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MANAGEMENT OF ANTICOAGULATION AND PLATELET RECEPTOR INHIBITORS IN CARDIAC SURGICAL PATIENTS

Jerrold H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Division of Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia

   
Introduction

  In the early era of angioplasty, when emergency coronary artery bypass grafting was all too common, we would bring patients to the operating room for acute closure or dissection of coronary vessels. The need for emergency CABG has dwindled, and rushing a patient in cardiogenic shock from the cardiac catheterization laboratory is now a far less frequent occurrence due to the advent of intracoronary stents, and newer pharmacologic agents such as the glycoprotein (GP) IIb/IIIa receptor antagonists.

The glycoprotein (GP) IIb/IIIa receptor antagonists have assumed a pivotal role in cardiology, and have had a major impact on the cardiac surgeon as well. Patients who have been treated with GP IIb/IIIa receptor antagonists pose a challenge, not only for the cardiac surgical team, but also for all the physicians and other health care personnel involved in their management. We are still learning how to effectively manage these patients for cardiac surgery and CPB. This presentation will review the non-aspirin antiplatelet agents currently available, and review the management of patients receiving GP IIb/IIIa receptor antagonists and requiring cardiac surgery.
   

Glycoprotein IIb/IIIa antagonists

  Because of the pivotal role of the platelet glycoprotein IIb/IIIa complex in platelet-mediated thrombus formation, potent antagonists of this "final common pathway" of platelet aggregation have been developed as therapeutic strategies to treat acute coronary thromboses. Three different GP IIb/IIIa antagonists are currently available, they differ in antagonist affinity, reversibility, and receptor specificity. Glycoprotein IIb/IIIa (IIbß3) is a receptor on platelets that binds to key hemostatic proteins, including fibrinogen and von Willebrand factor (vWF), thus allowing for cross linking of activated platelets and platelet aggregation. By blocking this final common pathway using GP IIb/IIIa antagonists, these drugs function as inhibitors of platelet participation in acute thrombosis.

Various antagonists of GP IIb/IIIa receptor are available. The first of these agents, the monoclonal antibody abciximab (ReoPro), has been approved for use in percutaneous coronary intervention (PCI). Tirofiban (Aggrastat), a nonpeptide, has been approved for treatment of acute coronary syndromes (unstable angina or nonQ-wave myocardial infarction) and eptifibatide (Integrelin), a peptide, for use both in PCI and acute coronary syndromes. Nonpeptide oral antagonists of GP IIb/IIIa intended for long-term use are also in various stages of clinical development and may find application in a broad spectrum of atherothrombotic disease.
   

Ticlopidine and clopidogrel

  Antiplatelet agents are used primarily to treat and prevent arterial thrombosis. Ticlopidine and clopidogrel are believed to inhibit the binding of adenosine 5'-diphosphate (ADP) to its platelet receptor; this ADP receptor blockade leads to direct inhibition of the binding of fibrinogen to the glycoprotein IIb/IIIa complex. Ticlopidine may also interfere with von Willebrand factor, resulting in less binding of von Willebrand factor to platelet receptors. Ticlopidine and its more recently developed analog, clopidogrel, are thienopyridine derivatives. Ticlopidine and clopidogrel can both be administered orally. Both agents are inactive in vitro, requiring breakdown to an unidentified active metabolite or metabolites to achieve in vivo activity. Activation seems to occur in the liver, and the active metabolites are primarily excreted renally.

Ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. Clopidogrel was approved by the FDA for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the increasing use of clopidogrel in coronary stenting, is rapidly growing. Many heart centers now administer clopidogrel before anticipated stenting procedures. The variability in bleeding in patients receiving these agents for cardiac surgery may relate to the time and duration of therapy.

   
Heparin

  Heparin represents the most commonly used anticoagulant to prevent clotting during cardiac or vascular surgery. Heparin is isolated from either porcine intestine or from beef lung where it is bound to histamine and stored in the mast cell granules. When heparin is isolated, the purification leads to a heterogeneous mixture of molecules. Heparin is an acidic polysaccharide with side groups, either sulfates or N-acetyl groups, attached to individual sugar group. The sulfate groups are extremely important in the anticoagulant activity of heparin. Heparin acts indirectly as an anticoagulant by binding to antithrombin III (AT III) enhancing the rate of thrombin-AT III complex formation by 1000 to 10,000 fold. Several other steps in coagulation cascade, including clotting factor X are also inhibited to a lesser degree by AT III. Anticoagulation thus depends on the presence of adequate amounts of circulating AT III. The advantage of this is that heparin anticoagulation can be re versed immediately by removing heparin from AT III with protamine. Heparin also binds to a number of other blood and endothelial proteins including high molecular weight kininogen, von Willebrand factor, plasminogen, fibronectin, lipoproteins and platelet and endothelial receptors. Each of these may potentially influence the ability of heparin to act as an anticoagulant, and may, along with AT III levels, affect heparin dose responses in patients. Heparin can also produce platelet dysfunction following acute and/or constant administration, especially with high dose administration during cardiac surgery.

Despotis reported that the maintenance of higher than usual patient-specific heparin concentrations during cardiopulmonary bypass (CPB) was associated with more effective suppression of hemostatic activation. Maintenance of higher patient-specific heparin concentrations during CPB more effectively suppressed excessive hemostatic system activation than did standard heparin doses chosen based on measurement of ACT. These findings may explain, at least in part, the significant reduction in perioperative blood loss and blood product use when higher heparin concentrations are maintained. Further, Mochizuki has shown that excess protamine can further alter coagulation and coagulation tests, and the careful exact titrated reversal of heparin avoiding excess protamine may be an important contribution of work by done Despotis.
   

New Anticoagulants

  Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening, adverse effect of heparin therapy produced by antibodies (IgG) to the composite of heparin-platelet factor 4 (PF4) that leads to the formation of immune complexes. These immune complexes bind to platelets via platelet Fc-receptors (CD 32) producing intravascular platelet activation, thrombocytopenia, and platelet activation with potential thromboembolic complications that can result in limb loss or death. When patients with HIT require CPB, the heparinoid danaparoid (Orgaran), ancrod, and several other drugs have been used with various degrees of success. Danaparoid is often used but it has limitations that include cross-reactivity with HIT antibodies, a relatively long half-life (t1/2 of antifactor Xa activity of 24 hours), and monitoring that is complicated by the need to measure antifactor Xa activity. Also, no antidote is available. Hirudin, an antithrombotic substance produced in leech salivary is the most potent and specific thrombin inhibitor currently known. It acts independently of cofactors such as antithrombin, and unlike heparin, it is not inactivated by PF4. Recombinant hirudin (Lepirudin) is currently available. Potch reported on using Lepirudin during cardiopulmonary bypass in patients with HIT using a 0.25-mg/kg bolus and then 5-mg boluses when hirudin concentration was <2500 ng/mL as determined by ecarin clotting time.

   
Other Anticoagulation Strategies

  One promising therapy currently under investigation is the use of purified antithrombin III (AT III). Despite high dose heparin for patients undergoing cardiac surgery, thrombin generation and activity continues during cardiopulmonary bypass (CPB). Antithrombin III (ATIII) levels, which are lower in patients receiving IV heparin prior to the procedure, and decrease further by 40 to 50% following initiation of CPB, may be critical in determining the extent of thrombin inhibition. Better anticoagulation during CPB may be associated with less bleeding post procedure, presumably related to preservation of critical coagulation components. Supplemental AT III, through improved heparin sensitivity and enhanced anticoagulation, may preserve hemostasis during CPB and thereby decrease the microvascular bleeding and complications during cardiac surgery. Adequate anticoagulation depends on the interaction between AT and heparin, however patients receiving intravenous heparin prior to surgery have significantly lower AT III levels and these levels further decrease following initiation of cardiopulmonary bypass (CPB). A potentially significant contributing factor that prevents the inhibition of thrombin generation and activity while on CPB is a low concentration of ATIII. Further, the use of heparin preoperatively is associated with a diminished anticoagulation response as measured by ACT and this is presumably due to the lower AT III levels. The importance of augmenting ATIII levels is also suggested by data from patients who have received warfarin preoperatively and who had higher AT III levels at the start of procedures, a greater prolongation of the anticoagulation response to heparin and less thrombin generation while on CPB with greater preservation of platelet function.

Because maintaining normal or elevated plasma AT III levels during cardiopulmonary bypass could potentially improve thrombin inhibition, we have investigated the role of increasing doses of AT III from transgenic recombinant sources as a potential source of AT III. The development of microvascular bleeding requiring transfusions of allogenic blood products, which is a significant complication of CPB, can be potentially minimized through better anticoagulation and thrombin inhibition during the period when the patient is on CPB. The advantage of use of transgenically produced recombinant proteins include safety when compared to plasma derived proteins as well as an unlimited supply thus potentially allowing applications of even supraphysiologic doses of the AT III.
   

Heparin Reversal

  Unfractionated heparin has a relatively short half-life. Protamine can immediately reverse the anticoagulation effect of unfractionated heparin by non-specific polyionic-polycationic (acid-base) interactions. There are different methods to determine the amount of protamine to be administered, but using a ratio of 1.0-1.3 mg protamine: 100 units of unfractionated heparin administered are effective. Although protamine has the potential to function as an anticoagulant, this effect is only seen when large excessive doses have been administered. More importantly, protamine, a polypeptide isolated from fish sperm, does have the potential to produce anaphylactic reactions, and therefore must be administered slowly.

Fractionated heparin sulfate enjoys wide use in clinical practice as an anticoagulant to facilitate extracorporeal circulation, to prevent prosthetic graft thrombosis during vascular surgery, and to prevent thrombus formation during invasive angiographic procedures. Heparin's advantage as an anticoagulant consists of its rapid offset of action upon administration of a neutralizing agent. Protamine, the mainstay neutralizing agent, is a basic polypeptide isolated from salmon sperm. Comprised mostly of arginine, protamine reverses heparin by a non-specific acid-base interaction (polyanionic-polycationic). Neutralization by protamine is immediate; it is the only drug widely available for clinical use. The literature documents a variety of adverse reactions to protamine ranging from minimal cardiovascular effects to life threatening cardiovascular collapse. Life threatening reactions to protamine probably represent true anaphylactic or allergic manifestations, mediated by immunospecific antibodies. Stewart reported a 27% incidence of reactions following cardiac catheterization in insulin dependent diabetics who were also receiving neutral protamine Hagedorn insulin preparations. Other reports do not corroborate the extreme results of Stewart. Levy reported the incidence of life threatening reactions in cardiac surgical patients ranges from 0.6% to 2% in patients at risk. Life threatening reactions to protamine represent true allergic reactions.
   

Managing patients receiving abciximab for cardiac surgery

  The management of emergency coronary revascularization afterabciximab treatment is still evolving. Lemmer recently reported on 12 patients over a 29-month period who required emergencycoronary artery bypass grafting within 12 hours (mean, 1.9 hours)of abciximab therapy. A standard heparin dose regimenwas used (500 units/kg, mean heparin dose, 53,000 U per patient). Each patientreceived a single platelet transfusion after protamineadministration, and further blood products were transfused asnecessary depending on the bleeding. No patients died and none were returned to the operatingroom for coagulopathy-related bleeding. Per-patient transfusionrequirements were: red blood cells, 3.6 units; apheresisplatelets, 1.4 units; and fresh frozen plasma, 1.5 units. Ascompared with predicted values, there was no excessive incidenceof mortality, stroke, or red blood cell transfusion requirements. Lemmer suggests coronary artery bypass graft operationsusing full-dose heparin can be performed successfully in acutelyischemic abciximab-treated patients. He suggests that prophylactic transfusionof platelets after protamine administration appears to be useful.

Boehrer described32 patients who required urgent CABG after abciximab treatmentin a large, multicenter trial (EPIC) comparing abciximab versusplacebo in 2,099 patients. A total of 5 of the 32 abciximab-treatedpatients requiring surgery died within 30 days (16% mortality),although 4 of the deaths were not due to bleeding. Red blood cell transfusions were administered to 88% of thepatients, and 76% required platelet transfusions, higher levelsthan in the placebo group, although not to a statistically significantdegree. Thespecific numbers of blood product units required per patientwere not reported. In the EPIC trial the medianduration from abciximab treatment to CABG was more than 24 hours,at which time significant normalization of platelet functionwould be expected.

Booth reported results in patients requiringurgent CABG in two large trials of abciximab administrationwith percutaneous intervention. Twenty patients randomized toreceive abciximab required CABG within 7 days of percutaneousintervention, versus 22 in the placebo group. The investigatorsreport similar transfusion and bleeding complication rates forthe two groups, with the exception of higher platelet transfusionrates (75% versus 46%) for abciximab-treated patients versuscontrols. In this abstract the time interval between abciximabtreatment and CABG was not specified. Thespecific numbers of blood product units required per patientwere also not reported.

Gammie reported the records of 11 consecutive patients who required emergency cardiac operations after administration of abciximab and failed angioplasty or stent placement. The interval from the cessation of abciximab administration to operation was critical in determining the degree of coagulopathy after cardiopulmonary bypass. The median values for postoperative chest drainage (1,300 versus 400 mL; p < 0.01), packed red blood cells transfused (6 versus 0 U; p = 0.02), platelets transfused (20 versus 0 packs; p = 0.02), and maximum activated clotting time (800 versus 528 seconds; p = 0.01) all were significantly greater in the early group (cardiac operation < 12 hours after abciximab administration; n = 6) compared with the late (cardiac operation >12 hours after abciximab administration; n = 5) group. This report suggests that the antiplatelet agent abciximab is associated with substantial bleeding when it is administered within 12 hours of operation.

Alvarez reported on 3 patients who underwent emergency CABGfor failed stent implantation shortly after receiving abciximab.All 3 patients were described as having a profound bleeding diathesis,and the transfusion requirements were large (mean, 28 unitsplatelets, 4.7 units RBCs, and 8.3 units plasma); 1 patientdied, although not of bleeding-related causes.

   
Managing patients receiving other antiplatelet agents for cardiac surgery

  There is little published data regarding the effects of other platelet inhibitors in cardiac surgery. Most of the information available is regarding abciximab, since it was the first on market, and has the longest half life of the IIb/IIIa inhibitors. Kleiman reviewed the pharmacokinetics and dynamics of these drugs. The elimination of abciximab from the body is the slowest of the agents: the catabolic beta half-life is approximately 7 hours. Although no studies investigating the route of elimination have been reported, renal clearance of the ReoPro fragments is generally more rapid than that of whole antibodies, and catabolism is likely to resemble that of other natural proteins. In comparison, the plasma half-life of tirofiban is approximately 2 hours and the primary route of plasma clearance is renal. Approximately 65% of the administered dose is excreted in urine, and an additional 25% is eliminated through feces. Plasma clearance of tirofiban is significantly lower (>50%) in patients with severely impaired renal function (creatinine clearance <30 mL/min), whereas moderate reduction was apparent in elderly patients (age >65 years). In patients with mild to moderate hepatic dysfunction, the rate of plasma clearance was not significantly different from that observed in healthy subjects. Plasma clearance of eptifibatide occurs with a half-life of 2.5 hours, and the majority of the drug is eliminated through renal mechanisms.

There is little data regarding the use ticlopidine and clopidogrel and bleeding in cardiac surgical patients. Mossinger reported in their series of 96/1166 CABG patients who were receiving ticlopidine, 83% of which were also on ASA. A total of 28% of the ticlopidine patients were urgent vs 9% of the other patients. Blood loss >1500 ml/24 hour period was more frequent in ticlopidine treated patients, (14% vs 5%). The ticlopidine patients received allogeneic blood more frequently 62%vs 45%, and required more packed red blood cell transfusions (2 units vs 0). The post operative chest drainage was also 30% greater in the ticlopidine treated patients.
   

Antiplatelet agents and ACT

  Abciximab and other antiplatelet agents are associated with prolongation of the ACT of 35-85 seconds. This effect was also observed in vitro by Ammar and Gammie, and has contributedto the suggestion that a smaller heparin dose should be usedfor abciximab-treated patients who require emergency operation.A similar suggestion was also made by Kereiakes and byFerguson. As previously reported for aprotinin treated patients, the use of reduced heparindoses for cardiopulmonary bypass in antiplatelet treated patients is problematic. Although antiplatelet agents inhibit arterial thrombus formation andprolong the ACT, the stimulus to thrombin generation is quite different during extracorporeal ciruclation because the blood is exposed to a large non-endothelized bypass circuit. Further, the effectiveness of using smaller heparindoses in reducing transfusion requirements in the setting ofcardiopulmonary bypass has not been demonstrated. The ACT is a complicated test and can be affected by a varieyt of factors including fibrinogen, platelets (which provide the phospholipid surface for clotting as a whole blood clotting test), heparin levels, temperature, plateletcount, and contact activation inhibitors (ie, aprotinin). Although abciximab does prolongthe ACT to some degree, it has not yet been demonstrated tobe a "heparin-sparing" agent allowing for safe extracorporealperfusion with lower-than-standard serum heparin levels. Finally, at the end of cardiopulmoanry bypass, the heparin is completely reversed with protamine.

Although suggestions have been made that platelet transfusion be performed beforethe operation, even en route to the operating room, platelet transfusions pose the potential risk of hypersensitivity reactions in a critically unstable patient. Further, platelets will be subsequently impaired due to cardiopulmonary bypass, and reversal of a therapeutic antiplatelet effect before surgical revascularization couldprecipitate abrupt closure of a stenotic coronaryartery whose patency is dependent on inhibiting platelet function.
   

Recommendations for managing patients receiving antiplatelet agents and requiring cardiac surgery:

  The following is a summary of recommendations for managing patients receiving antiplatelet agents and requiring cardiac surgery.
   

SUMMARY

  Safety: Based on the data in press and published, urgent cardiac surgery can be safely performed on patients who have received abciximab or one of the other GPIIb/IIIa receptor inhibitors

Bleeding: Although the relative risk of abciximab -related bleeding may be increased within twelve hours, this should not preclude urgent revascularization. Platelets may be needed and should be available when operating on abciximab -treated patients.

Heparin dosing: There are no data supporting reductions in heparin dosing during cardiopulmonary bypass and for cardiac surgery. Therefore, standard-loading doses should be considered and additional heparin doses, based on time and duration of bypass or on actual heparin levels, should be maintained.

Platelets. Platelets can be transfused to correct the bleeding defects associated with abciximab use. However, patients should not receive routine platelet transfusion prior to surgery and cardiopulmonary bypass. Rather, platelets should be administered after heparin reversal by protamine and after extracorporeal circulation.

Anticoagulation. When blood is activated during bypass, a pathological prothrombic stimulus is initiated. Anticoagulation is achieved by unfractionated heparin administration, which binds to antithrombin and heparin cofactor II to inhibit thrombin. Despite the use of high dose heparin, thrombin generation and activity continues during extracorporeal circulation. New approaches with old and novel agents for anticoagulation will be considered. Protamine reactions and novel agents to reverse heparin will be also reviewed.
   

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Levy JH, Pifarre R, Schaff H, Horrow JC, Albus R, Spiess B, Rosengart T, Murray J, Smith P, Kleinfield R: A multicenter, placebo-controlled, double-blind trial of aprotinin to reduce blood loss and the requirement of donor blood transfusion in patients undergoing repeat coronary artery bypass grafting, Circulation 1995; 92: 2236-2244.
2.
D'Ambra MN, Akins CW, Blackstone EH, Cosgrove DM, Levy JH, Lynch KE, Maddi RR, Kirklin JW: The effect of aprotinin in primary cardiac valve replacement and reconstruction: A double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996; 112: 1081-1089.
3.
Miller BE, Bailey JM, Levy JH, Mochizuki T,Tam VKH, Tosone SR,Kanter KR: Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 1997; 85:1196-1202.
4.
Levy JH, Morales A, Lemmer JH: Pharmacologic approaches to prevent or decrease bleeding in surgical patients. Chapter in Transfusion Medicine, Speiss B, Counts R, Gould S (eds), Williams & Wilkins, 383-398, 1997
5.
Miller BE, Tosone SR, Tam VKH, Kanter KR, Guzzetta NA, Mochizuki T, Levy JH: Hematologic and economic impact of aprotinin in reoperative pediatric cardiac surgery. Ann Thorac Surg 1998; 66:535-540.
6.
Mochizuki T, Olson PJ, Ramsay JG, Szlam F, Levy JH: Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg1998; 87:781-785.
7.
Alderman EL, Levy JH, Rich J, Nile M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B; Nadel A: International multi-center aprotinin graft patency experience (IMAGE). J Thorac Cardiovasc Surg 1998; 116:716-730.
   
Anticoagulation
1.
Despotis GJ. Levine V. Joist JH. Joiner-Maier D. Spitznagel E. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg. 1997;85(3):498-506.
2.
Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro SA. Spitznagel E. Weitz JI.Goodnough LT. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemostasis. 1996; 76(6): 902-8.
3.
Dietrich W. Dilthey G. Spannagl M. Richter JA. Warfarin pretreatment does not lead to increased bleeding tendency during cardiac surgery. J CardiothVasc Anesth 1995; 9(3):250-4.
4.
Dietrich W. Spannagl M. Schramm W. Vogt W. Barankay A. Richter JA. The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1991; 102(4):505-14.
5.
Greinacher, H. Völpel, U. Janssens, V. Hach-Wunderle, B. Kemkes-Matthes, P. Eichler, H. G.Mueller-Velten, and B. Pötzsch. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia : a prospective study. Circulation 1999; 99:73-80.
6.
Hirsh J, Ginsberg JS, Marder VJ. Anticoagulation with coumarin agents. In: Colman RW HJ Marder VJ, Salzman EW, ed. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: J.B. Lippincott, 1994; 1567-1583.
7.
Kikura M, Lee MK, Levy JH: Hexadimethrine and methylene blue reversal of heparin following cardiopulmonary bypass. Anesth Analg 1996; 83: 223-227.
8.
Levy JH, Cormack JG, Morales A: Heparin neutralization by platelet factor 4 and protamine. Anesth Analg 1995; 81: 35-37.
9.
Levy JH. Anaphylactic Reactions in Anesthesia and Intensive Care. 2nd Edition. Butterworth-Heinemann, 1992.
10.
Levy JH, Despotis GJ, Olson PJ, Weisinger A, Szlam F: Transgenically produced recombinant human ATIII enhances the antithrombotic effects of heparin in patients undergoing cardiac surgery. Blood 1997; 90:298A (Supp I).
11.
Mochizuki T, Olson PJ, Ramsay JG, Szlam F, Levy JH: Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 1998;87:781-785
12.
Pötzsch B, Madlener K, Seelig C, Riess CF, Greinacher A, Müller-Berghaus G. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass: assessment of the whole blood ecarin clotting time. Thromb Haemost. 1997; 77:920-925.
13.
Riess FC. Potzsch B. Bader R. Bleese N. Greinacher A. Lower C. Madlener K. Muller-Berghaus G. A case report on the use of recombinant hirudin as an anticoagulant for cardiopulmonary bypass in open heart surgery. European Journal Cardioth Surg. 1996; 10(5):386-8.
14.
Salzman EW, Hirsh J, Marder VJ. Clinical use of heparin. In: Colman RW HJ Marder VJ, Salzman EW, ed. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: J.B. Lippincott, 1994; 1584-1591.

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