Hematologic Aspects of Cardiac SurgeryLinda Shore-Lesserson, M.D. Bronx, New York
314Page 1
Introduction
The hematologic management of the cardiac surgical patient entails a complex balance between extreme degrees of anticoagulation and the restoration of normal hemostasis after the procedure. These two opposing processes must be managed carefully and modified with respect to preoperative disease state, duration of cardiac surgery, use of extracorporeal 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 heparinresistance and heparin-induced thrombocytopenia. Following CPB, coagulation abnormalities, platelet dysfunction,and fibrinolysis occur and render the patient hemostatically impaired. Bleeding should be managed using carefulhemostasis monitoring. Fibrinolysis can be prevented and transfusions minimized by the use of
antifibrinolytictherapy.
Proper use of these agents and their safety will be discussed. Uncontrolled hemorrhage has beenanecdotally treated with success using
activated Factor VII
, and this therapy has thus gained increasing popularity in postoperative hemorrhage. This complex hemostatic picture is coupled with the concurrent use of anti-thromboticmedication in the cardiovascular patient 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 theyincrease bleeding after surgery and they increase bleeding-related complications.
Biocompatibility
It is well-accepted that the bio-incompatibility of the CPB circuit and the blood trauma incurred as a resultof the pump and cardiotomy suction are responsible for the disruption of homeostatic systems. The major threehomeostatic systems affected are the coagulation, fibrinolytic, and inflammatory cascades. Efforts to reduce theactivation of these systems can reduce morbidity and improve outcome. Coated circuits, either with heparin, or other substances have been demonstrated to reduce the inflammatory response to CPB. Markers of leukocyteactivation and complement activation are lower when heparin-coated circuitry is used.
1
The use of cardiotomysuction is traumatic to blood cells, yet it is such an integral part of most cardiac surgical procedures. Data supportthat when cardiotomy suction is avoided, platelet function is better protected and inflammatory markers arereduced.
2,3
Neurologic outcomes have not been definitively shown to improve despite a reduction in cerebralembolic phenomenon. Activation of thrombin occurs during CPB. When thrombin is activated, anticoagulant proteases are released, and fibrin cross-linkage, fibrinolysis, and platelet activation occur. It should be evident thenthat prevention of thrombin activation should be a major goal of the management of CPB. Heparin alone is aninadequate method for deactivating thrombin. Heparin has adverse effects and thrombin inhibiting effects that areinferior to those of the direct thrombin inhibitors. (see Table 1) The following section will describe the thrombininhibitor drugs and their use in cardiac surgery.
Heparin Direct Thrombin InhibitorsMode of action Indirect DirectCatalyst needed Yes- anti-thrombin III NoInhibits clot-bound thrombin No YesActivates platelets Yes (LMWH moderately yes) NoAntigenicity Yes No (bivalirudin) Yes (hirudin)Antidote drug Yes- protamine No
Heparin Resistance
Patients on preoperative heparin therapy traditionally require larger heparin doses to achieve a given level of anticoagulation when that anticoagulation is measured by the ACT. Presumably this “heparin resistance” is due todeficiencies in the level or activity of antithrombin III (ATIII). Other possible etiologies include enhanced factor VIII activity and platelet dysfunction causing a decrease in ACT response to heparin.
4,5
Platelet activation is less prevalent with the direct thrombin inhibitors and was thought to be less prevalent with low molecular weight
314Page 2heparin. Data now suggest that LMWH also contributes to platelet activation and heparin resistance.
6
Montes andLevy have shown that the in vitro addition of ATIII enhances the ACT response to heparin.
7
It is unclear that these patients have increased heparin requirements during CPB since the ideal ACT and monitoring techniques have yet to be elucidated. ATIII concentrate is now available and represents a reasonable method of treating patients withdocumented ATIII deficiency.
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 antibody binding to the complex formed between heparin and platelet factor 4 (PF4). 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 has been used to delineate the course of IgG and IgM antibody responses in patients exposed to unfractionated heparinduring cardiac surgery. Bedside antibody tests are being developed that may speed the diagnosis of this condition.
8
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 and disseminated intravascular coagulationdespite positive laboratory testing. Heparin-induced thrombocytopenia should possibly be considered in thedifferential diagnosis of intraoperative heparin resistance in patients receiving preoperative heparin therapy.
9
The options for treating these patients are few. If one has the luxury of being able to discontinue theheparin for a few weeks, often the antibody will disappear and allow a brief period of heparinization for CPBwithout complication.
10,11
Changing the tissue source of heparin is no longer an option since most heparin is porcineanyway. Some types of LMWH have been given in heparin-induced thrombocytopenia but reactivity of the particular LMWH with the patient's platelets should be confirmed in vitro. Supplementing heparin administrationwith pharmacologic platelet inhibition using prostacyclin, iloprost, aspirin, or tirofiban have been reported, all withfavorable outcomes.
12,13
Plasmapheresis may be used to reduce antibody levels. The use of heparin could beavoided altogether by anticoagulating with hirudin or bivalirudin.
Hirudin
A coagulation inhibitor isolated from the salivary glands of the medicinal leech (Hirudo medicinalis), hirudin is a potent inhibitor of thrombin that, unlike heparin, acts independently of AT III and inhibits clot-bound thrombin aswell as fluid-phase thrombin. Hirudin does not require a cofactor and is not susceptible to neutralization by PF4.This would seem beneficial in patients in whom platelet activation and thrombosis is a hallmark of the disease. R-hirudin was given as 0.25 mg/kg bolus and an infusion to maintain the hirudin concentration at 2.5 mcg/ml asdetermined by ecarin clotting time. Hirudin is a small molecule (MW 7kD) that is eliminated by the kidney and iseasily hemo-filtered at the end of CPB.
Bivalirudin
Bivalirudin is a small 20-amino acid molecule with a plasma half-life of 24 minutes. It is a synthetic derivative of hirudin and thus acts as a direct thrombin inhibitor. Bivalirudin binds to both the catalytic binding site and theanion-binding exosite on fluid phase and clot-bound thrombin. The part of the molecule that binds to thrombin isactually cleaved by thrombin itself, so the elimination of bivalirudin activity is independent of specific organmetabolism. Bivalirudin has been used successfully as an anticoagulant in interventional cardiology procedures as areplacement for heparin therapy. In fact, in interventional cardiology, bivalirudin has been associated with less bleeding and equivilent ischemic outcomes when compared to heparin plus a platelet inhibitor.
14
This may be theresult of bivalirudin being both an anti-thrombin anticoagulant and an anti-thrombin at the level of the platelet.Merry et al. showed equivilence with regard to bleeding outcomes and an improvement in graft flow after off-pumpcardiac surgery when bivalirudin was used (0.75 mg/kg bolus, 1.75 mg/kg/h infusion).
15
Case reports confirm thesafety of bivalirudin use during CPB, and a large-scale randomized trial confirms non-inferiority of bivalirudin toheparin.
16,17
ACT monitoring has been used for the direct thrombin inhibitors, but plasma modified ACT tests will be more correlative with anti-thrombin activity and drug levels.
18
314Page 3
Antifibrinolytic Therapy
Prophylactic use of synthetic antifibrinolytic agents aminocaproic acid (EACA), tranexamic acid, and the serine protease inhibitor aprotinin has been shown to reduce bleeding and transfusion requirements after CPB inrandomized trials and in multiple meta-analyses.
19
Presumably these effects are a result of the inhibition of fibrinolysis and the indirect inhibition of plasmin’s anti-platelet effects. It seems that the beneficial hemostaticeffects of these drugs are most pronounced in the higher risk patients in whom the occurrence of microvascular bleeding is high. Aprotinin is a superior hemostatic agent and has anti-inflammatory properties, however a recent publication has created concern about its effects on renal function in comparison with the syntheticantifibrinolytics.
20
The preponderance of prospective randomized evidence suggests that a small rise in creatinineseen after aprotinin treatment does not translate into a clinical decrement in creatinine clearance, urine output, or renal failure.
21
A recent observational study describes an increased occurrence of renal dysfunction in non-randomized patients using a propensity score matching procedure to eliminate confounding variables.
20
It is notclear that propensity scoring was able to successfully eliminate all confounders in this study.
22
A large-scale prospective trial is underway in Canada, that compares 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 bemost beneficial.
Anti-Platelet Therapeutics
Anti-platelet therapy has been rapidly advancing due to the introduction of the thienopyridine derivatives ticlopidineand clopidogrel (Plavix®, Sanofi). These drugs act by non-competitive antagonism at one of the platelet ADPreceptors, the P2Y12 receptor.
23
The P2Y12 receptor inhibits cyclic AMP production and potentiates plateletaggregation.
24
The duration of anti-platelet activity is the life-span of the platelet because the P2Y12 receptor is permanentlyaltered. The effects of clopidogrel plus aspirin are not just additive, they are synergistic and this may explain whycardiac surgical patients having received this combination of drugs seem to have excessive postoperative bleeding.Patients on these medications who then present for cardiac surgery are at increased risk for bleeding complicationsand have a documented increase in transfusions and reoperations for bleeding.
25
Specific monitoring of the platelet defect induced by these anti-thrombotic drugs would be advantageous for anumber of reasons. For therapeutic efficacy, the degree to which patients are protected from thrombotic events isrelated to the degree of platelet inhibition. Thus platelet function monitoring can be used for titrating drug effect.Alternatively, patients taking these medications who present for surgery can be assayed for their degree of plateletdysfunction and their risk of bleeding and need for transfusion. (see table 2)
Instrument Mechanism/Agonist Clinical UtilityThromboelastograph® Viscoelastic/ Thrombin (native),ADP, aracidonic acid (AA)
26
Post-CPB, liver transplant, pediatric,obstetrics, drug efficacySonoclot® Viscoelastic/ Thrombin Post-CPB, liver transplant,PlateletWorks® Pltt count ratio/ ADP, AA, collagen Post-CPB, drug therapyPFA-100® In vitro bleeding time/ ADP,epinephrinevWD, congenital disorder, aspirintherapy, post-CPBUltegra® Agglutination/TRAP, AA, ADP Drug therapyClot Signature Analyzer® Shear-induced in vitro bleedingtime/CollagenPost-CPB, drug effectsWhole blood aggregometry Electrical impedance/Many Post-CPB
Recombinant Activated Factor VII
Recombinant Factor VIIa (Novo Seven, Novo Nordisk (Denmark)) has been reported to be effective in restoringhemostasis that results from severe hemorrhagic complications after CPB. Originally this drug was prescribed for patients with specific factor deficiencies such as Hemophilia A with inhibitors. The principle upon whichrecombinant factor VIIa induces hemostasis is that it acts directly at the site of bleeding by binding to locallyexpressed tissue factor. This activated Factor VII then activates Factor X of the common coagulation pathway andFactor IX of the intrinsic coagulation pathway. Thrombin generation is enhanced but without systemic activation of coagulation. This is the reason that hypercoagulability and thrombotic occurrences are rare. Another potentialmechanisms of activity is that recombinant factor VIIa acts independently of tissue factor and enhances platelet
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