Ann Thorac Surg 2006;81:S2360-S2366
© 2006 The Society of Thoracic Surgeons
Supplement
Coagulopathy and Inflammation in Neonatal Heart Surgery: Mechanisms and Strategies
James Jaggers, MD
a
,
*
,
Jeffrey H. Lawson, MD, PhD
b
a Department of Pediatric Cardiothoracic Surgery, Duke University Medical Center, Durham, North Carolina
b Division of Vascular Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
* Address correspondence to Dr Jaggers, Department of Pediatric Cardiothoracic Surgery, Duke University Medical Center, Durham, NC 27710. (Email: Jagge003{at}mc.duke.edu).
Presented at the Symposium on Harnessing the Effects of Neonatal Cardiopulmonary Bypass at the Fourth World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, Sept 21, 2005.
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Introduction
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Open cardiac surgery has enjoyed significant improvement in outcome during the last several years. Complex heart defects once considered fatal are now readily addressed with low mortality. However, repair of these defects requires the use of cardiopulmonary bypass (CPB), which results in significant alteration of normal homeostatic mechanisms. Normal hemostasis reflects a highly complex interaction between endothelial cells, platelets, local and systemic inflammatory mediators, and coagulation factors [1, 2]. The inflammatory and coagulopathic complications are manifest as diffuse capillary leak syndrome, coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects [3]. Clinical experience reinforces that these adverse effects seem to be more pronounced in neonates and young infants as compared with older children. In this review we will discuss the pathophysiology of coagulation in neonates and small infants undergoing open cardiac surgical repairs and discuss existing and potentially strategies directed toward limiting coagulopathy.
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Normal Hemostasis in Neonates and Infants
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At birth, concentrations of the vitamin K–dependent clotting factors (FII, FVII, FIX, and FX) and contact factors (FXI and FXII) are reduced to about 50% of normal adult levels, and natural anticoagulant and inhibitory factors (antithrombin III, protein C, protein S, CI esterase inhibitor, and plasminogen) are similarly reduced [4]. This may be a result of decreased hepatic synthesis and accelerated clearance caused by increased metabolic rates [5]. There may also be a functional immaturity of the normal mechanisms of coagulation factor binding in neonates. In adults, coagulation remains intact with factor levels as low as 30% for all factors except factor V, which requires only 15% of normal levels for normal function [6]. In neonates functional integrity of the coagulation system is also preserved in the presence of decreased factor levels as measured by thromboelastography [7]. Because healthy term and premature infants do not develop spontaneous hemorrhagic or thrombotic complications, the collective balance of both coagulant and inhibitory factors may be considered hemostatic.
The inflammatory cascades and the coagulation cascades are interrelated and interdependent [8]. These systems function through means of a complex interaction of proteases, tissue factor activation, thrombin generation, and fibrinolysis. Many components of the coagulation pathways including thrombin, Xa, and VIIa have either direct or indirect inflammatory properties. Vascular endothelial cells perform a pivotal role in mediating responses to systemic inflammation and associated coagulopathy [9, 10]. Endothelial cells are able to express adhesion molecules that result in neutrophil and platelet adhesion, migration, and degranulation. Activated endothelial cells also express tissue factor that results in activation of the extrinsic pathway of coagulation. It is widely accepted that the extrinsic coagulation pathway involving tissue factor expression and thrombin generation is the biologically relevant process by which hemostasis is achieved [11] (Fig 1).
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Fig 1. Activation of the extrinsic coagulation pathway is initiated by the expression of tissue factor (TF) at the endothelial cell. This expression results in formation of the TF/factor VIIa complex, which stabilizes the active site of factor VIIa. This results in the conversion of factor IX to factor IXa and subsequently factor X to factor Xa. Then, in the presence of activated cell membrane and calcium, the prothrombinase reaction occurs in which factor Xa catalyzes the conversion of factor V to factor Va and subsequent prothrombin (factor II) to thrombin (factor IIa). (Reprinted from [22] with permission.)
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Coagulopathy and Cardiopulmonary Bypass
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Coagulopathy and bleeding after surgical repairs on neonates and young infants is a serious problem and results in multiple transfusions, lung injury, increased intensive care unit stays, and mortality. Studies regarding the coagulopathic effects of CPB in neonates and infants are remarkably few. Multiple factors affect the delicate balance of coagulation, hemostasis, and inflammation in neonates and small infants (Table 1). Cyanotic infants may be particularly impaired secondary to polycythemia, low platelet count and abnormal platelet function, decreased concentrations of factors V, VII, and VIII, and increased fibrinolysis [12]. Functional tests such as bleeding time and platelet contractile force are altered after CPB [13, 14]. Williams and colleagues [15] found that platelet counts dropped to an average of 48,000/µL, and fibrinogen dropped to 85 mg/dL, levels that are significantly lower than normal prebypass levels. In this study, preoperative risk factors for postoperative bleeding were activated partial thromboplastin time of 49 seconds or greater, thromboelastography 
of less than 34 degrees, platelet count less than 190,000/µL, and hematocrit of 45% or greater. Thrombocytopenia seems to correlate with the degree of hemodilution and is more profound in infants and neonates. Platelet dysfunction during and after 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, platelet factor 4, ß-thromboglobulin, adenine nucleotides, and guanosine nucleotides.
Cardiopulmonary bypass does result in an inflammatory response. This response is well characterized by other authors in this section. One of the sites of biologic activity of this inflammation is at the level of the endothelial cell. In response to cytokines, ischemia, abnormal shear stresses, activated platelets, and other stimuli, tissue factor is expressed on the endothelial cell surface. Tissue factor expression results in FXa activation and ultimately thrombin generation [16]. Indicators of thrombin formation (prothrombin fragment 1.2, fibrinopeptide A, thrombin–antithrombin III complexes) have been shown to be elevated at the end of CPB in neonates, and this coagulopathy persists for up to 3 days postoperatively. Neither heparin concentrations, antithrombin III levels, nor activated clotting time values appear to be correlated with thrombin generation [17]. Thrombin levels increase within minutes of the onset of CPB [18, 19]. Levels of tissue plasminogen activator are elevated in neonates during CPB, and levels of plasminogen activator inhibitor have been found to be elevated after CPB [20, 21]. Tissue factor activity has also been shown to be elevated 4 hours after CPB and again at 24 hours after CPB [22]. The findings of increased extrinsic pathway activity and increased plasminogen activator inhibitor levels after CPB may result in hypercoagulability in neonates and young infants for several hours after surgery.
In addition to its central role in coagulation, thrombin is a powerful inflammatory mediator, chemoattractant, and activator of mast cells [23, 24]. Thrombin is a potent activator of endothelial cells, promoting the expression of adhesion molecules and causing neutrophil adherence, activation, and ultimately neutrophil-mediated damage [25]. Thrombin, VIIa, and Xa all appear to exert their action through interaction with the protease-activated receptor (PAR) family to stimulate cells to express cytokines such as interleukin (IL)-1 and IL-6, chemokines such as IL-8 and monocyte chemotactic protein-1, and adhesion molecules such as P-selectin, E-selectin, and intercellular adhesion molecule-1. This secondarily can trigger local accumulation of leukocytes and platelets and transudation of plasma [26, 27]. The PAR family currently comprises four members of the G protein–coupled receptor gene family. Protease-activated receptor-1 through PAR4 are widely expressed on platelets and cells of the vasculature. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may contribute to vascular permeability and inflammation. The activation of PAR1 receptors on mast cells provokes histamine, platelet activating factor, and cytokine release (Fig 2).
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Fig 2. Involvement of protease-activated receptor (PAR) family receptors in the regulation of function of cells participating in blood coagulation and inflammation. PAR-1 is expressed on platelets and on endothelial and mast cells. Thrombin activates (1) endothelial PAR-1, leading to the secretion and expression of the mediators of inflammation and anticoagulants (nitric oxide [NO], intracellular adhesion molecule [ICAM-1]); (2) PAR-1 and PAR-4 of platelets, stimulating adhesion and aggregation followed by the activation of blood clotting cascade; and (3) PAR-1 of mast cells, inducing the secretion of proinflammatory (histamine, platelet-activating factor [PAF], and cytokines) and antiinflammatory (NO, heparin) mediators. Factor Xa activates prothrombin conversion to thrombin, and also interacts with endothelium through effector cell protease receptor-1 (EPR-1) and PAR-2 receptors and with mast cells through PAR-2. (Reprinted from [67] with permission.)
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Contact of blood elements with the artificial surfaces of the bypass circuit also results in activation of the coagulation [28]. High-molecular-weight kininogen, plasma kallikrein, and FXII are grouped together as the contact system. With CPB, contact activation is typically described in a context of negatively charged circuit surfaces. However, contact activation is a misnomer. A negatively charged surface is not necessary for in vivo activation of this system. In fact the contact system can assemble on neutrophil and endothelial cell membranes [29, 30]. The main inhibitors of FXIIa in vivo are C1 inhibitor, 2-macroglobulin, and antithrombin III. Kininogens may have some counterregulatory anticoagulant effect. One mechanism of anticoagulant effect is the ability of kininogen to block the ability of thrombin to activate the PAR1 receptor. Kininogen is also able to inhibit platelet calpain, thus decreasing platelet aggregation.
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Strategy to Prevent Coagulopathic Complications
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Strategies that attempt to limit alterations in coagulation and inflammation are relatively limited. Neonates and small infants are even more so because of their small size and the relatively large surface area of the artificial surface of the CPB circuit. Most centers have done what they can with the existing commercially available technology to miniaturize circuits, decreasing prime volumes. The use of modified ultrafiltration and use of coated circuits may also curb the inflammatory response. Conflict exists whether the use of deep hypothermic circulatory arrest or low-flow hypothermic bypass decreases inflammatory and coagulopathic insults. There are data in children to suggest that the use of high-dose steroids given before induction of operation and in the CPB circuit will decrease the inflammatory response, improve pulmonary function postoperatively, and improve cardiac function [31–33]. There are also data in adult patients undergoing CPB with aprotinin showing that high-dose methylprednisolone results in decreased postoperative blood loss [34]. There is, however, no clear evidence that steroids improve hemostasis in pediatric or neonatal patients.
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Serine Protease Inhibitors
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Serine proteases play a central role in kinin–kallikrein, fibrinolytic-coagulation, and complement systems. Most of the major coagulation factors are serine proteases. Inhibition of the serine proteases provides a therapeutic window in which both inflammation and coagulation may be modified. Although there is new information emerging concerning recombinant serine protease or kallikrein inhibitors (eg, DX88, a Kunitz domain plasma kallikrein inhibitor), aprotinin is the commercially available agent used in clinical practice. Even though aprotinin is generally regarded to be an effective procoagulant agent, it has been suggested to be simultaneously hemostatic and antithrombotic [35]. Aprotinin achieves these two apparently contrary functions by selectively blocking the proteolytically activated thrombin receptor on platelets, while leaving the adenosine diphosphate–dependent platelet aggregation unaffected [36–38]. Aprotinin inhibits intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not E-selectin expression on tumor necrosis factor –activated endothelial cells [39]. Transendothelial neutrophil migration is suppressed under these conditions.
Aprotinin significantly reduces bleeding and transfusion requirements in adults who undergo CPB, but it is of indeterminate value in reducing transfusion in neonates and infants [40, 41]. One possible explanation for this inconsistency is that some aprotinin dosing regimens in pediatric patients do not achieve therapeutic concentrations [42, 43]. In a report by Oliver and colleagues [44], aprotinin was infused through a dedicated central venous catheter. After a test dose, a 25,000 KIU/kg bolus, 35,000 KIU/kg prime, and 12,500 KIU · kg–1 · h–1 continuous infusion of aprotinin was administered. In this study, they found that in the patients weighing less than 10 kg, aprotinin levels were significantly lower at all points when compared with older, larger children [44]. The significance of aprotinin concentrations centers on the fact that in vitro plasma concentrations of aprotinin have been related to antifibrinolytic and antiinflammatory activity at concentrations of 50 to 125 KIU/mL and 200 KIU/mL, respectively [45, 46]. It may be that the antiinflammatory activity associated with kallikrein inhibition occurs at a much higher plasma aprotinin concentration than the concentration necessary for antifibrinolysis [47].
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Effect of Aprotinin on Protease-Activated Receptor Function
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Protease-activated receptor-1 is cleaved by the serine protease activity of thrombin. This results in transmission of G protein–coupled signals into the cell. Platelet dysfunction in CPB is thought to be caused by selective activation of PAR1 after exposure to thrombin generated in the bypass circuit. Aprotinin has been shown to selectively inhibit PAR1-dependent platelet activation in vitro and in vivo [48, 49]. In the report by Day and coworkers [49], inhibition of the PAR1 receptor by aprotinin occurred at levels of 50, 100, and 200 KIU/mL. Blockade of platelet PAR1 by aprotinin does not exacerbate bleeding because platelets maintain their ability to be activated by other stimuli such as collagen and adenosine diphosphate. This minimizes the systemic inflammatory and coagulopathic effect of platelet activation and maintains the local hemostatic effects of platelets at the site of tissue injury.
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Antifibrinolytics
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Fibrinolysis and consumption of coagulation factors is characteristic of coagulopathy and postoperative hemorrhage after cardiac surgery in children. Tranexamic acid and 
-amino-caproic acid are lysine analog antifibrinolytics that have been commonly used in adult cardiac surgery. They inhibit binding of plasminogen and tissue plasminogen activator to the fibrin strand, reducing the amount of plasmin produced and thus decreasing fibrinolysis. In a study by Reid and associates [50], high-dose tranexamic acid (average 250 mg/kg) given as a bolus dose can result in decreased postoperative blood loss and higher fibrinogen levels after repeat cardiac surgery in children. In another study, Chauhan and colleagues [51] found both -amino-caproic acid and tranexamic acid to be equally effective in children with cyanotic heart disease in reducing postoperative blood loss, as well as blood and blood product requirements. There have been no studies focused on neonates and small infants with these agents, and expert opinion would hold that there is minimal benefit to either tranexamic acid or -amino-caproic acid.
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Recombinant Activated Factor VII
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Recombinant activated factor VII (rFVIIa) was developed to prevent bleeding episodes in patients with hemophilia and inhibitors of clotting factor VIII and IX. It acts by creating a supraphysiologic concentration of factor VIIa that saturates tissue factor binding sites and thus results in increased thrombin generation. Recently its use has been described in both adult and pediatric cardiac surgical patients with intractable postoperative hemorrhage [52, 53]. In the study by Egan and associates [53], 6 patients (2 neonates) experienced excessive bleeding after cardiac surgery despite adequate medical therapy and surgical hemostasis. An intravenous dose of rFVIIa (180 µg/kg was given and repeated after 2 hours) was delivered, and hemostasis was achieved in all patients. Although these small, uncontrolled experiences are encouraging, and the use of rFVIIa may reduce the risks associated with postoperative blood loss, repeat sternotomy, and blood transfusions, caution is warranted. Safety and efficacy requirements have clearly not been met, and the potential hypercoagulable state may have catastrophic effects.
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Whole Blood Versus Blood Component Therapy
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In an attempt to deal with the dilutional effects of induction of CPB in neonates and infants, many surgeons insist on the use of whole blood in the pump prime instead of reconstituted whole blood with component therapy (packed red blood cells and fresh-frozen plasma) or asanguinous primes. Proponents of whole blood suggest that hemodilution is limited, platelet counts preserved, and inflammation decreased. There is very little evidence to support this. Some studies have suggested that treating blood loss after surgery in children younger than 2 years of age with fresh whole blood results in decreased transfusion requirement [54]. In a recent article, Mou and associates [55] challenged the accepted convention that fresh whole blood resulted in less inflammatory activation and decreased blood loss after cardiac surgery in infants and neonates. In this study, the use of fresh whole blood did not confer a significant advantage in blood product exposure or cytokine release over priming with component blood products, and in fact, the use of fresh whole blood was associated with prolonged intensive care unit stays, greater total body edema, and a trend toward prolonged ventilation. Thus, the use of fresh whole blood in the CPB machine prime does not seem to confer any advantage over component therapy. There may be some evidence that the use of an asanguinous prime in a miniaturized circuit may result in less inflammatory insult and decrease the dilutional thrombocytopenia associated with larger priming volumes.
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Biocompatible Coating on Circuits
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For many years there has been hope that making the CPB circuitry more biocompatible would result in decreased adsorption of proteins, platelet activation and degranulation, decreased complement and inflammatory mediator activation, and decreased thrombin generation during CPB. Some of the initial hopes were that heparin coating on the circuit might allow CPB to be conducted without systemic heparin and thus may decrease the tendency for bleeding. Coated circuits have resulted in decreased complement activation and decreased cytokine generation. However, none have resulted in prevention of thrombin generation or shown improvement in outcome. Currently three coating processes are available.
The first uses a strategy of biomembrane mimicry. This process incorporates phosphorylcholine into a copolymer methacryloyl-phosphorylcholine/laurylmethacrylate, MPC:LM, which is hydrophilic and referred to as hydrogel. This material is quite stable and resists fibrinogen adsorption [56, 57]. Platelet binding and activation under static conditions is also inhibited. Factor XII activation is also decreased [56]. Clinical testing is in early stages, but has revealed that MPC:LM coating results in decreased complement activation, decreased platelet activation, and decreased thromboxane B2 generation [58]. No data exist that hemostatic mechanisms are preserved.
The second group of biocompatible surfaces is the heparin-coated circuits. The heparin may be ionically bound (Duraflo, Jostra, Germany) or covalently bound (Carmeda Medtronics, Minneapolis, MN). The basis for effect with these systems is that the surface-bound heparin used systemic antithrombin III and resulted in local and systemic anticoagulation. The heparin-coated circuits have been shown to inhibit complement activation, interleukin 8, and monocyte chemoattractant protein [59, 60]. Heparin-coated circuits may prevent the activation of kallikrein by high-molecular-weight kininogen on the surfaces of the circuit. This approach, however, has not resulted in eliminating the need for systemic heparin for CPB as thrombin generation is not prevented.
The third method of biocompatible surfacing uses a method of alternating hydrophobic (polysiloxane) and hydrophilic (polycaprolactone) domains on the blood-contacting surface of the circuit. The two available circuits are X-coating (PMEA Terumo, Tokyo, Japan), and SMARxT (Sorin Biomedical, Mirandola, Italy). By controlling the distance between the domains it is possible for the competing processes at each domain to inhibit one another. This effectively limits protein adsorption. These surfaces have shown a clear effect on limiting the generation of thrombin and fibrinolysis as well as preservation of platelet counts and decreased degranulation [61].
The process of making circuits more biocompatible has progressed remarkably, but inflammation and coagulopathy persist. Thus the need for pharmacologic modulation of the systemic inflammatory response is still necessary.
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New Methods for Coagulation Inhibition
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Heparin is currently the favored and safest anticoagulant in use for the conduct of CPB. However, heparin has multiple adverse effects and inadequately prevents thrombin generation. Platelet function is impaired, and the drug has to be reversed with protamine, which itself is an immunogenic agent and has anticoagulant and inflammatory effects. Heparin also can result in heparin-induced thrombocytopenia, after which heparin therapy is prohibited. Because of this, significant effort is being directed toward developing more targeted anticoagulants.
Potential therapeutic antagonism to coagulation-dependent inflammation includes tissue factor downregulation, tissue factor blockade with active site–inactivated factor VIIa, exogenous tissue factor pathway inhibitor, and PAR blockade [62–64]. Newer anticoagulant agents may provide a more targeted approach to thrombin inhibition. This, possibly combined with contact activation inhibitors, may provide the most logical approach to anticoagulation for CPB.
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Direct Factor Xa Inhibition
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Inhibition of FXa could have profound effects on the generation of thrombin in response to the inflammation associated with CPB. Factor Xa and thrombin have significant inflammatory effects. DX-9065 is the first in a class of small-molecule specific reversible inhibitors of FXa. It is a synthetic nonpeptide amidinoaryl derivative that binds FXa at two sites. This agent effectively blocked the formation of thrombin and was also able to block the FXa in the fully assembled prothrombinase complex [65]. This agent is already in phase II trials in the treatment of acute coronary syndromes. There are currently no studies using this agent as an anticoagulant or antiinflammatory agent for use with CPB.
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Therapeutic Aptamers
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Aptamers are single stranded oligonucleotides that fold into specific three-dimensional structures that enable them to directly bind to and inhibit a protein target. Properties that favor therapeutic use as anticoagulants are that they are highly specific and have high-affinity binding, are nonimmunogenic, and are reversible through an antidote. Two agents are currently in clinical trials. The first agent, a direct thrombin inhibitor termed ARC-183 (Archemix Corp, Cambridge MA), is a very short half-life agent that inhibits both free and clot-bound thrombin. Its effect can be rapidly reversed by cessation of infusion. In vitro analysis of the antithrombin activities of ARC-183 demonstrated that this aptamer inhibits thrombin activity by preventing the thrombin-catalyzed conversion of fibrinogen to fibrin. It was found that this aptamer could prolong clotting times in pure fibrinogen and plasma assays [66]. The second agent is an antidote-controlled, direct factor IXa (FIXa) inhibitor termed REG1 (Regado Biosciences, Inc, Research Triangle Park, NC). Factor IXa in complex with cofactor VIIIa is the catalyst for FX activation. This FIXa aptamer inhibits the cleavage of FX so that thrombin will not be generated by the prothrombinase reaction. Moreover, this aptamer can be reversed by antidote oligonucleotide. Factor IXa is an attractive target because it involves both the initiation and the propagation of the clotting process. The reversibility of this agent makes it attractive for use in CPB.
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Summary
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Surgical results for complex congenital heart disease in neonates and infants have improved steadily during the last 10 years. This has paralleled the explosion of new knowledge regarding the mechanisms of inflammation and coagulation. It is clear that neonates and small infants suffer significantly increased risk of bleeding and secondary transfusion when compared with adults and older children. The derangement in coagulation with resultant bleeding and thrombosis remains a challenge. Serine protease inhibitors like aprotinin may have significant antiinflammatory and platelet-sparing properties via its interaction with the PAR receptors. Despite this, we continue to be limited in our ability to prevent coagulopathy and inflammation secondary to CPB. New agents like direct thrombin inhibitors and therapeutic aptamers may further improve the safety and outcomes of neonatal cardiac surgery.
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Introduction
Normal Hemostasis in Neonates...