologic Injury: Implications for Patient Outcomes, Vancouver, BC, Canada, May 6, 2001.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Pathophysiology of excessive...
 Attenuation of hemostatic system...
 Conclusion
 References
 
Patients undergoing cardiac surgery with cardiopulmonary bypass are at risk for excessive microvascular bleeding, which often leads to transfusion of allogeneic blood and blood components as well as reexploration in a smaller subset of patients. Excessive bleeding after cardiac surgery is generally related to a combination of several alterations in the hemostatic system pertaining to hemodilution, excessive activation of the hemostatic system, and potentially the use of newer, longer-acting antiplatelet or antithrombotic agents.

Although several nonpharmacologic strategies have been proposed, this review summarizes the role of pharmacologic interventions as means to attenuate the alterations in the hemostatic system during CPB in an attempt to reduce excessive bleeding, transfusion, and reexploration. Specifically, agents that inhibit platelets, fibrinolysis, factor Xa and thrombin, as well as broad-spectrum agents, have been investigated with respect to their role in reducing consumption of clotting factors and better preservation of platelet function.

Prophylactic administration of agents with antifibrinolytic, anticoagulant, and possibly antiinflammatory properties can decrease blood loss and transfusion. Although aprotinin seems to be the most effective blood conservation agent (which is most likely related to its broad-spectrum nature), agents with isolated antifibrinolytic properties may be as effective in low-risk patients. The ability to reduce blood product transfusions and to decrease operative times and reexploration rates favorably affects patient outcomes, availability of blood products, and overall health care costs.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Pathophysiology of excessive...
 Attenuation of hemostatic system...
 Conclusion
 References
 
Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk for microvascular bleeding. The frequency of excessive bleeding with CPB varies according to the definition used. Although a recent analysis indicated that 11% of patients have excessive bleeding after cardiac surgery [1], only 5% to 7% have blood loss of more than 2 L within 24 hours postoperatively [2]. If excessive bleeding is defined by patients who require reexploration, two large series show that the incidence is between 3.6% [3] and 4.2% [4]. Excessive microvascular bleeding can result in reexploration and prolonged hospitalization [4, 5]. Patients require exploration to exclude a surgical source of bleeding or to evacuate blood, causing hemodynamic compromise such as a pericardial tamponade. When patients undergo reoperation, fewer than 50% exhibit surgical sources of bleeding [4]. The majority are found to have acquired hemostatic defects [3, 6]. Two large studies have demonstrated that reexploration can be associated with a variety of negative outcomes such as increased mortality, renal failure, sepsis, atrial arrhythmias, prolonged requirement for mechanical ventilatory support, and longer hospital stay [3, 4].

Transfusion of allogeneic blood or blood components is potentially associated with a number of adverse events such as blood-borne disease transmission, increased incidence of wound infections, hemolytic and nonhemolytic transfusion reactions, increased mortality [4, 5, 7], increased operative time, [8] as well as increased cost. Based on a national annual frequency of 500,000 adult cardiac surgical procedures per year, an average cost of $250/U of blood and an average transfusion rate of 4 U/patient (3.9 ± 5.9 U) [2], costs related to red cell and nonred cell transfusions approximate $500 million annually.


   Pathophysiology of excessive bleeding
Top
 Footnotes
 Abstract
 Introduction
 Pathophysiology of excessive...
Attenuation of hemostatic system...
 Conclusion
 References
 
Excessive bleeding after cardiac surgery is generally related to a combination of several cardiopulmonary bypass (CBP) –related alterations in the hemostatic system (Fig 1). In addition to hemodilution [8], there is excessive activation of the hemostatic system, which is related to interaction of blood with the extensive, nonendothelial CPB surfaces [9], activation of the extrinsic clotting pathway [10] secondary to surgical trauma and retransfusion of pericardial blood [11]. The contact activation and tissue factor pathways converge resulting in activation of factor X, which, in combination with prothrombinase complex, factor Va, and calcium, leads to the generation of thrombin, which can be quantified by measuring either prothrombin fragment 1.2 or thrombin-antithrombin III complexes (Fig 2) [10]. Activation of fibrinolysis occurs simultaneously by means of several mechanisms. Tissue plasminogen activator (t-PA) release contributes to fibrinolysis and is promoted by CPB-mediated contact activation of factor XII, thrombin, hypothermia, traumatized endothelial cells, and returned blood from the pericardiotomy suction [12]. Mechanisms related to heparin and protamine are additional factors that will be addressed later.



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  		Fig 1. Pathophysiology of hemostasis abnormalities with extracorporeal circulation. CPB crystalloid prime refers to crystalloid solution required to prime the cardiopulmonary bypass circuit whereas cardioplegia volume refers to volume of crystalloid required for cardioplegic myocardial arrest. Contact activation via extracorporeal circulation (ECC) refers to contact activation related to interface of blood with nonendothelial surface of extracorporeal circuit. Pericardial activation refers to activation of the hemostatic system via the tissue factor pathway mediated by transfusion pericardial blood containing tissue thromboplastin, tPA = tissue plasminogen activator; Gp = platelet glycoprotein receptors (e.g., IIb/IIIa or Ib), Mechanical (i.e., as related to ECC) refers to shear forces imposed by some of the components of the ECC circuit as listed.

 


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  		Fig 2. Mechanisms and effects of excessive hemostatic activation with cardiac surgery. The coagulation system is subdivided into three pathways intrinsic or contact, extrinsic or tissue factor and common (i.e., below conversion of X to Xa); the conversion of factor X to Xa is within all three pathways. Dashed line designates release of protein cleavage by-products. Abbreviations (activated factors are designated using a small "a" whereas inactivated factors are designated using a small "i"): Factor XII = XII; Factor VII = VII; Factor X = X; Factor VIII = VIII; Factor IX = IX; Factor V = V; Factor XIII = XIII; prothrombin fragment 1.2 = PT 1.2; calcium ions = Ca++; fibrinopeptide A = FPA; PL = phospholipid; PAP = plasmin-antiplasmin complexes; EC = endothelial cells; tPA:PAI1= tPA PAI1 complexes; fibrin monomer = fibrin (m); fibrin polymer = fibrin (p); fibrin cross-linked polymer = fibrin (L); plasminogen activator inhibitor = PAI1; tissue plasminogen activator = tPA; fibrinogen/fibrin degradation products = FDP; polymerized fibrin degradation products = D-dimers; * designates endothelial cell related.

 
When blood is activated, a consumptive process ensues that is mediated by thrombin and plasmin. Thrombin mediates the conversion of fibrinogen to fibrin monomer, initiates fibrinolysis by mediating release of tPA, and also activates factors V, VIII, XIII, and platelets. Thrombin has recently been shown to activate the inflammatory system, specifically complement [13]. Thrombin, in combination with thrombomodulin on the endothelial cell surface, activates protein C, which acts to clear the previously generated activated factors V and VIII. Thrombin also down-regulates hemostasis by releasing tissue factor pathway inhibitor, which inhibits the tissue factor pathway and stimulates release of tPA, which cleaves plasminogen to plasmin. Plasmin cleaves fibrinogen and fibrin monomer into fibrin split products and cross-linked fibrin polymer into D-dimers, respectively, inactivates coagulation factors V and VIII, and has direct effects on platelet membrane receptors. Specifically, plasmin leads to either internalization or destruction of the adhesive glycoprotein Ib receptor on the platelet surface [14] and may detrimentally affect IIb/IIIa receptors. Thus, it is important to attenuate the effects of both thrombin and plasmin to maintain coagulation homeostasis during CPB, as unrestricted thrombin and plasmin activity ultimately lead to consumption of coagulation factors and platelets (ie, a disseminated intravascular coagulation state during CPB).

An exaggerated inflammatory response may also affect the hemostatic system as mediated by means of elastase released from leukocytes or complement activation. Rinder and colleagues [15] described adhesion of leukocytes to platelets during CPB, whereas another study demonstrated a significant relationship between percentage increase in white cell count before and after bypass and blood loss [16]. Whether our recent observation was a cause/effect relationship or a marker of a relationship between the inflammatory response and hemostatic activation is not clear, but it does suggest that agents with antiinflammatory properties may be beneficial in terms of preservation of the coagulation system. This is supported by two additional recent studies. Rinder and associates [17] observed that inhibition of the complement membrane attack complex attenuates the reduction in platelets and decreases formation of platelet-leukocyte complexes during simulated CPB. In another randomized trial, Fitch and coworkers [18] demonstrated that inhibition of the complement cascade using an antibody against C5 resulted in a 40% reduction in myocardial injury, an 80% reduction in cognitive defects, and a 30% reduction in postoperative chest tube drainage.


   Attenuation of hemostatic system activation
Top
 Footnotes
 Abstract
 Introduction
 Pathophysiology of excessive...
 Attenuation of hemostatic system...
Conclusion
 References
 
Numerous pharmacologic and nonpharmacologic strategies have been proposed as means to attenuate the alterations in the hemostatic system during CPB. This review focuses on pharmacologic interventions including agents that inhibit platelets, fibrinolysis, factor Xa and thrombin.

Platelet inhibition
Reports have detailed the variable efficacy of preoperative antiplatelet agents such as aspirin and dipyridamole in attenuating platelet consumption. In a prospective randomized trial comparing dipyridamole with placebo, postoperative blood loss and transfusion requirements decreased significantly in the treatment cohort but the magnitude of change was small [19]. Fish and colleagues [20] found significant platelet-sparing properties with prostacyclin (PGI2), whereas DiSesa and colleagues [21] found none. These inconsistent findings combined with the potential for hypotension explain why PGI2 has never gained popularity for routine use during CPB. Some reports have described the successful intraoperative use of specific platelet inhibitors such as PGI2 [22] or prostaglandin E1 (PGE1) [23] as supplements to heparin in patients with immune-mediated heparin-induced thrombocytopenia (HIT).

Clinical use of new platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab and eptifibatide is increasing in acute coronary syndromes based on evidence demonstrating enhanced coronary artery patency after high-risk angioplasty and stenting procedures with these agents [24]. Abciximab (c7E3, Reopro Eli Lilly, Indianapolis, IN) is a monoclonal antibody directed at the platelet GpIIb/IIIa receptor complex (fibrinogen receptor) that has relatively long-term platelet inhibitory effects [25]. Abciximab has been associated with hemorrhagic complications after angioplasty [26]. In addition, some reports have indicated that abciximab use may increase transfusion requirements [27, 28] after cardiac surgery, especially if this agent is administered within 12 hours before surgery [28]. In a recent analysis of the data on patients enrolled in the Epilog and Epistent trials who also required cardiac surgery, those patients who received abciximab (n = 28) and those who received placebo (n = 40) had similar blood loss [29]. Similar blood loss and transfusion requirements were also observed in a study comparing urgent cardiac surgical patients receiving eptifibatide with patients receiving placebo [30]. Findings from another study indicate that glycoprotein IIbIIIa receptor antagonists may actually preserve hemostasis and platelets if they are short-acting or readily reversible [31].

Inhibition of fibrinolysis and broad-spectrum agents
Agents that preserve hemostasis through plasmin inhibition include tranexamic acid (TA), {varepsilon}-aminocaproic acid (EACA), and aprotinin. The common mechanism is inhibition of the fibrinolytic pathway, as illustrated in Figure 3. EACA and TA are synthetic agents that competitively inhibit plasmin. They adhere to the lysine-binding sites of plasminogen and plasmin to interfere with plasmin’s ability to digest fibrinogen, fibrin, and platelet glycoprotein receptors (ie, Gp 1b). These agents reduce blood loss and transfusion requirements [32–42].



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  		Fig 3. Agents that preserve hemostasis. Dashed line designates release of protein cleavage by-products. The following coagulation factors, hemostatic mediators and by-products are abbreviated using the following (activated factors are designated using a small "a"): Factor XII = XII; Factor VII = VII; Factor X = X; Factor VIII = VIII; Factor IX = IX; Factor V = V; Factor XIII = XIII; prothrombin fragment 1.2 = PT 1.2; calcium ions = Ca++; fibrinopeptide A = FPA; fibrin monomer = fibrin (m); fibrin polymer = fibrin (p); plasminogen activator inhibitor = PAI1; tissue plasminogen activator = tPA; fibrinogen/fibrin degradation products = FDP; polymerized fibrin degradation products = D-dimers; EACA = epsilon-amino caproic acid; TA = tranexamic acid; vWF = von Willebrand Factor; Gp = glycoprotein receptors.

 
In contrast, aprotinin is a broad-spectrum protease inhibitor that inhibits factor XII and kallikrein-mediated conversion of plasminogen to plasmin. It has antiinflammatory and anticoagulant properties that may preserve hemostasis by inhibiting the contact pathway [43] and possibly the tissue factor pathway [44]. Marx and colleagues demonstrated that aprotinin-treated patients had reduced thrombin (measured by fibrinopeptide A) and fibrinolytic (measured by D-dimers) activity [45]. Dietrich and associates [46] supported these findings in a recent study in which F 1 + 2 levels and fibrin monomer concentrations were lower during CPB in aprotinin-treated patients than in controls. Aprotinin may also preserve platelet integrity and function by inhibiting proteolytic alterations in von Willebrand factor and platelet glycoprotein Ib and IIb/IIIa receptors, increase circulating factor Va and VIIIa through inhibition of protein C activity, attenuate the inhibition of platelet function by heparin [47, 48] and reduce thrombin-mediated platelet consumption through inhibition of the PAR1 receptor [49].

Two recent meta-analyses have revealed that EACA, TA, and aprotinin are all effective in reducing blood loss and transfusion [39, 40]. Both analyses indicated that aprotinin, EACA, and TA reduced transfusion and reexploration. However, aprotinin reduced mortality by 50% in the analysis by Levi and colleagues [39], and aprotinin reduced blood loss to a greater extent (53%) compared with EACA (35%) in the meta-analysis by Muñoz and colleagues [40] Unfortunately, these two meta-analyses are limited by the inclusion of early studies that investigated the effect of either TA or EACA in a retrospective nonrandomized fashion, frequently using historical control groups.

To evaluate further the comparative efficacy between the lysine analogues and aprotinin, we examined the results of a subset of trials that were used in the meta-analyses, as well as more recent studies. In contrast to early studies that examined the use of either TA or EACA, four well-controlled, double-blind, randomized, United States multicenter clinical trials have demonstrated improved outcomes in aprotinin-treated groups versus placebo [50–53]. Specifically, a substantial reduction in blood loss (50% reduction in chest tube drainage), transfusion (50% to 90% reduction in total donor exposures), and reexploration (40% to 60% reduction) was evident in patients who received aprotinin (Fig 4). [50–53] In contrast, only a modest 25% reduction reduction in blood loss and red cell transfusion was observed in patients who received EACA compared with placebo in seven trials that we reviewed [32–38]. Nine other studies directly compared the relative efficacy of aprotinin with the other two agents [41, 42, 54–60]. Three of six studies that compared TA with aprotinin as well as four of six studies that compared EACA with aprotinin found a greater reduction in blood loss in aprotinin-treated patients. Two more recent studies examined the comparative efficacy of tranexamic acid to either aprotinin [42] or aprotinin and EACA [41]. In a large, recently published study involving low-risk patients, Casati and colleagues demonstrated that tranexamic acid was as effective as aprotinin with respect to reducing blood loss when compared to EACA, although at a lower cost [41]. In another large randomized trial (n = 1040) by the same investigators, tranexamic acid was shown to have similar blood loss and transfusion profiles as aprotinin in a series of patients at low risk for bleeding [42]. However, neither of two dosing strategies for tranexamic acid was found to be effective in reducing either blood loss or transfusion when compared to placebo in another large series of low-risk patients (n = 510) by the same investigators [61], which leads one to question the merit of using any of these agents in patients at low risk for bleeding.



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  		Fig 4. Effects of aprotinin on blood loss and transfusion requirements in patients undergoing cardiac surgery involving CPB: A summary from four large, recent, multi-center US trials [50–53]. A = aprotinin-treated patients; P = placebo-treated patients; Blood loss = cumulative 24 hours blood loss; CTD = chest tube drainage; U = units; Primary = first cardiac surgical procedure; Repeat = one or more previous cardiac procedures. Percentage of patients reexplored for each cohort within the box labeled "Reexploration."

 
A recent multicenter trial (n = 204) by Bennett-Guerrero and colleagues [57] compared the use of EACA and aprotinin in a series of patients undergoing repeat cardiac surgical procedures. The findings in this study of reduced platelet transfusions in patients who received aprotinin, along with less blood loss, supports the notion that aprotinin, because of its broad-spectrum actions, may be a more effective agent in patients at higher risk for bleeding. Nevertheless, the authors concluded that aprotinin may not be cost-effective. In summary, as revealed by the recently published meta-analyses, aprotinin, TA, and EACA are all effective in reducing transfusion and reexploration after cardiac surgery, particularly in patients at higher risk for transfusion. Aprotinin was shown to reduce mortality and may be more effective in reducing blood loss, especially in high-risk patients.

Concerns have been raised regarding thrombotic complications with aprotinin. There have been a few reports of clot formation on pulmonary artery catheters [62], thromboembolic complications [63–66], and decreased graft patency [64]. However, a study involving deep hypothermic arrest [67] and several placebo-controlled, blinded prospective trials have not demonstrated an increased incidence of thrombotic complications [50, 51] or reduced graft patency [51, 68, 69]. A recent 13-center trial is the most extensive investigation of this issue [53]. In this trial, graft patency was assessed using angiography preoperatively and postoperatively (median 7 to 10 days) in a series of 860 patients undergoing primary coronary revascularization who were randomly assigned to receive either aprotinin or placebo. A slightly lower (p = 0.03) vein graft patency rate was observed in aprotinin-treated patients (93.5%) when compared with controls (95.5%) whereas myocardial infarction rates were similar in both groups. Interestingly, vein graft patency rate was similar in US study sites in both groups, and the risk for vein graft occlusion was comparable when the investigators corrected for other established risk factors (namely gender, poor native vessel size/quality, and poor intraoperative vein graft preservation technique). The initially reported reduced stroke rate [50, 70] observed in aprotinin-treated patients, possibly related to this agent’s anticoagulant or antiinflammatory properties, has been confirmed in a extensive analysis of the US aprotinin database by Smith and colleagues [71].

Inhibition of thrombin
Since the few isolated reports of thromboembolic complications were initially described in cardiac patients whose heparin administration was based on celite activated clotting time (ACT) protocols [63, 64], numerous investigators have assessed the impact of aprotinin on coagulation assays, which have generally shown that aprotinin affects only celite ACT values and that reduced doses of heparin are administered if this method of anticoagulation is used in patients who receive aprotinin. It is of interest to note that in three recent multicenter evaluations, the incidence of thrombotic complications was not increased in aprotinin-treated patients in whom heparin administration was based either on whole blood heparin measurements or on a fixed-dose regimen [50, 51, 53, 68]. Because aprotinin attenuates the inhibition of platelet function by heparin [48] and reduces bleeding when higher doses of heparin are administered [47], we suggest administration of higher doses of heparin (eg, 600 to 700 U/kg total doses) when patients receive this agent.

The concept that enhanced anticoagulation during CPB and, thus, thrombin inhibition results in better preservation of hemostasis is supported by findings from several studies. Dietrich and coworkers [72] measured thrombin/antithrombin complexes as an index of thrombin activity during the peribypass period in patients receiving warfarin preoperatively for prevention of stroke versus patients not receiving this agent. Substantially better suppression of thrombin activity was observed during CPB in patients treated preoperatively with warfarin. We recently enrolled 254 patients in a prospective trial to examine the potential benefits of maintaining patient-specific heparin levels on blood loss and transfusion [73]. In this trial, patients were randomized to either our standard care group (standard heparin dosing based on Hemochron-derived [International Technidyne Corp, Edison, NJ] celite ACT values) or to an intervention cohort (invidualized heparin dosing based on ACT and maintenance of patient-specific heparin concentrations derived from pre-CPB patient-specific response to heparin). Patients in the intervention cohort received 35% more heparin (i.e. 600 u/kg) during CPB compared with the standard group. Patients who had therapeutic levels (eg, those consistent with therapeutic ACT values before CPB) of heparin maintained throughout CPB) had significant reductions in the number of nonred cell units (platelets, plasma, cryoprecipitate) transfused [73]. In a subsequent analysis [74], an indirect relationship between heparin concentration (anti-Xa assay) and fibrinopeptide-A was observed, indicating that if heparin levels are maintained between 4 and 5 U/mL, thrombin activity is better suppressed. More importantly, less consumption of consumable coagulation factors occurred with this regimen [74]. Preservation of factors V, VIII, fibrinogen and antithrombin-III were found when higher patient-specific heparin concentrations were maintained during CPB compared with standard heparin dosing (Fig 5). There was also indirect evidence of reduced thrombin-mediated platelet consumption in the patients with the higher heparin concentrations, as shown by lower template bleeding times on arrival in the intensive care unit. The latter findings support the concept that enhanced anticoagulation preserves hemostasis, and these results have recently been confirmed for patients undergoing aortic aneurysm repair with circulatory arrest [75].



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  		Fig 5. Relationship between hemostatic changes in platelets and coagulation factors with cardiopulmonary bypass (CPB) and excessive microvascular bleeding. Percent decreases were compared in patients without microvascular bleeding (nonbleeders) who averaged two hours on CPB as compared to patients with excessive microvascular bleeding who averaged over three hours on CPB. Percent decreases were calculated using Pre-CPB and Post-CPB values in the following equation: ([post-CPB/pre-CPB] - 1) x 100. Average absolute values for hemostatic variables are also indicated. Coagulation Factors V, VII, VIII, IX, X and XII are expressed as % activity, fibrinogen concentration is expressed as mg/dl and platelet count is expressed in 1,000/µl. * p <0.05. (Reprinted with permission from Despotis et al [74].)

 
The topic of heparin dosing for CPB, however, is not without considerable debate. As summarized in a recent review [76], when compared with either fixed-dose or ACT protocols, the impact of heparin concentration monitoring on bleeding and blood conservation has been variable. Some authors have suggested that excessive bleeding is related to use of greater doses of bovine heparin during CPB [47, 77], while others found no differences in blood loss when either bovine [75] or porcine heparin was used [2, 73]. The discrepant results may be related to differences between studies in one or more demographic, operative, or procedure-related issues, particularly duration of CPB. The ACT is prolonged by factors other than heparin such as hemodilution, hypothermia [78], and thrombocytopenia, and thus does not in itself provide an accurate indicator of thrombin inhibition or heparin anticoagulant effect during CPB. Thus, ACT-based anticoagulation protocols will result in administration of lower doses of heparin, which may contribute to a hemostatic consumptive state, particularly in patients requiring prolonged use of CPB. As suppression of fibrinopeptide A generation [77, 79] and inhibition of clot-bound thrombin [80] have been shown to relate directly to heparin concentration, maintenance of heparin concentrations that more effectively inactivate thrombin can preserve hemostasis during prolonged CPB [74, 75]. The notion has been proposed that higher, stable heparin concentrations during CPB may preserve platelets through a dose-related inhibition of platelet function [81]. The alternative perspective is that inhibition of platelet function by a high dose heparin may be detrimental in a subgroup of patients as a result of the extent of inhibition [82], the nontransient nature or lack of reversibility by routine doses of protamine [83], or activation of platelets by heparin [84].

Protamine dosing and other heparin adjuncts
As summarized in a recent review [76], many studies have examined the effect of reducing protamine doses in an attempt to reduce protamine-induced, platelet-related bleeding. Monitoring protocols can markedly influence protamine doses used to neutralize heparin. Of eight published studies that evaluated the clinical impact of reducing protamine dose, four showed either reduced blood loss or transfusion requirements, whereas four did not. However, a reduced protamine dose was not associated with increased blood loss or transfusion in any of these studies. The discrepancy in outcomes between these studies probably relates to differences in the relative extent of reduction in protamine dose and the overall protamine-to-heparin ratio in the intervention cohort. In the four studies that demonstrated a favorable difference in outcome, better bleeding or transfusion outcomes occurred when the reduction in protamine dose was approximately 50% or greater and when the protamine-to-heparin ratio was less than 1.0. The four negative studies had either smaller reductions in protamine dose (27% to 38%) or protamine-to-heparin ratios consistently more than 1, or both. The decreases in perioperative blood loss associated with reduced doses of protamine may result from less complement activation [85] or from reduced protamine-induced platelet dysfunction [22, 86, 87]. Based on published survey results [76], 48% of clinicians polled probably administered excessive doses of protamine as a result of using empiric regimens based on a fixed-ratio (1:1 or greater) of protamine to the total heparin dose administered.

In an attempt to simulate the antithrombotic properties of the normal endothelial surface, heparin has been bonded to the extracorporeal circuit. Among nine studies summarized in a recent review [76], all but one have demonstrated that the use of heparin-bonded circuits attenuates the inflammatory response to CPB as judged by reduced complement or granulocyte activation. Studies examining the effect of heparin-coated circuits on hemostasis have not consistently found reductions in sensitive biochemical markers of hemostatic system activation. Some studies using reduced systemic heparin doses showed increased activation with heparin-coated circuits (as evidenced by increases in prothrombin fragment 1.2, fibrinopeptide A, D-dimer and beta thromboglobulin values). However, others demonstrated either no significant differences [88] or reductions in these markers both ex vivo [88] and in simulated CPB models [89]. Reduced systemic heparin doses in the presence of heparin-bonded circuits has also been associated with reduced platelet activation [90]. However, findings have been inconsistent regarding normal heparin doses, with some studies showing lower platelet activation and others showing no difference. Lower heparin doses and ACT thresholds have been advocated when heparin-coated circuits are used, based on data from six studies that have demonstrated reduced blood loss, transfusion requirements, and a seemingly similar risk of perioperative thrombotic complications. However, the majority of these studies had short CPB times and were not powered adequately to address the safety of lower heparin doses with heparin-coated circuits. In addition, some of these studies have shown larger increases in markers of coagulation activation in patients who receive lower heparin doses during use of heparin-bonded circuits, and others have described thrombotic events when extracorporeal life support was used without systemic anticoagulation [91] or during cardiac surgery [92]. This has led Edmunds [93] to suggest that lowering heparin dose with heparin-coated circuits is inappropriate because of the lack of adequate safety data. In the absence of large-scale, prospective trials addressing this important safety issue, we agree with this conclusion.

Enhancement of the antithrombotic properties of heparin by antithrombin III (ATIII) supplementation can preserve the hemostatic system during CPB, especially in patients who have acquired ATIII deficiency from preoperative heparin infusions [72] or CPB-related hemodilution or consumption [74, 94]. The initial findings of decreased thrombin (measured by fibrinopeptide A) activity observed by Hashimoto and colleagues [79] in pediatric patients who were given pooled ATIII concentrates was recently confirmed by Levy and associates [95] using recombinant transgenic ATIII. Inverse relationships were observed between ATIII concentration and markers of both thrombin (fibrin monomer) and fibrinolytic (D-dimer) activity [95]. In addition, it has recently been shown that use of transgenic ATIII can reduce the requirement for fresh frozen plasma (FFP) in patients with heparin resistance [96]. Specifically, in this study, 92% of patients randomized to the placebo cohort required FFP to achieve a therapeutic ACT (>480 seconds) after administration of more than 400 U/kg of heparin, compared with only 21% of patients who received transgenic recombinant ATIII. Further studies are needed to define clearly the role of ATIII concentrates in patients with acquired ATIII deficiency and heparin resistance during cardiac surgery, and specifically to examine the effect of ATIII supplementation on bleeding and thrombotic complication rates.

Use of newly developed antithrombotic agents may be useful when heparin cannot be used (eg, heparin-induced thrombocytopenia with thrombosis) or as adjuncts to decrease consumption of coagulation factors and platelets by overcoming the inability of heparin to completely inhibit clot-bound thrombin [80] and platelet-bound Va/Xa activity [97]. Major limitations of routine use of any new agent include a long pharmacodynamic half-life in the setting of no reversal agents, insufficient investigations regarding safety, inadequate definitions of therapeutic levels, and lack of appropriate monitoring strategies.

Heparin analogues or derivatives such as dermatan sulfate [98], low–molecular weight (LMW) heparin (eg, enoxaparin, dalteparin) [99–101], or the heparinoid Orgaran (Org 10172, Organon Teknika, Oss, The Netherlands) that consists of heparan, chondroitin, and dermatan sulfate [102, 103] can decrease activation of the hemostatic system by inhibiting thrombin and factor Xa. Dermatan sulfate predominately inhibits thrombin. Low–molecular weight heparin preferentially inhibits factor Xa but also inhibits thrombin to a lesser extent, whereas Orgaran inhibits both thrombin and factor Xa to the same extent. Low–molecular weight heparin inhibits thrombin minimally, and both LMW heparin and Orgaran are neutralized incompletely by protamine, limiting the clinical usefulness of these agents. In fact, the lack of reversibility has led to excessive blood loss after CPB in patients who have received either LMW heparin [99–101] or Orgaran [102, 103]. New agents such as heparinase [86], recombinant platelet factor 4 (rPF4) [104], and protamine derivatives [105] have been shown to reverse LMW heparin. Monitoring the antithrombotic properties of LMW heparin and Orgaran during CPB can be difficult; however, assays such as the Heptest that directly assesses anti-Xa and anti-IIa activity may be useful.

Defibrinogenating agents such as ancrod (Knoll Pharmaceuticals, Mt Olive, NJ) [106] have been used instead of heparin in patients with HIT; however, blood loss has been excessive because fibrinogen must be replaced before clotting can resume [106]. New whole-blood fibrinogen assays may be useful when defibrinogenating agents are used to confirm therapeutic hypofibrinogenemia during CPB and restoration of levels after CPB [107].

Newly developed, direct thrombin inhibitors such as bivalirudin, recombinant hirudin, argatroban, thrombin inhibitor peptide, or polypeptide aptamer, which do not require ATIII or heparin cofactor II to inhibit even clot-bound thrombin (Fig 6), can circumvent some of the limitations of heparin and may be useful in patients with HIT. The direct thrombin inhibitor r-hirudin or lepirudin (Refludan, Hoechst Marion Roussel, Kansas City, MO) has been suggested as an alternative anticoagulant for patients with HIT requiring cardiac surgery. Although bleeding complications can potentially result from its potent binding of thrombin, especially in the setting of reduced renal clearance [108] and lack of currently available reversal agents, r-hirudin has been used in a few patients without major bleeding complications [109–111]. Concurrent use of a platelet inhibitor may be required for patients whose anticoagulation regimens during CPB involves use of direct thrombin inhibitors because these agents do not directly inhibit platelets. This is illustrated by the marked decrease in platelet function during CPB in 2 patients who received recombinant hirudin [109]. The ecarin clotting assay, a clot-based method that uses a prothrombin-activating snake venom derivative, may be a reasonable monitoring method; however, additional studies are needed prior to routine use of this assay to monitor anticoagulation during CPB. Both ecarin clotting time and activated partial thromboplastin time (APTT) values have been used to monitor clotting in patients who received hirudin [109, 112]. A poor correlation between r-hirudin concentration and both ACT and APTT values was observed in one recent study, but a good correlation was observed between r-hirudin levels and ecarin clotting time values [113].



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  		Fig 6. Inhibition of thrombin activity. Left panel depicts normal physiologic inhibition of fluid phase thrombin by high molecular weight (HMW) heparin molecules and the limitations of heparin in inhibiting clot-bound thrombin. The thrombin molecule has three major binding sites: the fibrinogen binding site (Exo I); the fibrinogen catalytic site (Cat Site); and the fibrin binding site (Exo II). After binding of heparin to the ATIII molecule via a critical pentasaccharide sequence, a conformational change in the C-terminal portion of the ATIII molecule is induced. Inhibition of the thrombin molecule requires heparin molecules with a critical oligosaccharide chain length of 18 units that serve as a template for the binding of antithrombin III (ATIII) with thrombin. However, thrombin inhibition via the ATIII-heparin mechanism is limited by availability of the Exo II site which can also be occupied by fibrin. Although low molecular weight fractions (LMW) of heparin induce a conformational change in the C-terminal portion of the ATIII molecule, they cannot serve as a template for ATIII and thrombin due to their short chain length. The right panel depicts the normal inhibition of clot-bound thrombin by the heparin cofactor II (HCII) - heparin complex and the sites of action of various direct thrombin inhibitors. A minimum chain length of six units for the heparin oligosaccacharide is required to activate HCII however 20-24 unit chain lengths result in a substantially greater thrombin inhibition via HCII. Direct thrombin inhibitors such as hirudin and hirulog bind to both the Exo I and catalytic sites of the thrombin molecule. In contrast, polypeptide aptamers and hirugen bind to the Exo I site whereas PPACK and argatroban bind to the fibrinogen catalytic site of thrombin. (As modified from Tollefson D, et al. Thromb Hemostas 1995;96:120-129. Reprinted with permission).

 
Another new agent, pentosanpolysulfate, was recently used as a heparin alternative during CPB [114], and ACT was used for monitoring this agent. New inhibitors of other factors within the intrinsic (eg, tick anticoagulant peptide, antistatin) [115] and tissue factor [116] pathways are being developed and may be useful in decreasing activation of the hemostatic system during CPB.


   Conclusion
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 Footnotes
 Abstract
 Introduction
 Pathophysiology of excessive...
 Attenuation of hemostatic system...
 Conclusion
References
 
Numerous strategies and interventions can reduce hemostatic activation during cardiac surgical procedures using CPB. This results in less consumption of clotting factors and better preservation of platelet function. Prophylactic administration of agents with antifibrinolytic, anticoagulant, and possibly antiinflammatory properties can decrease blood loss and the need for transfusion. The ability to reduce blood product transfusions and to decrease both operative times and reexploration rates favorably affects patient outcomes, availability of blood products, and overall health care costs.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Pathophysiology of excessive...
 Attenuation of hemostatic system...
 Conclusion
 References
 
Dr Despotis discloses that he has a financial relationship with Medtronic Blood Management, Genzyme Transgenics, and Bayer Corporation; Dr. Hogue with Bayer Corporation; and Dr Avidan with Medtronic Blood Management.


   References
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 Abstract
 Introduction
 Pathophysiology of excessive...
 Attenuation of hemostatic system...
 Conclusion
 References
 

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