406 Hematologic Aspects of Cardiac SurgeryPage 1 Linda J. Shore-Lesserson Bronx, New YorkIntroductionThe hematologic management of the cardiac surgical patient entails a complex balance between extreme degrees ofanticoagulation and the restoration of normal hemostasis after the procedure. These two opposing processes mustbe managed carefully and modified with respect to preoperative disease state, duration of cardiac surgery, use ofextracorporeal circulation, and the desired hemostatic outcome. During cardiopulmonary bypass (CPB), optimalanticoagulation dictates that coagulation is minimized and platelets are kept quiescent, so that microvascular clots donot form on the extracorporeal circuit. The dramatic increase in interventional cardiology procedures to treatcoronary artery disease utilizing stents, lasers, and other new technology have made anticoagulation mandatoryduring and after these procedures. The increase in heparin exposure has heightened our awareness of heparin resistance and heparin-inducedthrombocytopenia. Following CPB, coagulation abnormalities, platelet dysfunction, and fibrinolysis occur andrender the patient hemostatically impaired. Bleeding should be managed using careful hemostasis monitoring.Fibrinolysis can be prevented and transfusions minimized by the use of antifibrinolytic therapy. Proper use of theseagents and their safety will be discussed. Uncontrolled hemorrhage has been anecdotally treated with success usingactivated Factor VII, and this therapy has thus gained increasing popularity in postoperative hemorrhage. Thiscomplex hemostatic picture is coupled with the concurrent use of anti-thrombotic medication in the cardiovascularpatient in both the preoperative and the postoperative periods. The frequent and prevalent use of multiple anti-platelet medication is of great concern to the cardiovascular anesthesiologist as it increases bleeding and bleeding-related complications after surgery.Heparin ResistanceHeparin resistance is marked by the inability to raise the activated clotting time (ACT) to therapeutic levels after theadministration of heparin. Non-responsiveness to heparin can be due to a congenital deficiency or abnormality ofthe activity of antithrombin III (AT3). In congenital states, the only way to elicit a response to heparin therapy is toadminister exogenous AT3, either in the form of plasma or a factor concentrate. Acquired resistance to heparinoccurs in patients who have been treated with heparin.1 These patients were initially responsive to heparin asevidenced by an elevated ACT, but with continued treatment with heparin, resistance to its anticoagulant effectsoccurs. Patients on preoperative heparin therapy traditionally require larger heparin doses to achieve a given levelof anticoagulation. Possible etiologies for this resistance include AT3 depletion, enhanced factor VIII activity,platelet activation, or any combination of these factors. Heparin is known to activate platelets which will shortenACT values. The direct thrombin inhibitors do not activate platelets, an attribute that will be discussed later in thischapter. Data now suggest that LMWH also contributes to platelet activation and heparin resistance.2 In vitroaddition of ATIII enhances the ACT response to heparin. Further, low levels of AT3 are associated with negativeoutcomes in cardiac surgery.3 But it is unclear if a low AT3 level portends adverse outcomes because of thediminished anticoagulant response to heparin, or because it serves as a “marker” for a patient with a more advancedrisk profile (on preoperative heparin). The true heparin requirement during CPB in patients with acquired heparinresistance is not known because the ideal ACT and its correlation with outcomes has not yet been demonstrated.4,5ATIII concentrate is now available and represents a reasonable method of treating patients with documented ATIIIdeficiency.Heparin Induced Thrombocytopenia The syndrome known as HIT develops in anywhere from 5% to 28% of patients receiving heparin. HIT iscommonly categorized into two subtypes. HIT Type I is characterized by a mild decrease in platelet count and is theresult of the proaggregatory effects of heparin on platelets. HIT Type II is considerably more severe, most oftenoccurs after more than 5 days of heparin administration (average onset time, 9 days), and it is mediated by antibodybinding to the complex formed between heparin and platelet factor 4 (PF4).6 Among patients developing HIT II, theincidence of thrombotic complications approximates 20%, which in turn may carry a mortality rate as high as 40%.Demonstration of heparin-induced proaggregation of platelets confirms the diagnosis of HIT type II. This can beaccomplished with a heparin-induced serotonin release assay, or a specific heparin-induced platelet activation assay.A highly specific enzyme-linked immunosorbent assay for the heparin/PF4 complex has been developed and hasbeen used to delineate the course of IgG and IgM antibody responses in patients exposed to unfractionated heparinduring cardiac surgery.7 Bedside antibody tests are being developed that may speed the diagnosis of this condition.
406Page 2 The risks and appropriate courses of action in patients with HIT II are unclear because the antibodiesassociated with heparin-induced thrombocytopenia often become undetectable several weeks after discontinuingheparin. Also the clinical syndrome does not always recur upon reexposure to the drug and sometimes resolvesdespite continued drug therapy. Many patients never develop thrombosis despite positive laboratory testing.Heparin-induced thrombocytopenia should possibly be considered in the differential diagnosis of intraoperativeheparin resistance in patients receiving preoperative heparin therapy. The options for treating these patients are few.If one has the luxury of being able to discontinue the heparin for a few weeks, often the antibody will disappear andallow a brief period of heparinization for CPB without complication. Supplementing heparin administration withpharmacologic platelet inhibition using prostacyclin, iloprost, aspirin, or tirofiban have been reported, all withfavorable outcomes. Plasmapheresis may be used to reduce antibody levels. The use of heparin could be avoidedaltogether by anticoagulating with a direct thrombin inhibitor. See Table 1. Table 1 Heparin Direct Thrombin Inhibitors Mode of action Indirect Direct Catalyst needed Yes- anti-thrombin III No Inhibits clot-bound thrombin No Yes Activates platelets Yes (LMWH moderately yes) No Antigenicity Yes No (bivalirudin) Yes (hirudin) Antidote drug Yes- protamine NoHirudin and CongenersHirudin is a coagulation inhibitor isolated from the salivary glands of the medicinal leech (Hirudo medicinalis). Hirudinis a potent inhibitor of thrombin. Currently available via recombinant genetics, this substance is a polypeptide(molecular weight of approximately 7,000 Daltons). The aPTT prolongation correlates well with plasma hirudinconcentrations but does not correlate well with chromogenic antifactor II levels. For this reason, a surrogate aPTT usingthe snake venom ecarin for activation has been described.8,9 Platelet aggregation is also better preserved with hirudinthan with heparin. Hirudin does not activate platelets nearly as much as unfractionated heparin does. This property ofdirect thrombin inhibitors makes them more “bio-friendly” than unfractionated heparin. Using direct thrombininhibitors preserves platelet activity and reduces release of platelet activation markers as compared to unfractionatedheparin. Bivalirudin is a synthetic peptide formerly known as Hirulog® and currently marketed as Angiomax® (TheMedicines Company, Parsippany, NJ, USA). A bivalent thrombin inhibitor, bivalirudin consists of one moiety that bindsthrombin on its active-site cleft, and a second hirudin-like C-terminal region that binds thrombin at its positively chargedsurface groove known as the anion-binding exosite. Bivalirudin is a synthetic derivative of hirudin and thus acts as adirect thrombin inhibitor. Thrombin itself cleaves the part of the bivalirudin molecule that binds to it,, so bivalirudinactivity elimination is independent of specific organ metabolism. Bivalirudin has been used successfully as ananticoagulant in interventional cardiology procedures as a replacement for heparin. In fact, in interventional cardiology,bivalirudin has been associated with less bleeding and equivilent ischemic outcomes when compared to heparin plus aplatelet inhibitor. Bivalirudin anticoagulation induces less P-selectin expression than do either UH or LMWH, indicatingless platelet reactivity and possibly some platelet protection. In off-pump coronary artery bypass surgery, Merry et al.found equivalent bleeding outcomes with bivalirudin and heparin, and the bivalirudin patients exhibited higher graftflows.10 A prospective randomized trial in 150 patients undergoing CPB surgery demonstrated similar proceduraloutcomes and adverse event rates with bivalirudin and heparin.11 This CPB trial dosed bivalirudin at 1 mg/kg as inintravenous bolus followed by 2.5 mg/kg/hr as in infusion. When bivalirudin is used, care must be exercised to ensurethe absence of stasis in the CPB circuit lest thrombin be formed and metabolize bivalirudin. The ecarin clotting time better correlates with anti-IIa activity and plasma drug concentrations than does theACT but it is currently not commercially available. Modified ACT (1 to 1 dilution of patient blood with FFP) and thestandard ACT have also been used safely to monitor the anticoagulant effects of bivalirudin. In recent clinical trialsusing bivalirudin during CPB, an ACT of two and one half times the baseline value was accepted as therapeutic. Argatroban (MW 527 Daltons) is a synthetic derivative of arginine that inhibits thrombin by binding onlyto its catalytic site. It is approved for use as an alternative anticoagulant to heparin for patients with HIT. Likehirudin and bivalirudin (and unlike heparin), argatroban inhibits both circulating and fibrin-bound thrombin. Theplasma elimination half-life is approximately 40 minutes, and the agent is metabolized by the liver with biliaryelimination. Thus, argatroban offers appeal in patients with severe renal insufficiency or renal failure. Argatrobananticoagulation for CPB is initiated (with or without a loading dose) with a bolus of 0.1-0.2 mg/kg followed by an
406Page 3intravenous infusion at 5-10 µg/kg/min (less if there is hepatic insufficiency), and the dose is then adjusted tomaintain the aPTT 1.5 – 3 times normal. The ACT may also be used to guide therapy, in which case the optimalACT level appears to be 300-400 seconds. Argatroban has been used safely as a heparin substitute for CPB, however many bleeding complicationshave been reported. Argatroban has also been used successfully for anticoagulation during pediatric cardiac surgerywith CPB and for extra-corporeal membrane oxygenation. Problems with both bleeding and clotting (even in thesame patient) have been reported, so the drug may be unsatisfactory for CPB, or alternatively the optimal dosing andmonitoring may have not yet been determined.Antifibrinolytic TherapyProphylactic use of synthetic antifibrinolytic agents aminocaproic acid (EACA), tranexamic acid, and the serineprotease inhibitor aprotinin has been shown to reduce bleeding and transfusion requirements after CPB inrandomized trials and in multiple meta-analyses.12 Presumably these effects are a result of the inhibition offibrinolysis and the indirect inhibition of plasmin’s anti-platelet effects. Aprotinin is a hemostatic agent and hasanti-inflammatory properties. Recent observational data describe an increased occurrence of renal dysfunction usingaprotinin in non-randomized patients using a propensity score matching procedure to eliminate confoundingvariables.13 The preponderance of prospective randomized evidence suggests that aprotinin treatment is notassociated with adverse end-organ outcomes. The use of aprotinin in the highest risk patients contributes to thestatistical finding of adverse outcomes when using the drug. It is not clear that propensity scoring was able tosuccessfully eliminate all confounders in this study. A large-scale prospective trial is underway in Canada, thatcompares the antifibrinolytic agents in high risk surgical procedures. The results of this trial, and a careful cost-benefit analysis will help to determine in which patients this drug will be most beneficial.Anti-Platelet TherapeuticsAnti-thrombotic therapy for the treatment of acute coronary syndromes and interventional cardiology procedures isincreasing and the development of new drugs continues to occur. Treatment of patients after implant of a drug-eluting stent includes 12 months of anti-thrombotic therapy which poses a risk for patients who require surgery inthat time period.14 Cardiovascular patients who are maintained on drugs such as clopidogrel, have increasedbleeding complications and morbidity after cardiac surgery.15 This class of drug (thienopyridine agents) act by non-competitive antagonism at one of the platelet ADP receptors, the P2Y12 receptor. The P2Y12 receptor inhibitscyclic AMP production and potentiates platelet aggregation. The duration of anti-platelet activity is the life-span ofthe platelet because the P2Y12 receptor is permanently altered. The effects of clopidogrel plus aspirin are not justadditive, they are synergistic and this may explain why cardiac surgical patients having received this combination ofdrugs seem to have excessive postoperative bleeding.16 Specific monitoring of the platelet defect induced by theseanti-thrombotic drugs would be advantageous for a number of reasons. For therapeutic efficacy, the degree to whichpatients are protected from thrombotic events is related to the degree of platelet inhibition. Thus platelet functionmonitoring can be used for titrating drug effect. However, when patients present for surgery after discontinuation ofclopidogrel, specific platelet function testing is useful in order to determine the risk of bleeding and possible needfor transfusion. A number of point-of-care platelet function assays have been developed that utilize ADP and canassess the degree of platelet inhibition with some degree of accuracy as compared with standard aggregometry.Platelet function tests are listed in Table 2.Testing is useful in transfusion algorithms.17 Aprotinin has been studied in small prospective trials in patients pre-exposed to clopidogrel therapy.18 In patients presenting after coronary intervention or after acute coronarysyndromes, bleeding was reduced in patients who received high dose aprotinin therapy during CPB, even ifclopidogrel was continued until the time of cardiac surgery.19
406Page 4Table 2 Instrument Mechanism/Agonist Clinical Utility Thromboelastograph® Viscoelastic/ Thrombin (native), Post-CPB, liver transplant, ADP, aracidonic acid (AA)20 pediatric, obstetrics, drug efficacy Sonoclot® Viscoelastic/ Thrombin Post-CPB, liver transplant, PlateletWorks® Pltt count ratio/ ADP, AA, Post-CPB, drug therapy collagen21 PFA-100® In vitro bleeding time/ ADP, vWD, congenital disorder, aspirin epinephrine17 therapy, post-CPB Ultegra® Agglutination/TRAP, AA, ADP Drug therapy Clot Signature Analyzer® Shear-induced in vitro bleeding Post-CPB, drug effects time/Collagen Whole blood aggregometry Electrical impedance/Many Post-CPBRecombinant Activated Factor VIIRecombinant Factor VIIa ([rVIIa]Novo Seven®, Novo Nordisk (Denmark)) has been reported to be effective inrestoring hemostasis that results from severe hemorrhagic complications after CPB. Originally this drug wasprescribed for patients with specific factor deficiencies such as Hemophilia A with inhibitors. rVIIa induceshemostasis directly at the site of bleeding by binding to locally expressed tissue factor. This activated Factor VIIthen activates Factor X of the common coagulation pathway and Factor IX of the intrinsic coagulation pathway.22Thrombin generation is enhanced but without systemic activation of coagulation. Occasional case reports indicatethat in severe uncontrolled hemorrhage, after other possible therapeutic modalities were exhausted, recombinantfactor VIIa was effective in attenuating bleeding after CPB and in other surgical settings.23 A small randomized trialin 20 cardiac surgical patients demonstrated significantly fewer transfusions in the rVIIa group.24 Observationaldata indicate a higher incidence of adverse events in bleeding patients who receive rVIIa late rather than early in thecourse of hemorrhage.25 Large-scale prospective randomized trials are underway in cardiac surgery to evaluatesafety and efficacy. Mechanistically, rVIIa may reduce the bleeding due to platelet inhibitor therapy. The thrombinburst that is created during the propagation phase of coagulation may augment platelet function to a degree that isclinically acceptable and restores hemostasis. This is another potential area of study for the clinical use of rVIIa.SummaryThe hematologic abnormalities of CPB result from contact with extracorporeal surfaces and the resultantabnormalities of coagulation, fibrinolysis, and inflammation. These abnormalities are not solely due to CPB as theyexist in off-pump cardiac surgical patients as well. Concomitant anti-thrombotic drug therapy has increasedbleeding in cardiac surgery and further underscores the need for point of care testing of the hemostatic system.Antifibrinolytic agents help to reduce bleeding and aprotinin has been shown to reduce clopidogrel-related bleeding.Combinations of therapies(antifibrinolytic therapy plus rVIIa) require further investigation in cardiac surgery toassess the benefit and risks.References: 1. Ranucci M, Isgro G, Cazzaniga A, Ditta A, Boncilli A, Cotza M, Carboni G, Brozzi S:Different patterns of heparin resistance: therapeutic implications. Perfusion 2002; 17: 199-204 2. Pleym H, Videm V, Wahba A, Asberg A, Amundsen T, Bjella L, Dale O, Stenseth R:Heparin resistance and increased platelet activation in coronary surgery patients treated with enoxaparinpreoperatively. Eur J Cardiothorac Surg 2006; 29: 933-40 3. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi S: Postoperativeantithrombin levels and outcome in cardiac operations. Crit Care Med 2005; 33: 355-60 4. Nicholson SC, Keeling DM, Sinclair ME, Evans RD: Heparin pretreatment does not alterheparin requirements during cardiopulmonary bypass. Br J Anaesth 2001; 87: 844-7 5. Shore-Lesserson L, Manspeizer HE, Bolastig M, Harrington D, Vela-Cantos F, DePerio M:Anticoagulation for cardiac surgery in patients receiving preoperative heparin: use of the high-dose thrombintime. Anesth Analg 2000; 90: 813-8 6. Warkentin TE: An overview of the heparin-induced thrombocytopenia syndrome. SeminThromb Hemost 2004; 30: 273-83
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