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Original Article

Heparin resistance and the potential impact on maintenance of therapeutic coagulation

Despotis, G. J.*,†; Avidan, M.; Levy, J. H.

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European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue - p 37-58
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After almost three decades of relative stability in anticoagulation practice and monitoring for cardiac surgery, recent developments call for review and reconsideration of these issues. Recent publications highlight the diagnosis and management of heparin resistance as well as the use of antithrombin III (ATIII) concentrates to effectively manage this condition. This review describes and interprets the literature on these topics.

Overview of the hemostatic system with cardiac surgery

The hemostatic system limits hemorrhage when vascular integrity is compromised and includes several major components: platelets, von Willebrand factor (vWF), coagulation and fibrinolytic factors and the blood vessel wall. The endothelium normally serves as a protective layer against hemostatic activation. When endothelium is denuded, activated platelets adhere to exposed subendothelium, a reaction largely mediated by vWF, and then aggregate to provide initial hemostasis. Platelets also provide an active phospholipid surface for interaction with coagulation factors. The coagulation system consists of many clotting active zymogens and co-factors, and is subdivided into three pathways (i.e., intrinsic, extrinsic and common) that ultimately lead to formation of a fibrin clot. Tissue factor activates the extrinsic pathway to form fibrin, which stabilizes the hemostatic platelet plug.

Several important physiologic mechanisms counterbalance the propensity of both platelets and coagulation factors to form clot. The physiologic inhibition of coagulation is mostly dependent on intact endothelium and comprises platelet inhibitors, such as prostacyclin (PGI2) and nitric oxide, and endogenous anti-coagulant peptides, such as proteins C and S, antithrombin III (AT III), heparin-cofactor II and tissue factor pathway inhibitor (TFPI). These mechanisms are illustrated in Figure 1. The activity of the most potent prothrombotic molecule, thrombin is substantially limited and localized to the injury site by the potentiation of ATIII by endothelial bound Heparan molecules or circulating heparin. Although thrombin can substantially activate the hemostatic system, lower concentrations of localized thrombin also down-regulate the hemostatic system via multiple mechanisms. Thrombin mediates activation of protein C which, when complexed with activated protein S and endothelial-bound thrombomodulin, converts activated factors V and VIII to inactive forms. Thrombin also mediates release of TFPI, which binds to tissue factor and mediates release of endothelial tissue plasminogen activator (tPA) to activate the fibrinolytic pathway. The fibrinolytic system consists of several plasmatic factors (e.g., tPA, plasminogen) that interact to produce plasmin, which lyses clots and potentially prevents vasocclusion at the site of vessel injury; the fibrinolytic system is regulated by other factors such as plasminogen activator inhibitor (PAI1) which binds tPA and α-1-antiplasmin and thrombin activated fibrinolytic inhibitor (TAFI) that bind plasmin.

Figure 1.
Figure 1.:
Antithrombotic mechanisms. The hemostatic system is under hoemostatic control via a number of mechanisms illustrated in this figure. Under normal physiologic conditions, these anticoagulant mechanisms are recruited to limit hemostatic system activation to site of injury whereas under pathologic conditions such as disseminated intravascular coagulation (DIC) which is generally triggered by systemic circulation of activated tissue factor in certain disease states (e.g. leukemia, ABO-incompatible transfusion, abruptio placentae, systemic hypoperfusion, localized tissue necrosis with splanchnic or limb ischemia etc), these mechanisms play an important role with respect to minimizing the propensity for endothelial injury and/or intravascular thrombosis. Both the extrinsic and intrinsic systems lead to formation of thrombin from prothrombin which is catalyzed predominately on the platelet surface by activated Factors V (FVa) and X (FXa). Thrombin has a major role in promoting hemostasis under normal conditions or leading to thrombotic complications with pathologic prothrombotic disease states. The major clearance mechanism for thrombin involves reticulendothelial clearance after binding to ATIII after this molecule has been altered for high affinity by either circulating heparin or endothelial-bound heparin molecules. Lower concentrations of thrombin activate protein C (PCa) which when bound with activated protein S (PSa) to endothelial thrombomodulin leads to inactivation of activated Factors V (FVa) and VIII (FVIIIa). Lower levels of thrombin also mediate release of tissue plasminogen activator (tPA) which results in conversion of plasminogen to plasmin. Plasmin has several effects which include degradation of fibrin monomers or fibrinogen to fibrin degradation products (FDPs) or cross-linked fibrin to D-dimers, internalization or destruction of adhesive platelet surface glycoprotein receptors (i.e., Gp 1b) and degradation of activated Factors V and VIII. Fibrinolysis is inhibited via three mechanisms in vivo: binding of plasminogen activator inhibitor (PAI1) to tPA or binding of either thrombin-activated fibrinolytic inhibitor (TAFI) or anti-plasmin to plasmin. 13-HODE=, NO=nitric oxide, PGI2=prostaglandin I2, EDRF=endothelial-derived relaxing factor, GAGs=glycosoaminoglycans, C, PC=protein C, IIa=thrombin.

Cardiac surgery with cardiopulmonary bypass (CPB) places patients at risk for excessive perioperative blood loss. This risk is influenced by the type of procedure [1,2] and the duration of CPB [3,4]. Although preexisting [2,3,5] or acquired [6] hemostatic abnormalities occasionally cause excessive perioperative bleeding, more often CPB impairs the hemostatic system which, results in excessive bleeding. Crystalloid or colloid solutions used to prime the CPB circuit and as a component of cardioplegia significantly dilute coagulation factors and platelets [2,7] and excessive activation of the hemostatic system can also consume them. This activation results from stimulation of both the intrinsic [8] and extrinsic [9,10] pathways from blood contact with extracorporeal and pericardial surfaces as well as from the subatmospheric pressure of cardiotomy suction. Excessive fibrinolysis can be triggered by CPB-mediated activation of Factor XII, kallikrein [11] and thrombin, hypothermia [12], retransfusion of tPA that has been released into the surgical field, [13] or intravascular release from injured endothelial cells [14]. Even after ‘complete’ protamine neutralization, heparin can potentially inhibit coagulation [15] and platelet function [16,17]. Similarly, excess protamine can inhibit coagulation [18] and affect platelet function [19-21]. Additionally, elastase release from polymorphonuclear leukocytes [22] and tumor necrosis factor [23,24] may impair hemostasis.

Increased thrombin and plasmin activity are important because they each mediate several reactions. As well as leading to generation of fibrin monomer, thrombin activates factors V, VIII, XIII and platelets. Thrombin-mediated consumption of these factors was suggested recently by inverse relationships between factor V levels and markers of thrombin generation (e.g., prothrombin fragment 1.2: r = −0.57) or activity (e.g., fibrinopeptide A: r = −0.53) at the end of CPB [25]. Despite high doses of heparin during CPB, thrombin and plasmin are generated progressively over time [9,26], as demonstrated by the increasing concentrations of prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complexes (TAT), fibrin monomers [27] and cross-linked fibrin degradation products (e.g., D-dimers) [28,29]. Excessive plasmin activity can lead to platelet dysfunction from fibrinogen/fibrin degradation products (FDP) [16], degradation of factors V, VIII and XIII [30], and, rarely, hypofibrinogenemia [2,31-33]. Plasmin can also either lyse [34] or internalize [35] [772} platelet membrane glycoproteins (GP) (e.g. GP Ib), impair the in vitro response of platelets to various agonists [36] and enhance platelet response to thrombin at lower temperatures [35] (Table 1).

Table 1
Table 1:
Summary of hemostatic abnormalities associated with cardiac surgery involving extracorporeal circulation.

In summary, activation of coagulation and fibrinolysis with consumption of platelets and labile coagulation factors can occur even with standard high-dose heparin-induced anticoagulation [2,3,5]. The consequences of this series of events include microvascular bleeding in the majority of patients and potentially micro or macrovascular thrombosis in a smaller percentage. Patients with excessive bleeding are generally managed with transfusion of allogeneic blood or blood components which are associated with a number of serious adverse events, such as transfusion associated acute lung injury (TRALI), blood-borne disease transmission, increased incidence of sepsis and wound infections and other potentially fatal hemolytic and non-hemolytic transfusion reactions. Most of the patients with excessive bleeding who require re-exploration are found to have one or more acquired hemostatic defects [5,37]. Excessive bleeding can result in re-exploration, a three to four-fold increase in mortality, a variety of complications (e.g. renal failure, sepsis, atrial arrhythmias, prolonged requirement for mechanical ventilatory support) and prolonged hospitalization [37-39]. Two large studies have demonstrated that re-exploration can be associated with various negative outcomes such as an increased mortality, and longer hospital stay [37,38].

Anticoagulation with cardiac surgery: heparin pharmacology and monitoring techniques

Anticoagulation is used during cardiac surgery to prevent overt thrombosis of the extracorporeal circuit and to minimize excessive CPB-related activation of the hemostatic system which may result in either bleeding (i.e., as related to consumption of coagulation factors and platelets) and/or thrombotic (i.e., as related to thrombin mediated platelet and coagulation factor activation) complications.

Unfractionated heparin: mechanisms of action and pharmacokinetics

Heparin is routinely used because it is effective, immediately reversible, generally well-tolerated and inexpensive. Heparin is a highly sulfated polysaccharide polymer that is composed of sugar molecules chemically linked to form a long chain polymer. Heparin is isolated from natural sources, either from porcine intestines or from beef lungs (although beef lung derived heparin has almost been discontinued because of the fear of bovine spongiform encephalitis). In these tissues, the heparin polysaccharide is attached to cell membranes of the tissue by protein linkages. The heparin polysaccharide and this linking protein are removed from the tissue by various extraction procedures. These purification procedures lead to various chain lengths of the heparin polysaccharide, not all of which have anticoagulant activity. The procedures for extracting pharmaceutical heparins are not well defined and are responsible for many of the problems noted with unfractionated heparins.

Unfractionated heparin (UFH) is a polysaccharide mixture of low and high molecular weight fractions (i.e., molecules ranging from 1,000-50,000 daltons) that differ functionally. Fractions with a minimum chain length of 18 oligosaccharide units and a molecular weight of approximately 4500 daltons or higher preferentially inhibit thrombin (i.e., factor IIa) [40]. Oligosaccharide chain length is important because thrombin inhibition requires simultaneous binding of thrombin and ATIII by heparin, which acts as a template (Fig. 2). A minimum chain length of 6 oligosaccharide units is essential for heparin to catalyze the inhibition of thrombin by heparin cofactor II, another important in vivo inhibitor of the hemostatic system (Fig. 2). However, inhibition (e.g., 10 000 fold increase inhibition) of thrombin via heparin cofactor II is optimal with a chain length of 20-24 oligosaccharide units [41]. The ability of heparin cofactor II to inhibit clot-bound thrombin may be important during CPB [42,43].

Figure 2.
Figure 2.:
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: 1. the fibrinogen binding site (Exo I), 2. the fibrinogen catalytic site (Cat Site) and 3. 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 HC II however 20-24 unit chain lengths result in a substantially greater thrombin inhibition via HC II. 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.

Since inhibition of factor Xa does not require simultaneous binding of Xa and ATIII via a heparin template, lower molecular weight fractions of unfractionated heparin easily inhibit factor Xa. The antithrombotic properties of heparin are predominantly mediated by binding of heparin to ATIII through a specific pentasaccharide sequence. This complex then inhibits both factor Xa (i.e., all molecular weight fractions) and thrombin (i.e., higher molecular weight fractions of unfractionated heparin) [44]. Only one in three unfractionated heparin molecules has the critical pentasaccharide sequence required for binding to ATIII [44]. Although binding of heparin to ATIII inhibits thrombin and factor Xa [45], this complex also inhibits several other sites in the intrinsic pathway. In addition, the extrinsic pathway can be attenuated by heparin-mediated release of TFPI [46] that inhibits activation of the extrinsic pathway [47]. Heparin may also inhibit [16,17,48,49] or activate [17] platelets and has been shown to initiate fibrinolysis [16].

Although unfractionated heparin is metabolized in the reticuloendothelial system and in the liver, at least 50 percent is eliminated unchanged via the kidneys. Plasma elimination half-life of unfractionated heparin varies with dose, increasing from 60 min with 100 U/kg to 150 min with doses of 400 U/kg [50-52]. Low molecular weight heparin (LMWH) compounds such as enoxaparin (Rhone-Poulenc Rorer, Collegeville, Pennsylvania) or dalteparin (Pharmacia & Upjohn Co, Kalamazoo, Michigan) have a more-consistent pharmacokinetic profile between patients due to the lower protein binding [53], less affinity for platelets [48], vWF [48] and endothelial cells [54], and clearance which is primarily renal [55].

Unfractionated heparin: pharmacodynamics and heparin resistance

Drug resistance can be related to two separate mechanisms: one involving a patient who does not respond normally to a standard therapeutic dose of a drug while another being related to biological changes in the causative agent, such as occurs with various types of bacteria, where the drug is no longer effective against the disease agent. Heparin resistance is related to the first mechanism and can be defined as impaired heparin responsiveness or the inability to achieve a target clotting time result with a standard dose of unfractionated heparin. Substantial variability of heparin anticoagulant responsiveness has been previously observed, as illustrated by a wide range of Heparin Dose Response Test-derived slope values (median: 95% CI), in patients undergoing cardiac surgery (mean= 79; range: 58-114− s U−1 ml−1) [56] when compared to normal volunteers (mean= 92; range: 77-117 s U−1 ml−1) [57]. Accordingly, although a good linear relationship between heparin concentration and activated clotting time (ACT) values can be observed for any specific patient (mean correlation coefficient= 0.98 ± 0.03) [58], the mean slope derived from those relationships can vary substantially between patients (110 ± 38 s/U/mL) [58]. This between-patient variability is also illustrated in Figure 3 by noting the excellent linear relationship (r2 = 0.96) when the mean ACT values obtained at each heparin concentration for all patients are used in the linear regression; this is in contrast to the obvious variability in the linear relationship (r2 = 0.62) when the all individual patient data points at each heparin concentration are used for the linear regression analyses [58].

Figure 3.
Figure 3.:
Linear relationship of mean kaolin activated clotting time (ACT) values to a range of vitro heparin concentrations in using specimens from a series of patients. Kaolin ACT expressed in seconds and in vitro heparin concentration expressed in units (U) of porcine heparin/milliliter (mL) of whole blood. Linear regression relationship is plotted for the whole series (n = 41) of patients as both the mean (triangles) and full range of values (represented by T-bars). To illustrate the substantial inter-patient variability, R-squared (r2) values are used for correlation between both the mean kaolin ACT values (r2 = 0.96) as well as all individual kaolin ACT values (r2 = 0.62). Accordingly, a range of whole blood (WB) heparin concentrations (HC) between 2.5 to 5.5 U/mL are required to provide a target ACT of 500 s in this series of patients.

Impaired heparin responsiveness or heparin resistance is often attributed to ATIII deficiency [57]. ATIII activity levels as low as 40 to 50 percent of normal, which are similar to those observed in patients with heterozygotic hereditary deficiency (i.e., 1 in 2-3,000 patients) [59], are commonly seen during and immediately after CPB [25,60-64]. Acquired perioperative reductions in plasma ATIII concentrations have been related to a time-dependent drop [65] with preoperative heparin use [62-64,66], hemodilution [61-63], or consumption during CPB [25]. AT III levels may also be reduced secondary to either reduced synthesis with impaired hepatic function or with renal losses. Other factors that may result in lower CPB AT III levels include preoperative sepsis or bacteremia (e.g., with bacterial endocardititis) or use of platelet-rich-plasma sequestration methodologies. The importance of ATIII in controlling platelet and coagulation activation is supported by recent findings that large increases in markers of platelet activation such as beta thromboglobulin (BTG) and thrombin activity, such as fibrinopeptide A (FPA), occurred when ATIII concentration was ≤ 0.6 U/mL (normal 0.8-1.2 U/mL) [57].

Although impaired heparin responsiveness or heparin resistance is often attributed to ATIII deficiency [57], other mechanisms can result in this clinical condition (Fig. 4). Significant variability in heparin anticoagulant response of the ACT (Fig. 3) [56,58] may also reflect inter-patient differences in heparin binding to endothelial cells [54], white cells [67], platelets [68,69], or proteins [15,45,70,71] such as vitronectin [72], vWF [48] or histidine-rich glycoprotein [53]. The heparin tissue source (i.e., intestinal vs. lung, porcine vs. bovine), method of preparation and molecular weight distribution of heparin used [15,73] and possibly the use of nitroglycerin infusions [66,74] (for which the mechanisms are unknown) may also contribute to impaired responsiveness. Although no currently available tests can help clinicians identify the specific cause of heparin resistance, there are several tests that can identify patients with heparin resistance.

Figure 4.
Figure 4.:
Diagram illustrating the potential etiologies for reduced heparin responsiveness or heparin resistance. The two major categories involve the effects of either reduced ATIII levels or heparin binding proteins. Reduced ATIII levels can result from either: (1) increased clearance with preoperative heparin use or DIC, renal losses, losses in cell salvage devices when obtaining platelet rich plasma or cardiopulmonary bypass circuits or with (2) reduced hepatic synthesis related to hepatic dysfunction or hereditary deficiency of synthetic enzymes. Abrreviations: AT III= antithrombin III, vWF = von Willebrand's Factor, PF4=platelet factor 4, HIT=heparin induced thrombocytopenia, Preop=preoperative, PRP=platelet-rich-plasma sequestration, DIC=disseminated intravascular coagulation, CPB=cardiopulmonary bypass.

Estimates of the incidence of heparin resistance vary substantially (e.g. 5-60% of patients undergoing cardiac surgery) in part related to the exact definitions used to characterize this condition such as the therapeutic or ‘target’ ACT (e.g. 400 vs. 480 seconds) as well as the dose of UFH required to achieve a ‘target’ ACT value (e.g. 300 vs. 375 vs. 400 vs. 500 U/kg) [56,75-78]. These estimates can also vary based on the percentage of patients receiving preoperative heparin as well as the duration of heparin use prior to the surgical intervention [65] and the absolute AT III level [77] (Fig. 5). Ranucci et al recently demonstrated a log linear relationship between preoperative AT III levels and the likelihood of having heparin resistance defined as the failure to reach an ACT longer than 490 seconds after 300 U/kg of UFH and/or a heparin sensitivity index or HSI< 1.0 (i.e., HSI=[ACT after heparin-ACT baseline]/heparin loading dose (IU/kg) [79]. Chan et al. recently identified that use of preoperative UFH or low molecular weight heparin as well as platelet count and albumin concentration were all statistically associated with heparin resistance defined as an ACT < 400 s after administration of 500 U/kg of UFH [78].

Figure 5.
Figure 5.:
A summary of studies that have examined the incidence of heparin resistance during cardiac surgery. The bars represent the incidence of heparin resistance in each published series of patients while the first authors of the manuscripts are listed above the corresponding bar along with the series of patient evaluated summarized in brackets. Four of the five studes used a target ACT of 480 seconds while the study by Cloyd et al used a Target ACT of 400 seconds to establish the diagnosis of heparin resistance. The respective dose of heparin used as the cutoff for the diagnosis of heparin resistance is listed below each bar or groups of bars in units (U) per kilogram (kg). The incidence of heparin resistance in patients not receiving heparin preoperatively is illustrated by the hatched bars while the incidence of heparin resistance in patients receiving heparin within each series is denoted by the solid bar. In the study by Dietrich et al., the spotted bar represents patients who had preoperative ATIII levels >80% activity while the solid bar represents patients who had preoperative ATIII levels < 80% activity.

Current anticoagulation monitoring methods

1. Monitoring heparin's anticoagulant properties: instruments that measure ACT

The ACT assay represents a modification of the Lee-White whole blood clotting time, employs an activator, either clay (kaolin) or diatomaceous earth (celite), to accelerate coagulation by activating the contact pathway. Test tubes or cartridges are inserted into each respective instrument for prewarming one or more min before test initiation since failure to prewarm prolongs ACT values [80]. Hemochron (International Technidyne Inc, Edison, New Jersey) automated instruments permit measurement of celite or kaolin ACT values. Blood (0.8 or 2.0 mL) either devoid of heparin or containing heparin up to 8 U/mL (higher levels prolong ACT values beyond the 1000 seconds detection limit) is transferred into an ACT tube that contains either celite or kaolin (or less commonly, saline) and a magnetic rod. The blood is then mixed by a manual, gradual shaking of the tube. Once the tube is inserted into a 37 °C heat block chamber, it rotates automatically until a formed clot engages the rod, at which time a sensor detects a change in magnetic attraction and stops a timer to yield an ACT value. This value relates linearly to the concentration of heparin in the blood specimen [81].

Hepcon or ACT II (Medtronic Blood Management, Parker, Colorado) automated instruments use kaolin or, less commonly, celite as the activator. Blood specimens (0.4 mL) are either automatically (Hepcon) or manually (ACT II) inserted in each of the two (ACT II) or 4-6 (Hepcon) wells of a cartridge. Each instrument then lifts a plunger/flag assembly that facilitates mixing and activation of blood by kaolin or celite. The presence of a clot is based on optical detection of a decreased rate of descent of the plunger-flag assembly.

ACT can also be measured using the Sonoclot instrument which is called the SonACT, which detects viscokinetic changes of blood as it undergoes coagulation. Whole blood or platelet-rich-plasma obtained via differential centrifugation (0.4 ml) is placed in a cuvette in which a vertically vibrating plastic probe is suspended. The changes in mechanical impedance to vibration exerted on the probe are recorded in a tracing called a Sonoclot signature. As fibrin strands form, impedance increases to a peak. The onset time (T1, normally 80-130 s) reflects the beginning of a fibrin (clot) formation and corresponds to the ACT. Although the SonACT may potentially be used to monitor anticoagulation, evaluations of this test during CPB are lacking.

Celite-ACT and kaolin-ACT correlate well (r = 0.91, r = 0.93, respectively) with laboratory-derived anti-factor Xa heparin concentration values in the pre-CPB period [82] and are commonly used during CPB to monitor anticoagulation. However, ACT prolongation during CPB is not necessarily due to heparin [83]. This may relate to the intrinsic variability of ACT measurements between patients (Fig. 4) [84,85], to other factors associated with CPB such as hypothermia [82,84,86] quantitative and qualitative platelet abnormalities [87-89], aprotinin (i.e., when celite is used as an activator) [90-94] and/or to hemodilution v. An inverse, independent relationship between core body temperature and ACT values (i.e., using multivariate statistical analyses) observed in one study may reflect inadequacy of specimen warming by the respective instruments [82]. What remains unclear is the degree to which this divergence reflects an increased sensitivity of coagulation proteins to heparin-induced anticoagulation in the presence of hypothermia. Unfortunately, no investigation has specifically assessed the relationship between ACT and blood heparin concentrations at various constant levels of hypothermia.

By affecting the ACT method, CPB-related factors (i.e., hemodilution and hypothermia) may ultimately contribute to variability in heparin levels during CPB when this test is used to guide heparin therapy [15,82,86,95,96]. Variability in heparin concentration was recently assessed by calculating the absolute deviation of heparin levels during CPB from the target, pre-CPB heparin levels (i.e., obtained after heparin administration but before initiation of CPB) for each of 32 patients [82]. When heparin dosing was guided by ACT values (i.e., < 480 seconds for additional heparin) during CPB, heparin concentration (i.e., anti-Xa activity) varied substantially (2.7 U/mL=mean absolute deviation for 32 patients) from those concentration values that were present at similar ACT values before CPB [82]. In most cases, the CPB heparin concentrations were lower than those observed before initiation of CPB. Mean absolute deviation was smaller (0.75 U/mL, p < 0.001) when heparin was infused continuously in another study [97].

2. Heparin concentration assays: automated protamine titration method and fluorometric assay

To provide an ACT alternative that is potentially unaffected by CPB-related hypothermia and hemodilution, several methods have been developed to measure whole blood heparin concentration. These techniques use either neutralization techniques (e.g., Automated Protamine Titration method, Heparin-responsive Sensor) or heparin activity (e.g., Fluorometric assay, HepTest whole blood anti-Xa/IIa activity). All of these techniques offer the advantage over ACT-based or empiric protamine dosing regimens of basing protamine doses on whole blood heparin concentrations present at the end of CPB. However, each one is limited by the need to use standard algorithms to calculate blood volume in a patient population where blood volume is likely to be variable. Other limitations include discontinuous measurements and the use of clotting as a surrogate end point rather than direct measurement of heparin concentrations. Alternatively, basing protamine on administered heparin doses or ACT-based estimates of heparin concentration may necessitate administration of larger protamine doses. The inability of assays that measure only heparin concentration to detect the antithrombotic properties of heparin constitutes a major limitation of this approach. This is important in patients who have a theoretically adequate blood heparin concentration but who also have an increased risk for thrombosis because of resistance to heparin-induced anticoagulation. Accordingly, since heparin concentration monitoring only assesses the amount or concentration of heparin which do not necessarily correlate with the anticoagulant effects of heparin, it may mislead the clinician regarding anticoagulant activity. The optimal monitoring system would accurately assess in vivo thrombin activity, yet not be artifactually affected by the effects of hemodilution or hypothermia unless these factors directly affect in vivo thrombin activity.

Whole blood heparin concentration measurements can be performed at the bedside using an automated heparin protamine titration method (Hepcon instrument, Medtronic Blood Management, Parker, Colorado) [83,98-100]. With this method, a thromboplastin reagent is used to accelerate coagulation via the tissue factor pathway, and the device then measures clotting times in several channels that contain varying amounts of protamine. The principle behind this test is that clotting occurs first in the chamber where the protamine to heparin ratio is nearest the neutralization point [83]. Since clot, and not absolute clot time, is the end point, this method is unaffected by reductions in clotting factors and platelets during CPB [101-103].

Heparin levels determined by this automated protamine titration method have been shown to correlate well with anti-Xa plasma heparin measurements (i.e., a laboratory gold standard) [82,103] even when aprotinin is present [104]. Hardy et al. found that measurements derived from the automated protamine titration method were biased (mean ± S.D. difference between values was 1.45 ± 1.65 U/mL), from anti-Xa measurements [105]. However, Hardy et al.'s findings were not confirmed in two subsequent studies [102,103] in which the bias between Hepcon and anti-Xa levels was lower, 0.002 ± 0.53 (range: −1.78 to 1.72) and 0.715 ± 0.99 U/mL, respectively. Although the exact relationship between whole blood (automated protamine titration assay) and plasma (anti-Xa chromogenic) heparin levels needs further investigation, another recent study demonstrated that patient-specific heparin concentrations can be maintained using the automated protamine titration assay [97].

3. Tests that predict heparin resistance

If heparin resistance is secondary to ATIII deficiency, detection and treatment of heparin resistance is potentially important with respect to the preservation of coagulation factors and platelets during CPB. Hereditary or acquired ATIII deficiency renders heparin less effective in suppressing thrombin generation or activity during extracorporeal circulation [61,63,106]. Because of this and the well-documented substantial inter-patient variability in the ACT response to heparin (Fig. 3) [56-58,107], Bull et al. [108] advocate a dose-response plot to predict the heparin requirements of individual patients.

Accordingly, assays such as the heparin dose response test (HDR, Medtronic Blood Management, Parker, Colorado) based on the kaolin ACT, and the Heparin Response Test (HRT: International Technidyne Inc., Edison, New Jersey), based on the celite ACT, have been developed. These automated or semi-automated tests add heparin to the patient's blood ex vivo to determine ACT responsiveness to heparin. Figure 6 illustrates a typical response of the kaolin ACT to varying final concentrations of heparin (i.e., 0, 1.5 or 2.5 U/mL) in the six channel HDR test cartridge. Although a targeted ACT of 480 s was achieved from the initial heparin dose predicted by the HDR test in 40 of 41 adult patients [58], further studies are needed to validate this test's ability to project the heparin dose needed to achieve any target ACT.

Figure 6.
Figure 6.:
This figure illustrates the Heparin Dose Response Test (HDR) which utilizes a six channel cartridge (illustrated by the six test tubes) that contain varying final concentrations of heparin (i.e., 0, 1.5 or 2.5 U/mL). This automated test adds performed on the Hepcon instrument adds heparin to the patient's blood ex vivo to determine the responsiveness of the kaolin activated ACT to unfractionated heparin. This figure illustrates a typical response (i.e., as illustrated by the data points as triangles and the linear regression line) of the kaolin ACT to varying final concentrations of heparin (i.e., 0, 1.5 or 2.5 U/mL) in the six channel HDR test cartridge. The linear regression relationship is denoted by the typical y = mx + b where the kaolin ACT represents the y, where m or the slope is represented by the HDR derived slope in seconds/unit of heparin/ mL of whole blood represented, the x is represented by the heparin concentration (Hepconc) and the y-intercept is represented by b. A normal slope using as displayed with a mean ± standard deviation is noted using data generated from pre-CPB blood specimens from a series of patients undergoing cardiac surgery [56].

In addition to estimating heparin requirements for individual patients before surgery, these tests should be able to identify patients with significant heparin resistance secondary to decreased ATIII levels [57]. Use of modifications of either the HRT or HDR test systems (i.e., with and without in vitro AT III) is supported by the demonstration of a progressive reduction in the responsiveness of whole blood to heparin (i.e., at high concentrations used with CPB) when ATIII concentration is < 80 U/dL [57]. In this study [57], strong linear relationships between kaolin (slope= 1.04ATIII−2, r2 = 0.78) and celite (slope= 1.36ATIII+ 6, r2 = 0.77) ACT slopes and AT III concentrations < 80 U/dL were observed. The substantial reduction in responsiveness of whole blood derived ACT values to heparin at ATIII concentrations < 80 U/dl is illustrated in Figure 7. These tests were used as part of anticoagulation management protocols in two recent studies showing that precise patient-specific control of heparin and protamine administration decreased blood loss (15 and 50 percent, respectively) and transfusion requirements (50 and 80 percent, respectively) [56,109]. In the study by Despotis et al., the heparin concentration required to reach that target ACT value was maintained throughout CPB even if ACT values exceeded the target values [56].

Figure 7.
Figure 7.:
The relationship between mean heparin dose/ACT response slope values (ACT/Heparin Slope) and antithrombin III (AT III) activity expressed as % in blood from eight normal volunteers [57]. Kaolin ACT (K-ACT) was measured using Hepcon instruments (Medtronic HemoTec, Parker, CO) whereas celite ACT (C-ACT) was measured using Hemochron instruments (International Technidyne Inc., Edison, N.J.). Data points are generated from mean values at each respective ATIII concentration for each test system evaluated; triangles represent mean celite ACT values used for the Heparin Response Test (HRT) while circles represent mean kaolin ACT values used for the Heparin Dose Response Test (HDR). Regression lines depict linear relationships data corresponding to AT III levels less than 100 U/dL.

Outcome analysis for anticoagulation monitoring schemes and anticoagulant adjuncts

Studies evaluating fixed dosing regimens vs ACT monitoring

The limitations of fixed dosage regimens without monitoring include the lack of confirmation of adequate anticoagulation and the inability to maintain a consistent heparin concentration for individual patients. However, one blinded study using fixed doses found no relationship between ACT values during CPB and bleeding outcomes [96]. In addition, Jobes et al. did not find reduced bleeding or transfusion requirements when heparin concentration monitoring was compared to fixed dosage protocols [83]. Eleven studies comprising 1865 patients that examined the potential usefulness of anticoagulation monitoring schemes with cardiac surgery were published over a thirteen year period (i.e., 1977 to 1990). Inconsistent outcomes (i.e., 5 of 7 studies demonstrating improved transfusion outcomes and 7 of 11 demonstrating reduced blood loss) have been observed when ACT monitoring was compared to fixed dosing regimens [96,110-119]. Only two of these 11 studies were prospective [96,111], and neither of these involved a randomized, blinded study design, which may limit the accuracy and reliability of the findings.

Studies evaluating fixed dosing regimens or ACT monitoring vs heparin concentration monitoring

When compared to either fixed dose [83] or ACT [56,98,99,120] protocols, the impact of heparin concentration monitoring protocols on bleeding and blood conservation has varied (Table 2). Although some authors suggest that excessive bleeding relates to use of larger doses (i.e., doses greater than those typically administered using ACT methods) of bovine heparin during CPB [99,121], other studies found no differences in blood loss when either bovine [98,122] or porcine heparin were used [4,56,109,120]. Table 2 summarizes important factors that help explain the differences in outcomes using several heparin monitoring protocols. To determine if heparin dose, as directed by an ACT-based protocol, relates to either blood loss or transfusion requirements, a multivariate analysis of 487 consecutive patients was recently performed [4]. Although this analysis was limited by its retrospective design, significant associations were demonstrated between lower initial/total heparin dosage and increased blood loss and transfusion requirements.

Table 2
Table 2:
Summary of studies that have examined the effect of higher heparin doses and method of anticoagulation monitoring on perioperative blood loss and transfusion outcomes.

In a subsequent prospective, randomized trial from the same institution, the impact of heparin and protamine administration as directed by a POC, whole blood hemostasis system (Hepcon instrument, Medtronic Blood Management, Englewood, Colorado) on bleeding and blood transfusion when compared to an ACT-based protocol was evaluated in 254 patients [56]. An empiric dosing regimen for heparin and protamine was used for control patients using ACT values, while the anticoagulation/reversal protocol for intervention patients was based on HDR, ACT and whole blood (WB) heparin concentration values. A patient-specific, reference heparin concentration (i.e., pre-CPB WB heparin concentration associated with kaolin ACT of 480 seconds, median: 3.4, 95 percent CI: 2-5.4 U/mL) was maintained during CPB and the protamine dose was calculated from the measured, residual heparin concentration. Patients in the intervention cohort received 25 percent larger total doses of heparin and had smaller protamine to heparin ratios (i.e., by 25 percent) when compared to control patients. A greater percentage of patients in the control cohort required platelet (34 vs. 22%, p = 0.03), plasma (31 vs. 11%, p < 0.001) and cryoprecipitate (5 vs. 0%, p = 0.01) units when compared to the intervention cohort. Control cohort patients also had 10 percent longer operative post-CPB closure times (p = 0.02), 15 percent more mediastinal chest tube drainage (p = 0.05) in the first four postoperative hours and twice as many control patients required hemostatic (e.g. platelets, FFP etc) transfusion (17% vs. 33%), p = 0.005).

Since generation of FPA [61,99] and inhibition of clot-bound thrombin [43] have been shown to relate inversely to heparin concentration, maintenance of heparin concentrations that more effectively inactivate thrombin may preserve hemostasis during prolonged CPB. This is supported by findings from two additional studies. The first study evaluated 31 patients requiring repeat or combined cardiac procedures (i.e., coronary revascularization plus valve repair/replacement) and thus at increased risk for excessive bleeding [25]. Maintenance of higher heparin concentrations better preserved consumable ATIII and factors I, V, and VIII most likely related to better suppression of thrombin (65 percent reduction in FPA levels) and fibrinolytic (i.e., 50 percent reduction in D-dimers) activity. The second study demonstrated that larger heparin doses can better suppress thrombin (i.e., lower TAT complexes) and fibrinolytic activity (i.e., lower D-dimers) in patients undergoing deep hypothermic circulatory arrest [122]. These studies suggest the superiority of higher heparin concentrations for procedures involving prolonged or complicated CPB. These findings may relate to the propensity of hemodilution and hypothermia to prolong ACT independent of blood heparin concentration, thus resulting in smaller heparin doses.

Higher, stable heparin concentrations during CPB can also preserve platelet function during prolonged CPB. In a recent trial, less platelet activation (i.e., lower platelet factor 4 and BTG levels) was demonstrated in patients who received larger heparin doses [122]. Preservation of platelets by higher heparin levels during CPB is supported by more prolonged bleeding times in patients who received less heparin during CPB [25]; in addition, a significant correlation (r = 0.51, p = 0.004) between FPA and BTG levels in that study suggests that platelet activation may relate directly to thrombin activity. Inhibition of platelet function by heparin [17,98,123] may relate to suppression of factor VIII-mediated platelet aggregation [49] or von Willebrand factor-related mechanisms [48]. However, other studies indicate that inhibition of platelet function by heparin may be detrimental, based on the lack of reversibility by routine doses of protamine [124], which may relate to the degree of platelet inhibition [17,125]. In one study, 59 percent of patients displayed mild-to-moderate inhibition whereas 33 percent of patients displayed severe inhibition and the degree of platelet inhibition by heparin correlated with blood loss [125]. Although these findings explain how platelet inhibition can be interpreted as being synonymous with platelet dysfunction [16], the duration of this inhibition by heparin has not been well-characterized and it is uncertain whether the inhibition by heparin is dose-dependent within the range of heparin concentrations used clinically (1-5 U/mL). In addition, these studies did not evaluate whether heparin-mediated platelet inhibition was influenced by the dose of heparin required to obtain a therapeutic anticoagulant response for a given patient.

In summary, since several studies reveal limitations to ACT monitoring during CPB [82-84,84-92], significant refinements of the clinical practices used for determining heparin doses should be considered. Until the possible impact of supplemental pharmacologic platelet inhibition are resolved, maintenance of higher patient-specific heparin concentrations should be considered to reduce thrombin-mediated activation and consumption of platelets in patients requiring longer CPB intervals.

Studies evaluating the usefulness of anticoagulant adjuncts

1. Warfarin and derivatives. The concept that enhanced anticoagulation during CPB and, thus, thrombin inhibition results in better preservation of hemostasis is supported by findings from several studies that characterized the effects of preoperative warfarin administration and hemostatic system activation, blood loss or transfusion requirements. Dietrich et al. measured thrombin/antithrombin complexes as an index of thrombin activity during the peribypass interval in patients receiving warfarin preoperatively for prevention of stroke versus patients not receiving this agent [64]. Substantially better suppression of thrombin activity (i.e., reduced thrombin-antithrombin complexes) and platelet activation (i.e., reduced levels of beta thromboglobulin and platelet factor 4) was observed during CPB in patients treated preoperatively with warfarin. In addition, two studies involving patients who received warfarin preoperatively have demonstrated an inverse relationships between postoperative INR and either blood loss [126] or transfusion requirements [127]. The first was published by Dietrich et al and involved 240 patients (i.e., 125 who received warfarin preoperatively and 115 patients who did not receive this agent and served as a control cohort) scheduled for cardiac surgery [126]. The postoperative blood loss after 6 and 12 h was 381 (CI 0.95: 329 to 434)/505 (CI 0.95: 439 to 571) mL for patients receiving warfarin compared with 472 (CI 0.95: 403 to 541)/612 (CI 0.95: 527 to 697) mL for control patients (p < 0.05). The second study by Morris et al involved 90 patients undergoing cardiac transplantation [127]. These authors documented inverse relationships between postoperative INR and total blood product exposures, as well as transfusions of platelets (partial r = −0.26, p = 0.03), fresh frozen plasma (partial r = −0.28, p = 0.02), and red cells (partial r = −0.25, p = 0.04). These findings support the concept that enhanced anticoagulation during CPB can better suppress hemostatic system consumption with a resultant decrease in postoperative bleeding.

2. Studies evaluating the use of Antithrombin III to manage heparin resistance or to preserve the hemostatic system.

With respect to managing heparin resistance, most of the previous literature regarding the use of either FFP or ATIII concentrates has been in the form of case reports, case series or prospective trials (Table 3) [61,63,128-135,135-138]. Between the years 1984 to 2005, thirteen reports have documented the successful use of either FFP (i.e., 2 of 13 reports) [128,133], recombinant (3 of 12) [135,137,138] or plasma-derived (8 of 13) [61,63,129-132,134-136] ATIII concentrates to manage heparin resistance. The vast majority (i.e., 12 of 13) of these reports indicated that administration of these agents resulted in an improvement of heparin responsiveness. Table 3 also illustrates the tremendous variability (400 to 1200 U/kg of UFH) with respect to the cutoff for heparin doses required to define heparin resistance. The use of factor concentrates offers unique advantages over FFP such as reduced blood-borne disease transmission with respect to lipid enveloped viruses and reduced incidence of fluid overload based lower volumes required to achieve a therapeutic concentration (e.g. 5 L of FFP vs 100 mL of ATIII when administering 70 U/kg). However, there are also potential complications such as a theoretical increase in transmission of non-enveloped viruses with administration of pooled, pasteurized products, increased cost, occasional unavailability and the potential for heparin-rebound related bleeding.

Table 3
Table 3:
Summary of studies that have examined the use of either FFP, plasma or recombinant ATIII concentrates to manage heparin resistance.

The most recent of these studies involved two similar but independent randomized, prospective trials that indicate that use of transgenic ATIII can reduce (i.e., by 80-90%) the requirement for FFP in patients with heparin resistance [137,138]. In both of these randomized, controlled studies, the study objective was to evaluate the safety and efficacy of recombinant human (rh) antithrombin III (AT III) for restoration of heparin responsiveness in heparin resistant patients scheduled for cardiac surgery.

The first trial was a multi-center (i.e., 14 U.S and European study centers), randomized, double-blind, placebo-controlled study in heparin resistant patients undergoing elective cardiac surgery [137]. Patients not achieving an activated clotting time (ACT) of ≥480 seconds after a heparin dose of 400 U/Kg were considered heparin resistant. Of 329 patients screened, fifty-four heparin resistant patients were randomized (1:1) into 2 cohorts. One cohort received a single bolus (75 U/Kg) of rh AT III, and the other a single bolus of normal saline. Treatment failures were patients requiring fresh frozen plasma (FFP) administration to achieve an ACT of ≥480 seconds after receiving study medication. Patients were closely monitored for adverse events (AEs) during hospitalization and postoperatively. Only 19% of patients who received rh ATIII required FFP administration to achieve an ACT ≥ 480 seconds, as compared with 81% of placebo treated patients (p < 0.001). There was no increased incidence of serious adverse events (SAEs) associated with rh ATIII administration. Although a lower percentage of rh ATIII patients required FFP (11%) in the perioperative period when compared to placebo (59%), rh ATIII patients tended to have (p = 0.06) greater 24-hour chest tube drainage (1580 ± 1048 mL) compared to placebo patients (1216 ± 777 mL). However, the mean rate of chest tube drainage during the 24-hour postoperative period was significantly higher (p = 0.041) among rh ATIII, which increased by 40%.

The authors speculated that achievement of near normal postoperative AT concentrations in rh ATIII-treated patients when combined with low levels of residual heparin may have provided a more profound anticoagulant effect in the postoperative period resulting in an increase in heparin-rebound related bleeding. Therefore, the increase in mean chest tube drainage among rh ATIII-treated patients was not totally unexpected in view of the lack of provisions to monitor and reduce heparin administration in the presence of normalized ATIII activity or more importantly, to monitor and treat heparin rebound postoperatively [70,139-141]. Therefore, it may be important to monitor for heparin rebound in the postoperative period and administer an accurate calculated protamine dose when it is identified.

In addition, FFP administered postoperatively to patients who received rh ATIII may have been on an empiric basis even though this approach has fallen out of favor based on studies, which demonstrate that both FFP [142,143] and platelets when administered prophylactically are clearly not beneficial. Attempt to control excessive bleeding by administering FFP, may have aggravated heparin rebound-related bleeding by further increasing ATIII levels. The authors concluded that treatment with a single dose (75 U/Kg) of rh ATIII is safe and effective for achieving anticoagulation for cardiopulmonary bypass in heparin resistant patients.

The second trial was also a multi-center (i.e., 6 European study centers), randomized, double-blind, placebo-controlled study in heparin resistant patients undergoing elective cardiac surgery [138]. Similarly, patients not achieving an activated clotting time (ACT) of ≥480 seconds after a heparin dose of 400 U/Kg were considered heparin resistant. Of 493 patients screened, fifty-two heparin resistant patients were randomized (1:1) into 2 cohorts. Six (21%) of the patients in the recombinant human ATIII group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo treated patients (p < 0.001). Administration of two units of fresh frozen plasma to patients in the placebo treated cohort did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human ATIII administration. In contrast to the first study published by Avidan et al. [137] postoperative 24-hour chest tube bleeding was not different in the 2 groups in the second study [138]; this may have been related to lower levels of ATIII achieved in the perioperative interval in this study relative to the other study (Fig. 8). Surrogate measures of hemostatic activation suggested there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human AT III group. The authors also concluded that treatment with a single dose (75 U/Kg) of rh ATIII is safe and effective for achieving anticoagulation for cardiopulmonary bypass (CPB) in heparin resistant patients. Both of these randomized trials confirmed that rh AT administration can substantially reduce allogeneic plasma exposure as related to the management of heparin resistance. However, based on the increased blood loss observed in the first study [137], two points should be considered. First, a lower dose of ATIII should be considered based on the absence of bleeding in the second study in which lower levels of ATIII were achieved. Secondly, use of one of several point-of-care tests (e.g. Heparinase ACT, heparin-neutralized thrombin time) should be considered to detect heparin resistance and direct protamine administration for reversal of heparin rebound-related bleeding in the setting of AT III supplementation. Further studies are needed to clearly define the role of ATIII concentrates for patients with acquired ATIII deficiency and heparin resistance during cardiac surgery and specifically examine the effect on blood loss after implementing three changes in study design: attainment of lower or near normal levels of ATIII with smaller doses of rh ATIII, utilization of a heparin rebound monitoring program to detect and manage excessive postoperative bleeding related to this mechanism and a standardized approach for the transfusion support of patients who have excessive chest tube drainage using results from point-of-care test.

Figure 8.
Figure 8.:
Perioperative ATIII levels measured in two randomized trials that examined the efficacy and safety of recombinant human (rh) ATIII with respect to the management of heparin resistance [137,138]. These trials are designated by the corporate sponsor Genzyme as GTC AT 97-502 [137] and GTC AT 97-504 [138] Mean values with SD T-bars are displayed for ATIII levels expressed as % activity for three separate perioperative time intervals: Baseline values obtained prior to initiation of cardiopulmonary bypass (CPB), CPB-30 min represents 30 minutes after initiation of CPB while Pre-Prot designates the period after discontinuation of CPB but prior to administration of protamine. The solid diamonds represent patients randomly assigned to receive rh ATIII while the open boxes represent placebo treated patients.

Enhancement of heparin's antithrombotic properties by ATIII supplementation can preserve the hemostatic system during CPB, especially in patients who have acquired ATIII deficiency related to preoperative heparin infusions [62-64,66] and/or CPB-related hemodilution or consumption [25,62,63]. Ultimately, reduced activation and preservation of the hemostatic system via therapeutic anticoagulation may result in reduced bleeding (i.e., as related to reduced platelet and coagulation factor consumption) or thrombotic complications (i.e., as related to reduce thrombin-mediated activation). The initial findings of decreased thrombin (e.g., fibrinopeptide A) activity observed by Hashimoto et al. [61] in pediatric patients supplemented with pooled ATIII concentrates was recently confirmed by Levy et al. [144] using recombinant (i.e., transgenic) ATIII. Inverse relationships were observed between ATIII concentration and markers of both thrombin (e.g., fibrin monomer) and fibrinolytic (D-dimer) activity in this latter study [144]. The implications of these findings are that ATIII supplementation may reduce either bleeding or thrombotic complications as related to attenuation of the ‘DIC’ like process secondary to cardiopulmonary bypass. This is supported by several case reports that suggest that patients with low AT III levels in the perioperative period are at increased risk for lifethreatening thrombotic complications (e.g. CPB circuit [145] or intravascular thrombosis [146]). The critical role of ATIII with respect to hemostatic balance is illustrated by comparing the incidence of venous thromboembolism in patients with isolated hereditary defects. When compared to other hereditary anticoagulant defects, patients with congenital AT III deficiency are at the highest risk for development of venous thromboembolism especially especially at older ages [147]. As previously addressed, currently available methods such as the HDR and HRT tests can identify patients with heparin resistance from ATIII deficiency who may be more susceptible to either bleeding or thrombotic complications related to very low AT III levels in the perioperative period [57]. Finally, two recent, retrospective analyses have demonstrated an association between lower levels of ATIII in the perioperative period and worse outcomes suggesting that AT III supplementation may improve outcomes. Ranucci et al recently demonstrated an inverse relationship between ICU AT III levels and the incidence of adverse neurologic outcomes, thrombembolic events, surgical reexploration and prolonged ICU stay in a series of 647 patients undergoing cardiac surgery [148]. Sodeck et al also reported an inverse relationship between AT III activity measured in the Emergency Department and 30 day mortality in patients undergoing repair of Type A aortic dissection [149]. Although these analyses can help clinicians uncover potential interactions and generate hypotheses, a cause-effect relationship cannot be clearly elucidated using data from retrospective analyses. However, they do provide a good foundation for setting up large, randomized controlled trials to examine the effect of ATIII supplementation with respect to this intervention's potential ability to reduce lifethreatening bleeding or thrombotic complication rates.


The literature indicates that enhanced anticoagulation via more sophisticated heparin monitoring schemes can reduce bleeding and transfusion and that antithrombin III concentrates can be used to effectively manage heparin resistance during cardiac surgery. Although optimal suppression of hemostatic system activation and inhibition of thrombin via enhanced, yet reversible anticoagulation can potentially result in improved outcomes, further randomized trials are warranted since the literature does not consistently support the clinical importance of either anticoagulation monitoring techniques or anticoagulant adjuncts during CPB. This is best reflected by studies that have examined the impact of the ACT method on blood loss and transfusion outcomes. Inconsistent findings from studies that evaluated the impact of ACT monitoring may be related to either suboptimal study design (i.e., retrospective, unblinded, non-randomized) or possibly the diagnostic inprecision of the ACT method utilized in these studies. There are well-controlled studies which suggest that bleeding and transfusion outcomes can be improved by refining heparin monitoring techniques by sustaining better anticoagulation during CPB especially when applied to operative cases that involve complex procedures that require long intervals on cardiopulmonary bypass.

Recent studies indicate that AT III concentrates can be used to effectively manage heparin resistance, reduce plasma utilization and enhance preservation of the hemostatic system during CPB. A few recent retrospective analyses indicate that lower ATIII concentrations are associated with negative outcomes. However, well-controlled, randomized studies are needed to better define the relative importance of AT IIII supplementation with respect to either the management of heparin resistance or with respect to optimization of anticoagulation during CPB and specifically if these interventions are able to attenuate the incidence of adverse bleeding and/or thrombotic complications. The ability to reduce bleeding and use of blood products and to decrease thrombotic complications has important consequences for patient outcomes, blood inventory, and blood costs, and overall health care costs.


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                                                                                                            Anticoagulation; Cardiac surgery; Heparin resistance; Hemostatic system; Herapin; Antithrombin; Bleeding; Disseminated intravascular consumption

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