Con: Heparin is not the best anticoagulant for cardiopulmonary bypass

Con: Heparin is Not the Best Anticoagulant for Cardiopulmonary Bypass Jane C.K. Fitch, MD SAY THAT heparin is the best anticoagulant for T Ocardiopulmonary bypass (CPB) is to say that no further alternatives to heparin should be sought. However, this is clearly not the case. Heparm is not the 1deal anticoagulant, and the quest for better heparin alternatives should be continued. Extracorporeal circulation induces a total body inflammatory response, resulting in the activation of various inflammatory cascades, only one of which is the coagulation cascade. Thrombin is the major player in the coagulation cascade. Thrombin contributes not only to fibrin generation but also to platelet activation and to activation of the fibrinolytic system. Antithrombin (AT) is the major plasma inhibitor of thrombin. Neutralization of thrombm by AT proceeds slowly in the absence of heparin but is dramatically accelerated in the presence of heparln. I Thus, heparin serves to facilitate the reaction between thrombin and antithrombin. Once the thrombin/antithrombin (TAT) complex is generated, heparin dissociates from the TAT complex and is able to bind another molecule of AT, thus allowing one molecule of heparm to provide multiple rounds of thrombln inhibition. However, during CPB, inactivation of thrombin is incomplete. Despite seemingly adequate heparlnizatlon, there ~s evidence for continued thrombin and fibrin formation in the microcirculation during CPB, as evidenced by the continued generation of prothrombin fragment 1.2 (F1.2), TAT complex, and fibrinopeptide A (FPA). 2,3 This coagulation in the microcirculation places the microvasculature at risk for occlusion. Although heparin is very effective at catalyzing the inhibition of free, circulating, or fluid-phase thrombin by AT, it is a less effective catalyst if the thrombin is bound to fibrin or to a surface. 4 Heparin thus incompletely inhibits clot-bound, fibrin-bound, or solid-phase thrombin because thrombin is protected from inactivation by the heparm/AT complex. Consequently, the bound thrombin remains enzymatically active and is able to facihtate further thrombin generation. When a cardmc patient's blood comes in contact with the large artificial surface of the CPB circuit (approximately 6 m2), contact activation and the extrinsic coagulation cascade are also stimulated. 2 Any thrombin that is accreted onto the CPB circuit may escape inhibition by heparin/AT, thus allowing continued thrombm generation. The continued generation of F1.2, TAT, and FPA despite adequate heparinization for CPB suggests that significant amounts of thrombin escape inhibition and are therefore able to facdltate additional thrombin generation

From the Department of Anesthestology, Yale Umverszty School of Medtcme, New Haven, CT Address repnnt requests to Department of Anesthesiology TMP 3, Yale UmversaySchool of Medwme, 333 Cedar Street, New Haven, CT 06510 Copyright © 1996 by W B Saunders Company 1053-0770/96/1006-002253 00/0 Key words heparm, antlcoagulatton, cardtopulmonarybypass

by remaining enzymatlcally active. These elevated levels persist for 24 hours postoperatively, raising the possibility that a thrombogenic stimulus persists long after heparin and protamine admimstration, thus potentially placing the patient at risk for graft occlusion or for thromboembolic events? The inability to inactivate factors that are bound to cell surfaces results not only in continued generation of local clotting, but in platelet activation as well. Tissue plasmmogen activator release from endothelial cells is also stimulated, contributing to a fibrinolytic state. In addition, activated platelets release the heparin-neutralizing substance, platelet factor 4 (PF4), which further contributes to local inhibition of heparin effects. 5 Heparm is problematic in its variability of action. 6 Heparln is heterogeneous with respect to its molecular size, anticoagulant activity, and pharmacologic properties. Molecular size varies from 3,000 to 30,000 kDa with a mean of 15,000 kDa, and actwlty depends on ammal and tissue source as well as on method of purification. Speofic anticoagulant activity also depends on the molecular weight distribution. Standard or unfractlonated (UF) heparin has an anti-Xa-to-anti-lla ratio of 1:1, whereas LMWH has a higher antl-Xa-to-anti-lla ratio of 2-4:1. Mucosal-bound heparln tends to have a lower molecular wmght, more anti-Xa than anti-lla activity, and thus is less responsive to protamine reversal. The action and potency of commercial preparations may vary from one manufacturer to another and from one lot to another. United States Pharmacopeia mandates that porcine mucosa heparin have greater than 140 U activity/rag and that bovine lung heparin have greater than 120 U activlty/mg. 7 However, only one third of the heparin admmistered has the unique pentasaccharide sequence necessary to brad both AT and thrombm. The differential clearance of heparm, with UF heparin being cleared more rapidly than LMWH, results in the accumulation of LMWH, which has reduced anti-lla activity. 8 Standard heparin is cleared through a combination of a rapid saturable mechanism revolving cellular uptake, with heparin binding to endothelial cells, macrophages, and plasma proteins, and by a much slower, nonsaturable, first-order mechanism of renal clearance. Thus, the biologic half-life of heparin increases with increasing doses (1 to 3 hours) and its variable binding plasma proteins and endothelial cells produce significant interlndividual variability in the heparin dose activated coagulation time (ACT) response. Heparin resistance or sensitivity is defined as surpassing the 95% confidence limits for the Gaussian distribution of the heparin dose-ACT response. 9 Heparin resistance in CPB patients is most likely attributable to AT deficiency. 1° The use of heparin is problematic in AT-deficient states, either congenital or acquired. Without adequate AT, hepatin cannot adequately inhibit thrombin generation. Acquired AT deficiency may be caused by decreased production, increased consumption (In patients on heparin infusions), increased excretion, drug-induced, or dilutional (CPB). Heparin may cause metabolism of AT during

Journal of Cardtothoractc and VascularAnesthesta, Vo110, No 6 (October), 1996 pp 819-821

819

820

formation of TAT complexes at a rate that is faster than hepatic synthesis of AT. II This patient population is presentlng with increasing frequency for CPB. They present a significant anticoagulation challenge in terms of increased heparin requirements, possibly requiring fresh frozen plasma or supplemental AT. Heparln-induced thrombocytopenla (HIT) and heparininduced thrombocytopenla with thrombosis (HITT) are significant causes of mortality and morbidity. 12 The incidence of HIT is between 1% and 5%. Heparin causes an immune-medmted platelet destruction. Heparin exposure results in the formation of autoantibodles that recognize the complex of heparin and PF4 as the major antigen. These platelet-assoclated antibodies accelerate platelet clearance by the spleen and hepatic retlculo-endothelial system. In severe cases, antibodies activate platelets, causing thrombosis due to platelet plugs. 13 UF heparm causes HIT and HITT much more frequently than LMWH. HIT does not always recur with reexposure; the incidence is dose independent but source dependent, occurring five times more frequently with bovine heparin than with porcine heparln. HITT occurs in 20% of patients with HIT. There is a 20% to 35% mortality and morbidity with HITT (commonly occurring are coronary, cerebral, splanchnlc, and peripheral arterial thromboses). The catastrophic complications of stroke or loss of hmb are devastating. Venous thromoembohsm also occurs, resulting in saphenous vein graft occlusion, deep vein thromboses, and pulmonary emboh 12 The management of patients for CPB who have a history of HIT or HITT can present as a major challenge. Heparin alternatives and/or platelet lnhlbitors must be considered. Other options to consider include thrombolytic therapy, plasmapheresis, and immunoglobuhn administration. ~ Heparin presents a problem with respect to heparm rebound) 5 After the heparln/protamine complex is cleared, protein-bound heparin that is not accessible to protamine dissociates slowly and binds to AT to produce its anticoagulant effect. Heparin rebound then occurs in the postoperative period when hemostasis is crmcal, often necessitating additional protamine dosing. Heparin is often not the problematic drug, rather, it is the protamine that is required for heparin reversal that is the culprit. Protamine reactions can and do occur. They usually manifest as anaphylaxis (either anaphylactic or anaphylactold) or catastrophic pulmonary hypertensive crises 16Thus, heparin alternatives would allow for the potential elimination of protamlne, as protamlne alternatives, such as rPF4 and heparinase, are still in the development phase. There are inconsistencies with regard to heparln dosing and monitoring. Dosing can be based on a fixed regimen or on a time-contingent basis or it may be based on heparindose response Monitoring can follow heparln activity (as with the ACT) or heparin levels (using protamlne titration). 17 Other problems associated with heparm administration include hemorrhage, decreased blood pressure (caused by decreased systemic vascular resistance), and pulmonary edema. Additional problems associated with long-term

JANE C K FITCH

heparin admlmstratlon include altered lipid metabohsm, osteoporosis, alopecia, hyperaldosteronlsm, and increased SGOT. I8 It is clear the search for alternatives to heparln must be considered. These options focus on LMWH, heparlnolds, thrombin mhibltors, defibrlnogenating agents, and antiplatelet drugs. All of these drugs share two common problems to be discussed, followed by examimng their individual differences. The first problem relates to coagulation monitoring. Currently, there are no whole blood-based point-of-care tests, which provide results in the operating room within minutes, to monitor the effects of these drugs when administered for the purpose of anUcoagulation for CPB. Presently, the effects of LMWH and heparinoids are best measured by a plasma-based chromogenic assay, performed in a standard laboratory, which measures antl-Xa activity. However, there are companies manufacturing whole bloodbased point-of-care testing equipment that feature a bedside antl-Xa activity test, which will make operating roombased use of these drugs much more practical. Likewise, current technology exists to allow whole blood-based pointof-care fibrlnogen testing that could be performed when using defibrmogenating agents for anticoagulation. Also available is the capability for both quantitative and qualitative platelet whole blood-based point-of-care testing. The second problem is that none of the previously mentioned drugs has an adequate reversal agent or antagonist. The current options for negating the effects of both the defibrinogenatlng agents and the antJplatelet drugs involve the transfusion of blood products at a time when the profession and society as a whole are looking for strategies to decrease transfusion requirements. LMWH has better bioavailabllity (90%) than UF (30%) because there is no binding to endothehal cells or heparin binding proteins. ~9 The half-life is longer (4 hours) and is independent of dose. Clearance is predominantly by renal ehmlnatlon. However, there is incomplete reversal by protamine, and these drugs still predispose the patient to problems inherent to heparin compounds. The potential advantages of LMWH relative to UF heparin are many and include improved antithrombotic activity (caused by high anti-Xa actmty), reduced hemorrhage risk caused by low antithrombin (antl-lla) activity, not lnhlbitable by PF4, much less Inhibition of platelet function, and no increases in vascular permeability. Examples of LMWH are as follows: Enoxaprin (Lovenox; Rhone-Poulenc Rorer, France), Dalteparin (Fragmin; KABI, Sweden), Rd Hepatin (Normiflo), Fraxiparln (Sanofi, France), and Logiparm (Novo, Denmark)39 Heparinolds, such as Lomoparin (Organon, The Netherlands), have an even higher anti-Xa to antMla ratio of 20:1, thus better inhibiting thrombus formation with less hemostatic disruption than when inhibiting lla and Xa together. 19 This may result in fewer bleeding complications These drugs are not inhibited by PF4, and, most importantly, can avoid the complications of HIT and HITT 20 Direct thrombln inhibitors, such as hirudin, inhibit throm-

PRO AND CON

821

bin without complexing with AT. 2~ Hirudin (American Diagnostica, New York, NY) is a specific, direct inhibitor of both free and clot-bound thrombin. There is minimal interaction with platelets and no reported immunogenloty. Other direct thrombin inhibitors include rHirudin, Hirulog (Blvahrudin), Hirugen (Biogen, MA), PPACK, and Argatroban (Novastatin; Texas Blotechnology, TX). These various thrombm mhibitors have slightly different mechanisms of action and ratios of inhibition of fluid- versus solid-phase thrombin lnhibinon that vary. Clot-bound thrombm is susceptible to inactivation by these thrombin inhibitors because the sites of their interaction are not masked by thrombm binding to fibrin.21 There are multiple other categories of drugs to be considered as heparin alternatives. Ancrod (Arvin) is a defibrmogenating agent. 22 It lyses fibnnogen and can reduce its levels to 40 to 80 mg/dL over 12 to 24 hours, predisposing to increased bleeding complications during that Interval. There are specific factor Xa mhibitors, such as tick anticoagulant peptide (rTAP), the Mexican leech (antistasin or rATS), and tissue factor pathway inhibitor.23 Other clot-lnhibmng drugs are available. Antiplatelet agents are being investigated and include cyclooxygenase inhibitor (ASA), thromboxane antagonist (Sulatroban), thromboxane inhibitor (Dazoxiben), dipyndamole (persantine), nonsteroidal anti-inflammatory drugs, ticlopldme

(Tlclid; Roche, NJ) prostacyclin (PG12), PGEb iloprost, PGF2, serotonin mhibitors, specific antibody to platelet glycoprotein llbllla (7E3), and RGD peptides inhibItors such as Bitistatin, Echlstatm, and Kistrin.24 Fibrinolytic agents, ~8 such as tPA and vampire bat plasminogen activator also are being investigated.23 Where do we go from here9 The technology is far too advanced to still be using heparin and protamine for the conduct of CPB. The mampulanon of porcine mucosa or bovine lung tissue with salmon sperm to achieve the desired hemostatic effect is crude state of art. These heparin alternatwes are all In the developmental stage. Each type has its own set of advantages and disadvantages Intraoperative momtormg and adequate reversal remain as two of the sigmficant challenges for acceptabihty of these drugs. Because thrombin is such a key player in coagulation, platelet activanon, and fibrmolysis, the author believes that research and development should concentrate on specific thrombm mhlbltors, their relative anticoagulation profiles, monitoring, and reversal agents. As the search for the ideal anticoagulant continues, not only must the drug itself afford better antlcoagulatlon, but also the momtorlng and reversal aspects must be acceptable. Heparm and protamine are tough acts to follow, but pursuit of the ideal anticoagulant for CPB must be continued.

REFERENCES 1 Rosenberg RD Biochemistry of heparln/AT interactions. Am J Med 87 S3B. 2s-9s, 1989 2. Brlster SJ, Ofosu FA, Buchanan MR: Thrombln generation during cardiac surgery' Is heparm the ideal anticoagulant? Thromb Haemost 70.259-262, 1993 3. Slaughter TF, LeBleu TH, Douglas JM, et al' Characterlzanon of prothrombln activation during cardiac surgery by hemostatic molecular markers. Anesthesiology 80.520-526, 1994 4. Weltz JI, Hudoba M, Massel D, et al. Clot-bound thrombln is protected from inhibition by heparln/AT J Clln Invest 86.385-391, 1990 5. Lane DA, Pejler G, Flynn AM, et al. Neutralizanons of heparm-related sacchandes by hlstldine-rlch glycoproteln and PF4 J Blol Chem 261:3980-3986. 1986 6 Lasker SE Heterogemoty of heparms Fed Proc 36'92-97, 1977 7 Umted States Pharmacopoem 8 de Swart CA, Nllmeyer B, Roelofs JMM, et al Kinetics of intravenously administered heparln Blood, 60.1251-1258, 1982 9 Esposlto, RS, Culhford AT, Colwn SB, et al Role of ACT in heparm admlmstratlon and neutralization for CPB J Thorac Cardlovasc Surg 85.180, 1983 10. Esposlto RS, Culhford AT, Colvln SB, et al Heparm resistance during CPB. J Thorac Cardmvasc Surg 85.346-353, 1983 11. Marcinmk E, Gockerman JP. Heparm-induced decreases in AT. Lancet 2.581-584, 1978 12. Warkentln TE, Kelton JG: Heparm and platelets. Hematol Oncol Clin North Am 4 243-264, 1990 13. Greinacher A, Potzsch B, Amlral J, et al' Heparm-

associated thrombocytopenla Isolation of the antibody and characterization of a multlmolecular PF4-heparln complex as the major antigen Thromb Haemost 71'247-251, 1994 14 Makhoul RG, McCann RL, Austin EH, et al Management of patients with heparln-assoclated thrombocytopenia and thrombosis requiring cardiac surgery. Ann Thorac Surg 43 617-621, 1986 15. Kultunen AH, Salmenpera MT, Heinonen J, et al" HeparJn rebound. J Cardlothorac Vasc Anesth 5.221-226, 1991 16. Horrow J. Protamme A review of ItS toxicity Anesth Analg 64'348-361, 1985 17. Gravlee GP, Haddon WS, Rothberger HK, et al Heparlndosing and monitoring for CPB J Thorac Cardlovasc Surg 99 518527, 1990 18 Levlne, MN Nonhemorrhaglc complications of anticoagulant therapy Semln Thromb Hemost 12.63-66. 1986 19. HIrsch J, and Levlne MN" Low molecular weight heparlns. Blood 79'1-17, 1992 20 Henny CP, ten Cite H, ten Cite JW, et al" A randomized bhnd study comparing standard heparln and a new heparlnold in CPB. J Lab Chn Med 196'187-196, 1985 21 Markwardt F' Pharmacology of selective thrombm lnhlbitors Nouv Rev Fr Hematol 30:161-165, 1988 22. Zulys VJ, Teasdale SJ, Michel JR, et al' Ancrod as an alternative to heparln antlcoagulatlon for CPB Anesthesiology 71'870-877, 1989 23 Rodgers GM' Novel antithrombotlc therapy West J Med 159'670- 674, 1993 24 Pedersen AK, F tzgerald GA The human pharmacology of platelet inhibition Circulation 72'1164-1176, 1985