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Sunday June 20 2004 |
From the Department of Anesthesiology, Mount Sinai School of Medicine, New York, New York, USA.
Address correspondence to: Dr. Linda Shore-Lesserson, Associate Professor of Anesthesiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1010, New York, New York 10029, USA. Phone: 212-241-7467; Fax: 212-987-6675; E-mail: Linda.shore{at}msnyuhealth.org
HEMOSTASIS in cardiovascular patients is a challenge that clinicians have only begun to embrace. Caring for patients with cardiovascular disease requires an understanding of the etiology of the disease and the predisposing characteristics that make these patients hypercoagulable, hyperthrombotic, both, or neither. Patients host a heterogeneous complement of genetic and environmental factors which render them susceptible to arterial injury, atherosclerosis, inflammatory processes, thrombosis, and fibrinolysis.
Coupled with the complex pathophysiology of the vascular patient, are the unique hemostatic perturbations that occur as a result of cardiac surgery utilizing cardiopulmonary bypass (CPB). The presence of extracorporeal circuitry and the oxygenator have demanded meticulous attention to maintaining adequate anticoagulation during CPB. As we understand more about the limitations of heparin, and as new drugs become available for use, the search for new anticoagulants and alternative monitoring techniques during CPB will continue to progress.
Hemostasis after CPB is still a vexing problem. Patients having been exposed to antiplatelet medications in the preoperative period are particularly prone to bleeding after CPB. This is due to the additive effects of the antiplatelet therapeutics and the well-known platelet defects that occur as a result of CPB. The two opposing processes of anticoagulation and hemostasis must be managed carefully and modified with respect to the patient’s hematologic status and desired hemostatic outcome. This review will summarize some potential new drugs for use as anticoagulants for cardiovascular procedures. Additionally, the new antiplatelet medications, and their respective mechanisms of activity will be described.
Anticoagulants
Heparin has been the gold standard for anticoagulation during cardiac surgery. Heparin has been used in a number of different dosing protocols and has proven to be a relatively safe drug for this purpose.1 Advantages of heparin include its rapid onset of activity, linear dose-response pharmacokinetics in the clinical range of use, and its ease of reversibility with protamine. However, many of these same advantages are included as disadvantages to the use of heparin. Heparin requires an adequate concentration of its cofactor antithrombin III (AT3) in order to inhibit coagulation.2 As a result of its size, and its necessary association with AT3, heparin only inhibits fluid-phase thrombin, not clot-bound thrombin.
Heparin resistance
Patients on preoperative heparin therapy traditionally require larger heparin doses to achieve a given level of anticoagulation when anticoagulation is measured by the activated coagulation time (ACT). Presumably this "heparin resistance" is due to deficiencies in the level or activity of AT3.3 Other possible etiologies include enhanced factor VIII activity and platelet activation causing a blunted ACT response to heparin.4,5 Montes and Levy have shown that the in vitro addition of AT3 enhances the ACT response to heparin.6 Lemmer demonstrated that heparin resistance, as measured by the ACT, does not correlate with low preoperative AT3 levels.7 It is unclear if these patients have increased heparin requirements during CPB since the ideal ACT and monitoring techniques in heparin-exposed patients have yet to be elucidated.8 AT3 concentrate is now available and represents a reasonable method of treating patients with documented AT3 deficiency.
Heparin activates platelets, rendering them aberrantly adhesive, yet less functional in performing normal hemostasis activities.9 The mere proaggregatory activity of heparin causes a mild reduction in platelet count. This often leads to the clinical syndrome "heparin-induced thrombocytopenia (HIT) type I." This fairly benign process usually occurs early in the course of heparin exposure and is characterized by a mildly reduced platelet count. In contrast, HIT II is an immunologically mediated process and is a more serious disease. The platelet surface contains platelet-factor (PF) 4, to which heparin binds. In certain patients, this heparin-PF4 complex generates an immune response and results in the clinical syndrome HIT II.
The heparin/PF4 complexes exist on platelets and endothelial cells and are activated when antibody binds. Associated immune-mediated endothelial injury and complement activation cause platelets to adhere, aggregate, and form platelet clots, or "white clots." Among patients developing HIT II, the incidence of thrombotic complications approximates 20%, which in turn may carry a mortality rate as high as 40%. Demonstration of heparin-induced pro-aggregation of platelets confirms the diagnosis of HIT type II. This can be accomplished 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 heparin during cardiac surgery.
The risks and appropriate courses of action in patients with HIT II are unclear because the antibodies associated with HIT often become undetectable several weeks after discontinuing heparin.10 Also the clinical syndrome does not always recur upon re-exposure to the drug and sometimes resolves despite continued drug therapy. Many patients never develop thrombosis and disseminated intravascular coagulation despite positive laboratory testing. HIT should possibly be considered in the differential diagnosis of intraoperative heparin 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 and allow a brief period of heparinization for CPB without complication.10,11 Changing the tissue source of heparin might avert the reaction since it may occur more frequently with bovine heparin. Some types of low molecular weight heparin (LMWH) have proven effective in HIT but reactivity of the particular LMWH with the patient’s platelets should be confirmed in vitro. Supplementing heparin administration with pharmacologic platelet inhibition using prostacyclin, iloprost, aspirin, or aspirin and dipyridamole, and recently, tirofiban, have been reported, with favourable outcomes. Plasmapheresis may be used to reduce antibody levels. The use of heparin could be avoided 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 AT3 and inhibits clot-bound thrombin as well as fluid-phase thrombin. Hirudin does not require a co-factor and is not susceptible to neutralization by PF4. It also does not activate platelets as unfractionated heparin does. This would seem beneficial in patients in whom platelet activation and thrombosis is a hallmark of the disease. When used during CPB, hirudin can be given as 0.25 mg·kg·1 bolus and an infusion to maintain the hirudin concentration at 2.5 µg•mL·1 as determined by ecarin clotting time. The ecarin clotting time, modified for use in the Bayer Rapidpoint® analyzer has been used in large series of HIT patients.12 Compared with standard treatment with heparin or LMWHs, hirudin treated patients maintain platelet counts and hemoglobin levels and have few bleeding complications, if renal function is normal. Hirudin is a small molecule (MW 7kD) that is eliminated by the kidney and is easily filtered at the end of CPB.
Bivalirudin
Bivalirudin is a small 20-amino acid molecule with a plasma half-life of 24 min. It is a synthetic derivative of hirudin and thus acts as a direct thrombin inhibitor. Bivalirudin binds to both the catalytic binding site and the anion-binding exosite on fluid phase and clot-bound thrombin. The part of the molecule that binds to thrombin is actually cleaved by thrombin itself, so the elimination of bivalirudin activity is independent of specific organ metabolism. Bivalirudin has been used successfully as an anticoagulant in interventional cardiology procedures as a replacement for heparin therapy. A series of patients undergoing coronary artery bypass grafting, both on pump and off-pump have also received bivalirudin for safe anticoagulation.13,14 Monitoring of anticoagulant activity is performed using the ecarin clotting time with similar prolongation as that seen with hirudin anticoagulation.15
Antiplatelet therapeutics
The glycoprotein IIbIIIa (GPIIbIIIa) receptor is responsible for mediating platelet-platelet aggregation via fibrinogen bridging. Drugs that inhibit this receptor in a reversible or an irreversible fashion are potent inhibitors of platelet aggregation and include abciximab (Reopro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®). They are frequently infused to prevent thrombus formation in patients who have undergone a high risk coronary interventional procedure. Large-scale multicentre studies have shown that re-thrombosis and infarction rates after percutaneous angioplasty and after stent procedures have been reduced with the use of these drugs.16 Reductions in mortality and re-infarction rates have been shown in such patient groups as diabetics and patients with prior cardiac surgery.17,18
Of the three iv GPIIbIIIa inhibitors, abciximab is a large monoclonal antibody which binds and causes permanent dysfunction of the GPIIbIIIa receptor, while also blocking other receptors due to its large size. Comparative studies and head-to-head comparisons have shown that abciximab is superior to the other agents in preventing ischemic complications, which explains its prevalence of use.19 However, its potent platelet inhibiting properties also render it likely to cause increased episodes of major bleeding. Patients who present for cardiac surgery after having received abciximab often require a prolonged operative time to achieve hemostasis and have an increased incidence of platelet transfusions.20 By contrast, the small molecule agents, eptifibatide and tirofiban are competitive blockers whose small size and half-life of approximately two hours, make it possible to conduct cardiac surgery without an increased risk of bleeding. Studies have documented lower myocardial infarction rates21 and similar bleeding rates22 in emergency coronary bypass patients who received eptifibatide compared with those that received placebo prior to surgery. Animal platelet studies suggest that platelets that are quiescent during CPB due to GPIIbIIIa receptor blockade have better recovery of platelet function after CPB.23
Antiplatelet therapy has been rapidly advancing due to the introduction of the thienopyridine derivatives ticlopidine and clopidogrel (Plavix®). Clopidogrel has almost completely replaced ticlopidine for this use as it has a wider therapeutic index, a lesser side effect profile, and is more efficacious at doses used clinically. These drugs act by non-competitive antagonism at one of the platelet adenosine diphosphate (ADP) receptors, the P2Y12 receptor. There are three known ADP receptor subtypes. The P2X receptor is a calcium ion channel. The P2Y1 receptor is the major receptor responsible for regulating calcium influx and subsequent aggregation. The P2Y12 receptor inhibits cyclic adenosine monophosphate production and potentiates platelet aggregation (Figure
).
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Specific monitoring of the platelet defect induced by these antithrombotic drugs would be advantageous for a number of reasons. For therapeutic efficacy, the degree to which patients are protected from thrombotic events is related to the degree of platelet inhibition.27 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 platelet dysfunction and their risk of bleeding and need for transfusion.
Platelet function monitoring
The most critical aspect of monitoring platelet function is the ability to measure the specific defect that is present. Platelet function is so complex, involving multiple pathways of activation, degranulation, cell-signaling pathways, and aggregation, that the proper agonist and end result must be measured if an accurate assessment of platelet function or dysfunction will be made. The following platelet function monitors have been studied for use in measuring the platelet defect in patients receiving antiplatelet medication. The platelet function analyzer (PFA-100, Dade-Behring, Dade, FL, USA) is an in vitro bleeding time that uses a collagen-coated membrane activated with ADP or epinephrine to measure platelet function at the point of care. By virtue of utilizing ADP as an agonist, the PFA-100 would seem useful in measuring platelet dysfunction induced by clopidogrel. It has been used in this fashion in interventional cardiology patients, but does not yet have the predictive capacity of a gold standard like aggregometry.
Ultegra® (Accumetrics, San Diego, CA, USA) is a point of care aggregometer that utilizes fibrinogen macrobeads and a thrombin agonist to activate platelets. When platelets become activated with thrombin, the GPIIbIIIa receptor is up-regulated and platelet to platelet aggregation via fibrinogen bridging occurs. In the Ultegra®, this bridging occurs via the fibrinogen macrobeads. The degree of agglutination is then measured using optical densitometry methods. When the GPIIbIIIa receptor is antagonized, the degree to which platelets aggregate is reduced and an appropriate reduction in the Ultegra® platelet function is measured. Ultegra® and the Clot Signature Analyzer (CSA®; Xylum Corp.) have been used to comparatively assess the platelet inhibitory capacity of the three iv GPIIbIIIa inhibitors. This study indicated that Ultegra® results were very close to those of standard aggregometry, while the CSA results were unable to detect platelet inhibitory capacity with any specificity.28 High degrees of platelet inhibition on Ultegra®27 have been shown to correlate with a lower incidence of adverse cardiac events after coronary interventions.
PlateletWorks (Helena, Beaumont, TX, USA) assesses platelet function using a platelet count ratio: the ratio of the unactivated platelet count to that in response to a platelet agonist. The reduction in platelet count after the addition of a platelet agonist (ADP, collagen) is directly related to the platelet function. In other words, a larger reduction in platelet count would indicate better platelet function, and visa versa. PlateletWorks has been used to assess the inhibition of platelet function in patients taking clopidogrel. The metabolism of clopidogrel to its active drug form is by cytochrome P450 A3. Other drugs that compete for this enzyme will reduce the effectiveness of clopidogrel as a platelet antagonist.29,30 This has been documented using the PlateletWorks instrument and with whole blood aggregometry techniques.31
Currently, there are no data that validate any point-of-care test as a gold standard measure of platelet function in patients taking thienopyridine antiplatelet agents. Results with the aforementioned devices have yielded inconsistent results and are considered preliminary investigations. The clinical history of the patient is an excellent indicator of efficacy of the oral antiplatelet agents. This history in conjunction with platelet-rich plasma aggregometry will yield the most reliable data in terms of bleeding risk during surgery or interventional procedures. Similarly, the performance of conduction anesthesia techniques32 should only be performed in patients exposed to the thienopyridine antiplatelet drugs if the drugs have been discontinued for seven to 14 days OR if a proven acceptable test of platelet function yields a normal result. Remember that the appropriate test of platelet function will differ based upon the platelet defect incurred. Different clinical scenarios and different drug regimens will almost certainly dictate different "gold standard" tests of platelet function or dysfunction. It is important to understand the platelet defect present so that the most appropriate testing platform may be selected.
References
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