18 Medications for Hemostasis
This chapter will examine specific treatments aimed at correcting coagulopathy and at reducing the requirement for transfusion of blood products by encouraging hemostasis. Although similar, these objectives are not the same. During many types of surgery, in vitro tests may only demonstrate mild coagulation defects, and yet the use of hemostatic medications may reduce blood loss and obviate the need to transfuse red cells.1,2 In the absence of these medications, bleeding itself is often unlikely to be life-threatening. In comparison, severe coagulopathic bleeding is, by its nature, life-threatening. Transfusion of blood products cannot be avoided and the hemostatic medications used are often the blood products themselves. Fundamentally, the equation of risk and benefit is very different in these two situations. In the former case, benefit will occur if the risk reduction associated with the avoidance of blood products is greater than any risk from the medication itself. In the latter case, the use of medications that carry a high risk of causing adverse effects is more acceptable if the aim is to prevent death from uncontrolled bleeding. As an example of this, aprotinin has been largely rejected for use during adult cardiac surgery as a strategy to reduce transfusion,3 whereas use of recombinant factor VIIa (almost certainly a more “hazardous” drug) is still considered appropriate for the treatment of life-threatening bleeding.
Avoidance of transfusion of human blood products seems to be a fundamentally good notion. However, many common ideas about the potential harm of transfusion may be mistaken. A national audit of the serious hazards of transfusion (SHOT) in the United Kingdom reported 3239 adverse events over a 10-year period; this is only 0.013% of all blood transfusions.4 These adverse events were more common in infants, but were only reported in 0.037% of infants given transfusions. The true incidence of events is likely to be more common because of underreporting, though many of these “events” were procedural errors not associated with actual harm. It is clear that the risk of immediate harm directly attributable to transfusion is exceptionally low. The risk of direct transmission of infection (the most feared risk in the public perception) is particularly small; the risk of transmission of HIV from transfusion of blood in the UK is 1 in 5 million, and no child has contracted a viral infection from transfusion in the last 4 years.4 The greatest hazard of immediate harm is of a mistake leading to transfusion of incompatible blood.5 However, subtle negative effects of transfusion on children’s outcomes may be considerably more important.6 Transfusion of blood may lead to deterioration in pulmonary function and immunologic effects that predispose children to infection. In addition, if the objective of transfused red cells is to boost tissue oxygenation by improving oxygen carrying capacity, then transfused blood is less effective than the child’s own blood for this function.7 Additional considerations include the increasing costs of transfused blood products, the logistical difficulties of maintaining a secure blood supply (in both well-resourced and less well developed health systems), substantially greater risks of transfusion (in poorly developed health systems), and the possibility of new, unrecognized infective agents entering the blood supply.
There are 2.3 million transfusions each year (37 per 1000 population) in the UK; 4.2% are given to children under 18 years of age (7.1 per 1000) and 1.7% to infants (52 per 1000). An audit of pediatric blood transfusion from Australia revealed 41% of blood transfused was given perioperatively,8 and blood was transfused during 6.3% of instances of anesthesia. The majority of units were used during heart surgery (58% of perioperative use) while a very small minority, 4% were used during major trauma surgery. Heart surgery (on and off bypass), craniosynostosis surgery, and liver transplantation were all commonly associated with blood transfusion. The epidemiology of major bleeding is less certain. Reports of blood use may be misleading (e.g., neonates undergoing cardiac surgery to correct congenital defects may receive few blood units despite significant bleeding), and blood is also used for purposes such as priming the bypass circuit. Observational studies have reported very heavy blood loss associated with heart surgery in children, with increased (per kg) blood loss in smaller children and more complex surgery.9,10 Cardiac surgery can probably be considered the main cause of major blood loss in children and will account for most severe bleeding events in children less than 1 year of age.
Physiology of Coagulation
The understanding of coagulation has shifted greatly in the last few years. The “traditional” model, which emphasizes the importance of a cascade of proteolytic enzymes has given way to the “cell based” model of coagulation that emphasizes the importance of cellular elements in coagulation and presents coagulation as a complex web of interactions rather than a linear process.11,12
To achieve effective hemostasis, a platelet plug must form at the site of vessel injury. In addition, the procoagulant factors need to remain localized to the injured site to avoid widespread clotting activation. This is achieved through changes at the cell surface and localization of the procoagulant reactions on the surfaces of specific cells. Different cells possess different procoagulant and anticoagulant properties; these are incompletely understood, but platelets and cells bearing tissue factor (TF) are central to the process. Intact endothelium is also vital to normal control of coagulation, as it keeps these different procoagulant components apart and modifies coagulation through expression of inhibitory proteins such as thrombomodulin. The described phases of coagulation are overlapping and involve initiation, amplification, and propagation.12
Initiation
Coagulation is initiated by a membrane-bound lipoprotein called tissue factor. This is usually expressed on subendothelial TF-bearing cells, such as stromal fibroblasts; in the absence of vessel injury it is separated from the vessel lumen. After injury, a complex is formed between TF and factor VIIa (TF/VIIa), which activates factors IX and X. Factor Xa, in association with cofactor Va, forms “prothrombinase” complexes on the surface of the TF-bearing cell, which activates a small amount of thrombin (factor IIa)12 (Fig. 18-1). The purpose of this small generation of thrombin and Xa is to activate platelets and factors V and VIII.
Low levels of IX and X activation occur in the absence of tissue injury without causing clot formation. The process only leads to amplification when damage to the vasculature allows intravascular platelets and a complex formed by factor VIII and von Willebrand factor (VIII/vWF) to adhere to the extravascular TF-bearing cells.11
Amplification
Small quantities of thrombin are generated on the TF-bearing cells. This sets up the subsequent propagation phase, during which thrombin is generated in large quantities (Fig. 18-2). This thrombin has many major functions:
Activation of platelets, exposing receptors and binding sites for clotting factors
Activation of factor XI to XIa13
Activation of factor XIII (fibrin stabilizing factor) and promotion of fibrin crosslinking
Cleaving fibrinopeptides A and B from fibrinogen (forming fibrin)
Propagation
Propagation occurs on the surface of activated platelets that are recruited to the site in large numbers. Activated factor IX (from both initiation phase and provided by factor XI on the platelet) binds to VIIIa. The resultant IXa/VIIIa complex activates factor X on the platelet surface. This factor Xa associates with factor Va and forms the prothrombinase complex. The prothrombinase complex causes a “burst” of thrombin generation to cause clotting via fibrinogen (Fig. 18-3).11
This sequence explains why children with hemophilia bleed despite having a normal TF/VIIa complex; the factor Xa during the initiation phase is broken down by ATIII and TFPI if it dissociates from the TF-bearing cell. It is therefore unable to activate the “burst” of thrombin generation that normally occurs in this propagation phase. The factor Xa needs to be generated on the platelet itself via the IXa/VIIIa complex.11
Of note, an alternative pathway is initiated by contact factors (XII, XI, prekallikrein, and high-molecular-weight kininogen [HMWK]). It is of no physiologic importance in terms of coagulation activation; however, it provides important acceleration loops through feedback activation of factors VIII, IX, and XI14 and is important in fibrinolytic and inflammatory pathways.15
Clot Inhibition
Several indirect systems inhibit thrombin, such as the protein C–protein S–thrombomodulin (TM) and the TFPI systems. Thrombin binds to TM on the surface of intact endothelial cells and can no longer cleave fibrinogen to form fibrin. The TM/thrombin complex is neither able to activate platelets nor activate factors V and VIII. Instead, this complex activates protein C, which binds to the cofactor protein S and inactivates factors Va (on the surface of endothelial cells and platelets) and VIIIa.11,14 TFPI bound to endothelial surfaces can form complexes with factor Xa that inhibit factor VIIa. Thrombin generation is therefore inhibited.14
Fibrinolysis
Fibrinolysis (the breakdown of fibrin into soluble degradation products) is mediated by the proteolytic enzyme, plasmin. Plasmin is formed from an inactive zymogen, plasminogen, which is produced in the liver. This process is controlled by activators and inhibitors. The principal plasminogen activators are tissue plasminogen activator (tPA) and urokinase (uPA). Although overlap exists between the functions of these activators, they have distinct physiologic roles. uPA is primarily involved in a wide variety of extracellular processes, including remodeling of tissues. tPA is the major intravascular activator of fibrinolysis and is discussed in more detail later.16 The main inhibitory proteins are plasminogen activator inhibitor-1 (PAI-1), antiplasmins (α2-PI and α2-macroglobulin), and thrombin activated fibrinolysis inhibitor (TAFI)17 (Fig. 18-4).
As well as cleaving fibrin, plasmin metabolizes a number of other proteins, including the platelet receptor for fibrinogen (glycoprotein IIb/IIIa) and fibrinogen.18 In addition, plasmin accelerates its own production by metabolizing the conversion of single chain plasminogen activators to more active two-chain versions. The action of plasmin on fibrin produces a series of degradation products some of which convey anticoagulant properties; this effect is achieved by preventing polymerization of fibrinogen and by inhibition of platelet function.
tPA is released by vascular endothelium of small blood vessels. Release is increased in the presence of stimuli such as trauma, endotoxins, ischemia, or normal exercise. This effect is mediated via contact activation (through the kallikrein system) and also by a series of other substances, including thrombin. Once released, tPA is rapidly metabolized by the liver with a half-life of approximately 5 minutes.17 Fibrin binds both plasminogen and tPA and greatly accelerates the conversion of plasminogen to plasmin (facilitating its own degradation, but also localizing the process to areas of clot). An alternative mechanism for plasminogen activation by tPA exists through binding to receptors expressed by certain cells (endothelium, white cells and some tumor cells); the importance of this in health or disease is unclear.
Excessive fibrinolysis can directly result from excess production of fibrin, as in disseminated intravascular coagulation. This is termed secondary hyperfibrinolysis and in this context the fibrinolysis is considered beneficial because it prevents widespread vascular occlusion. Therapy is directed at replacement of consumed clotting factors, inhibition of excessive coagulation, and treatment of the underlying cause. Primary hyperfibrinolysis can occur during cardiac bypass, massive blood loss, trauma, and liver transplantation.19 During the anhepatic stage of liver transplant surgery, there is hyperfibrinolysis because of failure to metabolize tPA. On reperfusion of the liver, a further surge of tPA occurs that can take several hours to return to normal. In coagulopathic patients, reduced thrombin formation may lead to reduced production of TAFI (important in inhibition of membrane bound plasmin), whereas conversion of single- to two-strand tPA by plasmin may further sustain the process. Individual susceptibility is likely to be important and may have a genetic component.20,21
Two groups of drugs are used clinically to inhibit fibrinolysis:
Synthetic lysine analogues are fairly specific inhibitors of plasminogen activation, working by competitively binding to lysine-binding sites on the plasminogen molecule (Fig. 18-5). This blocks the binding of plasminogen to fibrin; a required step for the conversion of plasminogen to plasmin by plasminogen activators.22 At larger doses, they may have additional effects through direct inhibition of plasmin; this includes inhibition of the plasmin mediated effects on platelets.
Aprotinin is a less specific inhibitor of proteolytic enzymes; it has actions on the kallikrein–kinin (contact) system, as well as enzymes involved in coagulation and fibrinolysis. In addition, aprotinin may be associated with greater preservation of platelet function, as well as an antiinflammatory effect. This wider spectrum of effects from aprotinin may have additional benefits over the antifibrinolytic lysine analogues. Some additional effects may not necessarily be of benefit; for example, the contact system may have protective effects against ischemic reperfusion injury that are inhibited by aprotinin.15
Developmental Coagulation
The hemostatic system in the neonate rapidly matures towards that of the adult (see also Chapter 9).23–25 One must consider how the coagulation system matures in the child to interpret coagulation tests and use appropriate modalities to manipulate hemostasis in vivo.
All fetal coagulation factors are produced independently of the mother; fibrinogen starts to be formed as early as 5.5 weeks gestation, and blood can clot at 11 weeks. The introduction of microassays in the 1980s allowed for the determination of reference ranges for the coagulation factors beginning at 19 weeks gestational age.14,23,24 In general, there are four fundamental differences between the coagulation systems in the infant and the adult26:
Concentrations of components of the hemostatic system
The turnover rate of various components of the coagulation cascade
Differences in the overall ability to generate and regulate the key enzymes: thrombin and plasmin
Despite the upregulation of coagulation factors at birth, the vitamin K–dependent factors II, VII, IX, and X in the neonate are only 50% of adult values; this leads to a slightly prolonged prothrombin time (PT) or international normalized ratio (INR).14 The contact factors HMWK, prekallikrein, and factors XI and XII are also approximately 50% of adult values.14,26 The reduced contact factors account for a disproportionally prolonged activated partial thromboplastin time (aPTT). The reduced concentration of factors at birth is probably explained by the reduced synthesis of factors by the liver; however, concentrations increase rapidly, reaching approximately 80% of adult values by 6 months of age.14,27
In contrast, the plasma concentrations of fibrinogen and factors V and VIII at birth are similar to those in adults, although the fetal form of fibrinogen differs in structure from that of the adult. The physiologic significance of this is not clear.28 Concentrations of vWF in the first 2 months of life are greater than those in adults.29
The inhibitor systems of coagulation also differ from adults. At birth, plasma protein C and S are 35% of adult values, although the fetal forms of the proteins differ from the adult forms. The concentration of protein C does not reach adult values until adolescence. Neonatal concentrations of ATIII and HCII are 50% of adult values; they reach adult concentrations by 6 months of age. The α2-macroglobulin value, however, is increased at birth and remains increased throughout childhood; it is postulated that this may be one of the mechanisms that protects young children from thromboembolic complications.30
Finally, thrombin generation in vitro is reduced in children to approximately 75% of adult values,30 but there is difficulty in interpreting the apparent discrepancy between the sufficient hemostasis seen in vivo and these in vitro laboratory thrombin generation assays. It still remains to be clarified whether neonates and children are more susceptible to bleeding14; however, the risk of thromboembolic complications appears to increase with age.30
Despite reduced plasma concentrations of many procoagulant and anticoagulant proteins in infants, there still appears to be an effective hemostatic balance; healthy fetuses, neonates, and children do not suffer excessive hemorrhage in the presence of minor challenges. This is consistent with the thromboelastogram (TEG) studies of healthy children younger than 2 years of age; no defects in coagulation were noted using this test compared with adults, indicating an intact hemostatic system.31 Another TEG study reported that infants younger than 1 year of age with complex congenital heart disease have an intact and balanced coagulation–fibrinolytic system but at a “lower level” than healthy children. This has been interpreted as a reduction in hemostatic potential with less reserve.32
Genetics of Bleeding
The hemophilias are a group of genetic diseases that cause excessive bleeding, often in response to minor trauma. von Willebrand disease and hemophilia A are the most common variants (see also Chapter 9), associated with low levels of von Willebrand factor and factor VIII respectively. A wide range of single gene defects resulting in deficiencies of single clotting proteins or regulatory proteins have now been described. A further group of single gene disorders may result in thrombophilic disorders, associated with abnormalities of inhibitory proteins.
Unexplained variation has been observed in bleeding between apparently similar patients in the absence of specific factor deficiency. The causes of this variation are likely to be multifold according to nuances of surgical technique and subtle difference in disease process and therapy. It might appear counterintuitive that genetic factors have a significant role in acquired bleeding resulting from surgery; however, recently there has been increased interest in the interplay of genetic and environmental factors in the progress of acquired diseases. The genetics of most clotting proteins has been described, and common variations within populations have been revealed for some. Of these, a common polymorphism of PAI-1 has been well described. PAI-1 is an important endogenous inhibitor of fibrinolysis, and deficiency is associated with increased bleeding.33 The G5/G5 polymorphism is common (about 20% in European populations) and is associated with lower levels of PAI-1. It has been linked (though not consistently) to bleeding after heart surgery and to increased benefit from use of antifibrinolytics.20,21 Should these findings be substantiated, then PAI-1 may still be an exceptional example. In general, the influence and consequences of genetic determinants of bleeding are likely to be more subtle. In infancy an additional factor in the mix may be the relationship between developmental and genetic factors. Many clotting proteins are present in infants as isoforms distinct from those in adults. This implies a different gene expression in the young. It is possible that understanding genetically determined variations in bleeding will increase our understanding of bleeding and, perhaps, allow us to guide therapy for the individual patient. The practical applications of such techniques, however, remain speculative.
Coagulopathy and Major Surgery
Coagulation changes during major surgery and bleeding are complex34 and depend on the clinical context in which bleeding occurs. Coagulation changes that occur in surgical patients have some similarities to those who present after severe trauma; however, the balance of pathophysiologic factors is likely to be very different. The factors underlying these coagulation changes include:
Dilution. Components of the coagulation system are lost in shed blood. The volume of blood lost is then replaced by crystalloid, colloid, or blood products lacking these components, leading to progressively smaller concentrations of these coagulation components. To some degree such changes are balanced, as the concentration of coagulation inhibitors also falls. In addition, coagulation components may be produced or released in response to trauma, which limits the reduction in concentration. To complicate this issue, a reduction in the concentration of one component of the coagulation system may not have the same clinical effect as the same reduction of another component. For example, substantial decreases in the concentration of many clotting proteins will not result in severe bleeding, while even modest decreases in platelet numbers or in the fibrinogen concentration may be significant (see also Chapter 10).
Physiologic derangement associated with blood loss. Acidosis, hypothermia, and hypocalcemia are associated with excess bleeding.35 Hypothermia will result in a general slowing of proteolytic enzyme activity, reduced fibrin synthesis, and reduced platelet function. These effects are largely reversible on rewarming. Acidosis is associated with a marked reduction in activity of coagulation proteins.36 These effects are not fully reversed by correcting acidosis. The degree to which coagulation changes reflect acidosis itself or reflect other underlying factors is unclear. During major bleeding, calcium ion concentration should be monitored and replaced as needed.
Effects of treatment. The use of some synthetic colloids may worsen bleeding to an extent greater than might be expected by dilution. The use of hydroxyethyl starch leads to increased risk of coagulation abnormalities and of acute kidney injury when compared to albumin, gelatins, or crystalloids. Whether differences exist in coagulation effects between different starches is controversial.37–39 Caution should be exercised in the use of starches in children at risk of coagulation problems, and in larger volumes.
Use of specific techniques during surgery. The important effects of cardiac bypass and anticoagulation are discussed later. Liver transplant surgery (see also Chapter 29) and major trauma (see also Chapter 38) are discussed in detail elsewhere in this book.
Alterations in Hemostasis during Pediatric Cardiac Surgery
Routine Anticoagulation
Heparin
Heparin remains the most effective anticoagulant used to facilitate cardiopulmonary bypass (CPB).40 The binding of heparin to lysine sites on ATIII causes a conformational change in ATIII. This results in an increase in ATIII potency; the inhibition of thrombin and factors IXa, Xa, XIa, and XIIa are increased by a factor of 1000.41,42 In infants ATIII levels are low until 3 to 6 months of age and other heparin cofactors, in particular, α2-macroglobulin may have greater importance. However neonates requiring surgery for congenital heart disease have unusually reduced concentrations of all major heparin cofactors, and this may explain the greater concentrations of thrombin production in these patients.43
There are limitations to the use of the ACT; first, the ACT is altered by hypothermia, hemodilution, platelet activation, activation of the hemostatic system, and aprotinin therapy.44,45 Accordingly, it does not accurately reflect the heparin concentrations. One study found that as soon as children go on CPB, the heparin concentrations decreased by 50% as a result of hemodilution, even though the ACT doubled.46 Second, in the bleeding child, the ACT is unable to differentiate between bleeding resulting from excess heparin or from other acquired hemostatic defects.46 The gold standard for measurement of heparin concentration is considered to be the antifactor Xa assay; however, this test remains too cumbersome for routine clinical use. A further method is protamine titration, which has been available as a point-of-care test for some years (Medtronic Hepcon HMS Plus, Medtronic, Minneapolis, USA). In adult patients, use of this system has been shown to lead to reduced thrombin formation47; however, the accuracy of the device has been questioned.48 Reduced bleeding and reduced thrombin generation in children has been demonstrated with the use of this system, whereas other studies have demonstrated reduced thrombin formation22,49 in infants. A trial in small infants was terminated early when increased bleeding and increased length of stay was demonstrated in children in whom the Hepcon device was used.49 The device underestimated heparin concentration in this group, leading to excess dosing of heparin and inadequate reversal with protamine. After modification of their protocol, use of the device demonstrated reduced bleeding, length of stay, and reduced thrombin formation compared to standard treatment.49 Agreement between protamine titration, measures of heparin concentration, and laboratory measures has been demonstrated, but the Hepcon devices tended to underestimate heparin concentrations in infants.50
A common feature of the pediatric studies using the Hepcon device is increased heparin use compared to regimes based on units/kg dosing or ACT. This is consistent with other studies of traditional dosing regimes. Using common pediatric heparin regimens (300 units/kg before CPB, then 100 units/kg to keep the ACT above 450 sec), 50% of children on CPB had low levels of heparin (less than 2 units/mL).46 It is suggested that reduced heparin concentrations during CPB is a major factor responsible for activation of coagulation and fibrinolysis. It is likely that widely used regimens for dosing of heparin in children lead to inadequate dosing, and that units/kg dosing fails to allow for important pharmacokinetic (PK) and pharmacodynamic (PD) differences in children.
Even effective dosing of heparin does not completely abolish the production of thrombin. Low-grade ongoing thrombin production leads to ongoing activation of the coagulation cascade, platelets, fibrinolysis, and the endothelium. The continued thrombin generation and activity during CPB reflects the inability of the heparin–ATIII complex to inactivate fibrin-bound thrombin or to inhibit thrombin-induced platelet activation.51 Theoretically, direct thrombin inhibition may be free of these limitations. Practically, the use of the current generation of thrombin inhibitors (such as hirudin and bivalirudin) is limited because of a lack of effective monitoring and reversal. Currently few reports exist of the use of hirudin in children, although it would be indicated in children in whom heparin use is not possible.52
Reversal of Anticoagulation with Protamine
Protamine is a positively charged polypeptide derived from salmon sperm. It neutralizes heparin by forming an ionic bond with heparin. The resultant complex is removed by the reticuloendothelial system. The most appropriate dosing regimen has yet to be determined. Current dosing used in pediatric practice fails to take into account the range of concentrations of heparin that occurs in infants and children.40,49 The administered heparin dose is often used to guide the dose of protamine; however, it is unclear how this should be modified by various factors, such as additional doses of heparin administered (to prime or during bypass), duration of bypass, techniques (e.g., ultrafiltration), or developmental coagulation differences in children.53
Excessive protamine has been associated with catastrophic pulmonary hypertension and hemorrhagic pulmonary edema. It is also known that protamine can be associated with coagulation abnormalities; an increasing ACT occurs at a protamine-heparin ratio of 2.6 : 1, and platelet aggregation occurs with a minimal excess in protamine.54 Although some studies on titrating protamine regimens in adults demonstrated encouraging results in terms of reduced bleeding,55 others failed to demonstrate differences in transfusion requirements.56
The clearance of protamine is greater than that of heparin, and “heparin rebound” is described as tissue-bound heparin redistributes.40 The diagnosis of residual heparin effect or heparin rebound is challenging. The ACT is not a specific measure of excessive heparin and is also poor at detecting heparin at low concentrations (less than 0.5 unit/mL).57 The aPTT and PT are similarly nonspecific and may be increased after CPB in the absence of heparin.58 An unmodified TEG does not reliably detect heparin rebound if the heparin concentration is small.59 The sensitivity of these tests may be improved by performing similar tests in parallel and comparing the results, such as a reptilase time (unaffected by heparin), or by eliminating residual heparin in vitro with heparinase or protamine. Protamine titration can be used to guide protamine dose in children; however, in infants protocols will require modification (50% higher than calculated dose).49 In practice most anesthesiologists continue to give protamine empirically at a protamine-heparin ratio of between 1 and 1.3 to 1.
Failure of Hemostasis Associated with Cardiac Surgery
Complex abnormalities occur in the coagulation system in cardiac surgery, owing to the profound surgical insult, hypothermia, acid-base disturbance, blood transfusion, anticoagulants, CPB (contact activation, platelet dysfunction, and hemodilution), and in some cases, deep hypothermic cardiorespiratory arrest. In addition children and infants with congenital heart disease may have preexisting coagulation defects or be taking medications that affect coagulation before surgery (Table 18-1).
TABLE 18-1 Causes of Excessive Bleeding after Pediatric Cardiac Surgery
Antiplatelet drugs such as aspirin or clopidogrel may exacerbate bleeding. The clinician must balance the risk of perioperative bleeding against the risk of drug discontinuation when deciding if and when to withhold the drug before surgery. In most cases aspirin can be safely discontinued 5 days before surgery. Prostaglandin E1 can inhibit platelet aggregation, acting in synergy with endothelial cell–derived factors (nitric oxide and prostacyclin) at clinically relevant concentrations,60 although this effect was too subtle to detect in vitro using the TEG.32 It is usually not possible to stop the prostaglandin E1 infusions, because neonates are dependent on its use to maintain ductal patency. For elective surgery in children on oral anticoagulant therapy, it is usually possible to transfer to heparin before surgery. An INR of less than 1.5 is usually considered acceptable for surgery. If urgent correction of anticoagulants is required, prothrombin complex concentrates, together with vitamin K, are more effective than FFP.61 FFP should only be used if prothrombin complex concentrates are not available.
In the child with cyanotic congenital heart disease, hemostasis is further impaired because of polycythemia, low platelet count and altered function, reduced factors V, VII, and VIII, and increased fibrinolysis.32,62 The degree of derangement is related to the degree of cyanosis.63 Preexisting coagulopathy may also occur in children with severe underlying illness or poor nutritional status.
Despite improvements in design and materials of the CPB circuit, abnormal activation of the coagulation and fibrinolytic systems persist. The normal balance of coagulation and fibrinolysis is particularly delicate in children, and more susceptible to exogenous perturbations.64 Shortly after CPB is established in children, all hemostatic protein concentrations are decreased (to a variable degree) as a result of dilution.65 Because of the relative volume of the circuit in relation to the size of the child, it is not surprising that the magnitude of the effect of hemodilution is greater than in adults.46
Reductions in coagulation factor concentrations after cardiac surgery contribute to bleeding in adult cardiac patients,66 and a reduction in platelet count is well described on initiation of bypass. In adults, the platelet count is reduced on CPB by approximately 50%.67 This is also attributed primarily to dilution, although other factors include organ sequestration, mechanical disruption, and adhesion to the circuit.68 A relatively greater reduction will occur in smaller children, although newer combined filter and oxygenators should considerably reduce the circuit volume and, hence, the degree of dilution. Significant platelet dysfunction also occurs.46,69 Low platelet counts have been strongly associated with increased bleeding.10,31,70
Further activation of platelets and denaturing of plasma proteins will occur at interfaces between blood and air, or on contact with extravascular tissue. CPB pump suction and spilling of blood into the pericardium will further contribute to coagulopathy. Greater coagulopathy is also seen during prolonged bypass and when deep hypothermic circulatory arrest is employed.71
The major mechanism for activation of the coagulation cascade during CPB is thought to be the “extrinsic” TF pathway, which is activated as a result of surgical trauma and inflammation.42,72,73 Inflammatory mediators such as tumor necrosis factor (TNF) and interleukin-1 induce expression of TF on endothelial cells and monocytes. The “intrinsic” coagulation system is also activated when factor XII is adsorbed onto the surface of the CPB circuit, causing activation of complement, neutrophils, and the fibrinolytic system via kallikrein.42 Although the intrinsic system has little role in initiating coagulation, activations of kinins will lead to increased fibrinolysis and inflammation.15
The blood loss in the first 24 hours after cardiac surgery can vary between 15 and 110 mL/kg, although the risk of excessive blood loss is greatest among those weighing less than 8 kg, younger than 1 year of age, and children undergoing complex surgery.10 The common preoperative and intraoperative risk factors for excessive bleeding are summarized in Table 18-2.
| Preoperative | Intraoperative |
|---|---|
| Age <1 year or weight <8 kg | Individual surgeon |
| High hematocrit | Complex surgery |
| Congestive heart failure | Low platelet count during CPB |
| Repeat sternotomy | Prolonged CPB |
| Congenital and preoperative acquired coagulopathy | Duration of hypothermia on CPB |
| Cyanotic congenital heart disease | Deep hypothermic cardiac arrest |
CPB, Cardiopulmonary bypass.
Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery. Anesth Analg 1999;89:57-64.
Blood loss and transfusion requirements in pediatric cardiac surgery vary inversely with age; neonates bleed more and receive more products per kilogram than any other age group.74 There are some correlations between coagulation tests before and during CPB and postoperative blood component transfusion requirements, although the sensitivity and specificity of the tests are not sufficient to justify routine coagulation tests while on CPB. Of all the tests, a platelet count of less than 108,000/mm3 while on CPB yielded the greatest sensitivity (83%) and specificity (58%) for predicting excessive blood loss.70
Medications Used for Hemostasis
The pathophysiology of coagulopathies and bleeding in children during surgery are complex, and the etiology is multifactorial (see Table 18-1). No single blood component or drug treatment can reverse the abnormal clotting profile. Initially an attempt should be made to identify causes of bleeding that can be remedied by surgical interventions. The anesthesiologist should attempt to ensure adequate reversal of heparin and restore normal physiologic variables, such as body temperature, serum [Ca2+], and acid-base balance. In the postoperative period, platelets, and other blood products, such as fresh frozen plasma (FFP) and cryoprecipitate, remain the mainstay of treatment for excessive bleeding.75 Blood products (see also Chapter 10) are briefly discussed here, primarily within the context of pediatric heart surgery.
Blood Products
Frequently it is necessary to administer blood products on a largely empirical basis; laboratory tests describe only parts of the coagulation process32 and are practically too slow to direct the anesthesiologist in real time as to the requirement for blood components. The TEG is a dynamic whole-blood test that is frequently used as a near-patient test to assess clot elasticity properties and, hence, more precisely delineate the bleeding and homeostasis profile. The role of TEG during pediatric heart surgery has been recently reviewed.76 The use of treatment algorithms based on TEG can limit transfusion of blood products in adults77–81 and children.82 In children, it may not be appropriate to use protocols originally designed for adults. An alternative approach has recently been proposed.76
