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DRUGS TO PREVENT AND REVERSE ANTICOAGULATION
PENOPERATIVE USE OF ANTICOAGULANTS AND THROMBOLYTICS
0889-8537/99 $8.00
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DRUGS TO PREVENT AND REVERSE ANTICOAGULATION Martin Franck, MD, and Robert N. Sladen, MB, ChB, MRCP, FRCP(C)
Bleeding or severe coagulopathy from inherited or iatrogenic coagulation defects can often be corrected by transfusion of specific factor deficiency. However, in some situations transfusional therapy can be augmented or avoided altogether by hemostatic drugs. Many hemostatic drugs have been evaluated, but only a few have proven clinical efficacy. This article will review the pharmacology and dosing of drugs commonly used for reversing anticoagulation and fibrinolysis. PROTAMINE Structure and Activity
Protamine is a strongly basic low molecular weight polycationic amine derived from the sperm or mature testes of salmon. Its alkalinity stems from the large proportion (over 65%)of its amino acid composition as arginine. Its primary indication is after cardiopulmonary bypass, when it is given to reverse the effects of heparin, a polyanionic mucopolysaccharide that produces anticoagulation via activation of antithrombin III. Protamine forms an ionic bond with heparin, and the stable complex neutralizes its anticoagulant effects.= The heparin-protamine complexes are ultimately removed by the reticuloendothelial system.
From the Department of Anesthesiology (MF, RNS) and Cardiothoracic-Surgical Intensive Care Unit (RNS), College of Physicians and Surgeons of Columbia University, New York, New York
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Neutralization of heparin requires an excess of protamine which competes with antithrombin I11 for binding with heparin.40Excess free protamine is broken down by an endogenous plasma protaminase, leading to instability of the heparin-protamine complex. The subsequent release of heparin restores its antithrombin activity, so-called heparin rebound.
Pharmacology and Dosage
Protamine is prepared as a powder or solution containing 250 mg in 25 mL (10 mg/mL). A number of dosing regimens have been developed for cardiopulmonary bypass in an effort to more precisely titrate the most appropriate reversal dose of protamine for a given dose of heparin. Difficulty arises because the neutralization ratio for protamine and heparin is different for different heparin sources. For example, 1 mg of protamine neutralizes 90 IU bovine lung heparin, and 110 IU porcine intestine heparin.23aThe most empiric approach is to administer 1 to 1.5 mg of protamine for every 100 IU of heparin, guided by the celite activated clotting time (ACT) measured 5 to 15 minutes after each dose. The end-point is to achieve correction of the ACT to pre-heparin baseline. Because heparin is rapidly metabolized, the amount of protamine required decreases with time after heparin administration. For example, if 30 to 60 minutes have elapsed, the protamine dose should be reduced to about 0.5 to 0.75 mg/100 IU heparin, and to about 0.25 mg/100 IU after 2 hours. The most established titration regimen is that of heparin response curves published by Bull et a1 in 1975.5The specific dose of protamine is calculated by in vitro titration of the patient's blood with protamine; approximately 1.3 mg/kg of protamine for each 100 IU of heparin present as calculated from the ACT. Weight-based heparin and protamine dosing strategies for cardiopulmonary bypass do not take into account wide interpatient variability. Despotis et a1 evaluated the Hepcon device in patients undergoing cardiopulmonary bypass who did not receive antifibrinolytic agents.1° The Hepcon is a whole blood hemostasis system that provides both ACT and heparin concentration measurements via an automated protamine titration method. Compared with a control method based on the ACT alone, patients in the Hepcon cohort received greater doses of heparin, had lower protamine-to-heparin ratios (0.71 versus 0.9:1), and received significantly fewer units of platelets, fresh frozen plasma, or cryoprecipitate. However, more recently, Shore-Lesserson et al4I found that an automated heparin and protamine titration system (Hepcon) did not result in a measurable improvement in perioperative hemostasis, although the predicted protamine dose could be lowered.
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Adverse Effects
Hypotension
Administration of protamine is frequently associated with acute, usually transient, hypotension as a result of histamine release, which induces vasodilation and myocardial depression. The response is quite predictable with rapid injection and can be attenuated or prevented by slow intravenous injection (i.e., a maximum rate of 5 mg/min). It has also been reported that reversal of heparin effect may be more complete when protamine is given as a 30-minute infusion rather than by bolus injection.46Attempts to induce pulmonary clearance of histamine by 32 or by the intra-arterial (intra-aortic or left atrial) admini~tration,2~, concomitant administration of intravenous calcium chloride, do not appear to prevent this phenomenon. It is suspected that vasodilator activity is blocked when protamine forms a complex with heparin. However, in an in vitro study Ordonez Fernandez et aI3O demonstrated that protamine induces endotheliumdependent systemic vasodilatation that is not blocked when protamine forms a complex with heparin in comparable concentrations of both drugs. Hypersensitivity Reactions
Protamine may induce a variety of allergic reactions, ranging from anaphylactoid-like symptoms (prolonged hypotension, dyspnea, bradycardia, flushing) through full-blown anaphylactic shock.'*, 21, 45 Patients who may be at risk include those with prior exposure to protarnine, NPH or protamine zinc ins~lin,'~ a history of fish allergy, or after vasectomy. The risk is greatest in individuals with antiprotamine IgG or IgE antibodies. The role of prophylaxis of hypersensitivity reactions in highrisk patients by corticosteroids and a combination of HI- and H2-blockers has not been established. The heparin-protamine complex may itself directly precipitate hemodynamic changes by complement activation via the classic pathway. Intense thromboxane release manifests as pulmonary vasoconstriction and bronchoconstriction.29This syndrome may be associated with acute right ventricular failure, shock, and/or noncardiogenic pulmonary edema. Protamine Overdose
Protamine administered in the absence of heparin interacts with platelets and proteins, including fibrinogen. These interactions may manifest as an anticoagulant effect of protamine and cause paradoxical bleeding by weakening formed clot and impairing adenosine diphosphate (ADP)-induced platelet aggregation. After cardiopulmonary bypass, bleeding associated with a prolonged ACT after protamine reversal
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of heparin could be misinterpreted as residual heparin anticoagulation. Additional protamine could further increase the ACT and exacerbate bleeding. In an in vitro study, Mochizuki et alZ8found that protamineto-heparin ratios of greater than 1.3:l significantly prolonged the ACT. This effect was either absent or attenuated by the use of alternate heparin antagonists (recombinant platelet factor 4 [rPF,], hexadimethrine). However, clinically significant alterations in coagulation parameters, such as prolonged activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) require protamine-heparin dose ratios which are at least 3-5:1, and as much as 100:l.33It is very unlikely that abnormal coagulation is induced by the doses of protamine routinely used after cardiopulmonary bypass. Heparin Rebound Heparin rebound implies the return of heparin antithrombin effect after initial neutralization of its activity by protamine after cardiopulmonary bypass. Its incidence is variable, and may occur within minutes or hours of protamine administration. The mechanisms are speculative but may include liberation of heparin from extravascular spaces or intravascular surfaces, or the breakdown of excess protamine by protaminase (discussed previously). Another potentially important mechanism is the administration of fresh frozen plasma after cardiopulmonary bypass because it contains antithrombin I11 and boosts heparin's antithrombin activity. Heparin rebound appears to be less likely to occur when an excess of protamine (i.e., a ratio of 1.5:l) has been administered. In contrast, the incidence is higher when the minimal amount of protamine required to neutralize heparin determined by titration methods is given.4O Alternatives to Protamine In an effort to avoid administration of protamine with its attendant complications, a number of substitutes have been or are being explored. Heparin substitutes, such as prostacyclin (PGI,) and Iloprost decrease (but do not replace) heparin requirements on cardiopulmonary bypass. Protamine substitutes with anti-heparin activity include heparinase I and hexadimethrine (polybrene), a synthetic quaternary ammonium salt.20Of these, the most promising is heparinase I (neutralase), a specific enzyme that inactivates heparin. Preliminary studies suggest that heparinase I is as effective as protamine in reversing the action of heparin, but lacks its hemodynamic or antiplatelet effects.', 26 An alternative is the use of a heparin removal device that separates plasma and adsorbs heparin on to ply-L-lysine. Although slower and less complete in heparin reversal than protamine, porcine studies suggest that it may provide sufficient clinical efficacyto be used in patients with known protamine hypersensiti~ity.~3
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DESMOPRESSIN Structure and Activity
Desmopressin acetate (DDAVP), 1-desamino-8-D-arginine vasopressin, is a synthetic vasopressin analogue. It is pharmacologically altered from naturally occurring vasopressin by deamination of hemicysteine at position one and substitution of D-arginine for L-arginine at position eight. These changes virtually eliminate vasopressor (V,-receptor agonist) activity, and enhance its antidiuretic (V2-receptor agonist) action. The antidiuretic-to-pressor potency ratio is increased from 1:l to 20004000:l. It also prolongs its duration of action from 2 to 6 hours to 6 to 36 by increasing resistance to enzymatic cleavage, delaying 24 absorption from the nasal mucosa, and enhancing generation of cyclic adenosine monophosphate (AMP) in the renal medulla.39Oxytocic activity is 4 to 75 times less than that of arginine vasopressin. Desmopressin is more potent than arginine vasopressin at the V2receptor in stimulating the endothelial release of factor VIII and von Willebrand factor into the plasma, where they form a complex with platelets and enhance their ability to aggregate. It has achieved a role in the preoperative prophylaxis of surgical bleeding in patients with mild certain forms of von Willebrand’s forms of hemophilia and in uremic thrombocytopathy.6 In hemophilia A, desmopressin decreases the aPTT but is ineffective if factor VII1:C levels are less than 5%. In the classic type I von Willebrand’s disease, desmopressin decreases the Ivy bleeding time, but in patients with type IIb it may actually induce thrombocytopenia by causing excess platelet aggregation.26If the type of von Willebrand’s disease has not been completely characterized, it is prudent to test the patient’s response to desmopressin about 2 weeks prior to elective surgery. Desmopressin enhances platelet function in uremic thrombocytopathy, but lack of effect may be encountered in critically ill patients on vasoactive drugs because catecholamines, such as epinephrine, also release factor VIII and von Willebrand’s factor from the endothelium. In these patients, it may be preferable to administer these factors directly in the form of ~ryoprecipitate.~~ In the mid-l980s, there was a flurry of interest in the hemostatic effect of desmopressin in patients undergoing cardiopulmonary bypass.3s However, the initial promise suggested by preliminary studies was never confirmed by larger trials. Its administration after cardiopulmonary bypass may exacerbate post-bypass hypotension.8*l2 Desmopressin also stimulates the endothelial release of plasminogen activator. Concomitant use of antifibrinolytic agents, such as epsilon-aminocaproic acid, may blunt its fibrinolytic effect and enhance thrombus formation.24 Dosage and Administration
Desmopressin was initially introduced for the treatment of chronic diabetes insipidus, for which it is given by nasal spray as 5 to 40 pg/d
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in divided doses. For acute diabetes insipidus (and in particular, donor preservation), it is given subcutaneously at 0.5 to 2 pg/d. For hemophilia A, von Willebrand’s disease, and uremic thrombocytopathy, desmopressin is given in a much larger dose, 0.3 pg/kg. Antidiuresis is not a concern because there is actually an inverse relationship between desmopressin dosage and its antidiuretic e f f e ~ tIt. ~is prepared in a concentration of 4 pg/mL, so, for example, an 80-kg patient should receive 24 pg (6 mL) diluted in 50 mL sterile saline and infused slowly over 15 to 30 minutes because of the risk of acute hypotension? Blood pressure and pulse should be closely monitored. Desmopressin is best given 30 minutes prior to the scheduled procedure because its beneficial effect on platelet function peaks at about 1 to 2 hours and lasts about 8 to 12 hours. Repeated administration within 48 hours usually results in tachyphylaxis, presumably because all available factor VIII and von Willebrand’s factor have been mobilized from the endothelium. Pharmacology
After intravenous injection, desmopressin has a distribution halflife of 7.8 minutes, and an elimination half-life of 2.5 to 4.4 ANTlFlBRlNOLYTlC AGENTS
Antifibrinolytic agents currently in use include synthetic lysine analogues, such as aminocaproic acid and tranexamic acid, and the naturally occurring kallikrein inhibitor, aprotinin. These compounds form a reversible complex with plasminogen and with the active protease, plasmin. They saturate the lysine-binding sites on plasminogen, and thereby displace plasminogen from the surface of fibrin and inhibit the proteolytic effect of plasmin. APROTlNlN
Structure and Activity
Aprotinin is a naturally occurring polypeptide inhibitor of proteolytic enzymes that is isolated from bovine lung.15It is known to inhibit human trypsin, plasmin, and tissue and plasma kallikrein by forming reversible enzyme-inhibitor complexes. Indications
Aprotinin is indicated for prophylaxis for perioperative blood loss during cardiopulmonary bypass (CPB).
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Pharmacology
Plasma aprotinin concentrations decrease rapidly after intravenous administration because of redistribution to peripheral tissues.23Aprotinin is rapidly eliminated from the circulation via glomerular filtration.
Dosage
The enzymatic activity of aprotinin is generally expressed in kallikrein inactivator units (KIU), with 1 KIU defined as the amount of aprotinin that decreases the activity of two biologic kallikrein units by 50%. One milligram of aprotinin is equivalent to 7143 KIU. Hemostatically effective plasmin inhibition requires a plasma aprotinin concentration of greater than 50 KIU/mL.23A 2-million KIU dose is needed to achieve the higher plasma concentrations necessary to inhibit kallikrein. The Celite ACT does not reliably monitor heparin effect in the presence of aprotinin. The kaolin ACT should be substituted. Standard Dosing for Cardiac Surgery with Cardiopulmonary Bypass
Aprotinin should be administered exclusively through a central venous catheter; no other drugs should be administered using the same line. Because of the potential for anaphylaxis (1%-2% risk in patients exposed to aprotinin within the previous 6 months), a test dose of 1 mL aprotinin (10,000 KIU) is administered intravenously at least 10 minutes prior to the loading dose. Signs of an allergic reaction (tachycardia, flushing, hypotension, bronchospasm) should be closely monitored prior to further dosing. After the induction of anesthesia, but prior to sternotomy, a loading dose of 2 million KIU is given over 20 to 30 minutes. An additional 2 million KIU of aprotinin is added to the priming fluid of the cardiopulmonary bypass pump. After the loading dose is given, a constant infusion of 0.5 million KIU/h is begun and continued until the patient leaves the operating room. Because of the high cost of the aprotinin regimen described above (about $1200 per case), an alternative reduced-dosage regimen has been advocated as being comparably effective in decreasing perioperative blood loss and transfusion requirements in patients undergoing coronary revascularization procedures. The dosing regimen is identical except that the doses have been halved-after a test dose, a loading dose of 1 million KIU of aprotinin is given, 1 million KIU is added to the pump prime, and a continuous infusion of 0.25 million KIU/h is run through the rest of the case.
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Adverse Effects
The major concern with aprotinin is the risk of a hypersensitivity reaction. With first-time exposure, the risk of anaphylaxis is estimated to be about 0.1%, but this increases to 1% to 2% with a history of exposure within the previous 6 month^.^ Aprotinin is renally eliminated and has the potential for nephrotoxic injury, producing dose-related increases in serum creatinine. AMINOCAPROIC ACID Structure and Activity
Epsilon-aminocaproic acid, an analogue of lysine, is a 6-aminohexanoic acid. Aminocaproic acid appears to inhibit fibrinolysis by inhibiting plasminogen activators and, to a lesser degree, by its antiplasmin activity. The fibrinolytic system consists of plasminogen activators (streptokinase, urokinase, tissue activators), plasminogen (profibrinolysin), and plasmin (fibrinolysin). Plasminogen activators convert plasminogen to plasmin, a proteolytic enzyme responsible for the degradation of thrombi. Excess plasminogen activation results in increased fibrinolysis and dysfunction of fibrinogen, fibrin, and other clotting components. Severe hemorrhage may result. Aminocaproic acid is a competitive inhibitor of plasminogen activators and inhibits plasmin to a lesser extent (at higher doses). Indications
Aminocaproic acid can potentially enhance hemostasis when fibrinolysis contributes to bleeding. It is specifically indicated as an antifibrinolytic agent in the treatment of bleeding resulting from systemic fibrinolysis and urinary fibrinolysis. Aminocaproic acid should not be used when there is evidence of an active intravascular clotting process. It is appropriate to use in primary fibrinolysis (hyperplasminemia), but may exacerbate intravascular clot formation in disseminated intravascular coagulation (DIC). Pharmacology
Aminocaproic acid is largely eliminated unchanged by renal excretion (65%),but about 35% undergoes hepatic metabolism to the metabolite, adipic acid, which also appears in the urine. The renal clearance (116 mL/min) approximates endogenous creatinine clearance, and total body clearance is 169 m L / m i ~ ~The . ~ l terminal elimination half-life for aminocaproic acid is approximately 1 to 2 hours.
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Dosage
The initial loading dose in an adult patient is 5 g administered over 15 to 20 minutes. Rapid intravenous administration may induce acute h y p o t e n s i ~ nThis . ~ ~ is followed by a continuous infusion at the rate of 1 g/h, for 5 to 8 hours or until the bleeding situation has been controlled. The dose of aminocaproic acid should be reduced by 15% to 25% in patients with renal disease or oliguria. Adverse Effects
The most common acute side effect is hypotension, associated with rapid intravenous administration. Other reported adverse effects are occasionally encountered with longer-term administration and include rash, nausea and vomiting, weakness, retrograde ejaculation, myopathy, and even rhabdomy~lysis.~~ TRANEXAMIC ACID Structure and Activity
Tranexamic acid (trans-4-aminomethyl-cyclohexanecarboxylic acid) is a competitive inhibitor of plasminogen activation, and, at much higher concentrations, a noncompetitive inhibitor of plasmin. Its actions are similar to those of aminocaproic acid, but tranexamic acid is about 10 times more potent in vitro, with higher and more sustained antifibrinolytic activity.2,44 However, there appears to be little difference in their therapeutic or adverse effects. Aminocaproic acid has been preferred in the treatment of subarachnoid hemorrhage, because the use of tranexamic acid has been associated with an unacceptable incidence of ischemic complications.'l Mechanism of Action
Tranexamic acid exerts its antifibrinolytic activity by occupying the lysine-binding sites of human plasminogen. This displaces it from the fibrin clot surface of cloti9 Plasmin-induced fibrinolysis is inhibited regardless of the rate of plasmin formation because tranexamic acid prevents it from binding to fibrinogen or fibrin monomers and exerting its proteolytic action at the serine-histidine enzyme site.44Tranexamic acid blocks the lysine binding sites of plasmin, making inactivation by alpha-2-antiplasmin impossible, and further inhibiting its proteolytic activity. Tranexamic acid may also provide a hemostatic benefit in recurrent or excessive bleeding by stabilizing fibrin structures and preventing
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fibrin dissolution, especially when fibrin formation is defective. Its effect in preserving the fibrin matrix may also enhance collagen synthesis and tensile strength in granulation tissue.22
Indications and Limitations Tranexamic acid is indicated to treat bleeding associated with primary fibrinolysis. This should be differentiated from DIC because, in the latter, it may increase intravascular thrombosis, unless low-dose heparin is given concomitantly. Tranexamic acid has been fairly widely used to prevent or treat bleeding with associated fibrinolysis during teeth extraction in hemophiliacs, recurrent epistaxis, upper gastrointestinal bleeding, or menorrhagia. It also appears to reduce the frequency of attacks of hereditary and nonheriditary angioneurotic edema. There are a number of clinical studies that attest to its effectiveness in decreasing blood loss and transfusion requirement after cardiopulmonary bypass. There is some evidence that it may be effective in surgical procedures such as total knee arthroplasty, but it is contraindicated for transurethral prostatectomy because of the risk of intravesicular clotting.
Pharmacology Only a small fraction of administered tranexamic acid is metabolized; the majority is excreted unchanged by the kidney. The dose must be substantially decreased in renal impairment: by about 50% with serum creatinine, 1 to 2 mg/dL; a further 50% with serum creatinine, 2 to 4 mg/dL; and a further 50% with serum creatinine greater than 4 mg/dL. Dosing adjustment is not necessary with liver disease. Pharmacokinetic studies have revealed that tranexamic acid has a volume of distribution of 9 to 12 L and an elimination half-life of about 2
Dosage
A wide range of dosage is used. In most instances, the single intravenous dose of tranexamic acid is 10 to 15 mg/kg. During cardiac surgery, a loading dose of 15 mg/kg is given prior to cardiopulmonary bypass, followed by a continuous infusion of 1 mg/kg/h for 5 to 8 hours. However, some studies have used doses as high as 100 to 150 mg/kg as a single load prior to cardiopulmonary bypass.
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Adverse Effects
Hypotension may be caused by rapid intravenous injection. As with aminocaproic acid, the major concerns have related to the potential for increasing the perioperative risk of thromboembolism, arterial thrombosis, myocardial infarction, and pulmonary embolism, which, although rare, have been reported with long-term therapy or with high doses in subarachnoid hemorrhage.”,
References 1. Ammar T, Fisher C F The effects of heparinase 1 and protamine on platelet reactivity. Anesthesiology 861382,1997 2. Andersson L, Nilsson IM, Colleen S, et a1 Role or urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann NY Acad Sci 146642,1968 3. Ariano RE, Seymour B: Inverse relationship between desmopressin dosage and antidiuresis. Clin Pharm 10912, 1991 4. Bichet DG, Razi M, Lonergan M, et a1 1-Desamino (8-D arginine) vasopressin (dDAVP) decreases blood pressure and increases pulse rate in normal individuals. Thromb Haemost 60348, 1988 5. Bull BS, Huse WM, Brauer FS, et al: Heparin therapy during extracorporeal circulation. 11. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69:785, 1975 6. Canavese C, Salomone M, Pacitti A, et al: Reduced response of uraemic bleeding time to repeated doses of desmopressin. Lancet 1:867, 1985 7. Cobb WE, Spare S, Reichlin S Neurogenic diabetes insipidus: Management with DDAVP(r) (1-Desamino-8-D Arginine Vasopressin). Ann Intern Med 88:183, 1978 8. DAlauro FS, Johns RA: Hypotension related to desmopressin administration following cardiopulmonary bypass. Anesthesiology 69:962, 1988 9. DAmbra MN, Risk SC: Aprotinin, erythropoietin and blood substitutes. Int Anesthesiol Clin 28:237, 1990 10. Despotis GJ, Joist JH, Hogue CWJ, et a1 The impact of heparin concentration and activated clotting time monitoring on blood conservation: A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 11046, 1995 11. Fodstad H, Forssell A, Liliequist B, et al: Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: A consecutive controlled clinical trial. Neurosurgery 8:158, 1981 12. Frankville DD, Harper GB, Lake CL, et al: Hemodynamic consequences of desmopressin administration after cardiopulmonary bypass. Anesthesiology 74988, 1991 13. Gupta SK, Veith FJ, Ascer E, et al: Anaphylactoid reactions to protamine: An often lethal complication in insulin-dependent diabetic patients undergoing vascular surgery. J Vasc Surg 9:342, 1988 15. Hardy JF, Desroches J: Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 73:395, 1994 16. Holmberg L, Nilsson IM, Borge L Platelet aggregation induced by l-desamino-8-Darginine vasopressin (DDAVP) in type IIB von Willebrand’s disease. N Engl J Med 3092316, 1983 17. Horrow JC: Desmopressin and antifibrinolytics. Int Anesthesiol Clin 28:230, 1990 18. Horrow JC: Protamine: A review of its toxicity. Anesth Analg 6 4 9 8 , 1985 19. Hoylaerts M, Lijnen HR, Colien D Studies on the mechanism of antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 67375, 1981
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20. Kikura M, Lee MK, Levy JH: Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. Anesth Analg 83:223, 1996 21. Konstadt SN. Protamine administration: Untoward responses and their mechanisms. Mt Sinai J Med 54:297, 1987 22. Kwaan HC, Astrup T Tissue repair in presence of locally applied inhibitors of fibrinolysis. Exp Mol Pathol 11232, 1969 23. Levy JH, Bailey JM, Salmenpera M Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 80:1013, 1994 23a. Majerus PW, Broze GJ, Miletich JP, et a1 Anticoagulants, thrombolytic, and antiplatelet drugs. In Hardman JG, Limbird LE, Molinoff PB, et a1 (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 1996, pp 13411360 24. Mannucci PM, Lusher JM: Desmopressin and thrombosis [letter]. Lancet 2:675, 1989 25. Mannucci P M Hemostatic drugs. N Engl J Med 339:245, 1998 26. Michelsen LG, Kikura M, Levy JH, et al: Heparinase I (neutralase) reversal of systemic anticoagulation. Anesthesiology 85:339, 1996 27. Milne B, Rogers K, Cervenko F, et al: The haemodynamic effects of intraaortic versus intravenous administration of protamine for reversal of heparin in man. Can Anaesth SOCJ 30:347, 1983 28. Mochizuki T, Olson PJ, Szlam F, et a1 Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 87781, 1998 29. Morel DR, Zapol WM, Thomas SJ, et al: C5 and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology 66:597, 1987 30. Ordonez Fernandez A, Hernandez Fernandez A, Borrego Dominguez JM, et al: The systemic vasodilatory action of protamine: Is it inhibited or mediated by heparin? Res Exp Med (Berl) 197:337,1998 31. Pagliaro LA, Benet LZ: Pharmacokinetic Data. J Pharmacokinet Biopharm 3:333, 1975 32. Pauca AL, Graham JE, Hudspeth AS Hemodynamic effects of intraaortic administration of protamine. Ann Thorac Surg 35:637, 1983 33. Perkash A: A comparison of the quantitative action of protamine and heparin on blood coagulation: Significance in clinical and laboratory usage. Am J Clin Pathol 73:767, 1980 34. Puigdellivol E, Carral ME, Moreno J, et al: Pharmacokinetics and absolute bioavailability of intramuscular tranexamic acid in man. Int J Clin Pharmacol Ther Toxic01 23:298, 1985 35. Rizza RA, Sclonick S, Conley C L Myoglobinuria following aminocaproic acid administration. JAMA 236:1845, 1976 36. Robinson AG: DDAVP(r) in the treatment of central diabetes insipidus. N Engl J Med 294:507, 1976 37. Salva KM, Kim HC, Nahum K, et al: DDAVP in the treatment of bleeding disorders. Pharmacotherapy 8:94, 1988 38. Salzman EW, Weinstein MJ, Weintraub RM, et al: Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 3141402, 1986 39. Seif SM, Zenser TV, Ciarochi FF, et al: DDAVPB (1-Desamino-8-Arginine Vasopressin) treatment of central diabetes insipidus: Mechanism of prolonged antidiuresis. J Clin Endocrinol Metab 46:381, 1978 40. Shanberge JN, Murato M, Quattrociocchi-Longe T, et al: Heparin-protamine complexes in the production of heparin rebound and other complications of extracorporeal bypass procedures. Am J Clin Pathol 87210, 1987 41. Shore-Lesserson L, Reich DL, DePerio M Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth 45:10, 1998 42. Swartz C, Onesti G, Ramirez 0, et al: Cardiac and renal hemodynamic effects of the antifibrinolytic agents, epsilon aminocaproic acid. Curr Ther Res 8:336, 1966 43. Tao W, Deyo DJ, Brunston RLJ, et al: Efficacy of a heparin removal device in comparison with protamine after hypothermic cardiopulmonary bypass. ASAIO J 43M825, 1997
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44. Verstraete M Clinical application of inhibitors of fibrinolysis. Drugs 29:236, 1985 45. Weiler JM, Freiman P, Sharath MD, et al: Serious adverse reactions to protamine sulfate: Are alternatives needed? J Allergy Clin Immunol 75:297, 1985 46. Zaidan JR, Johnson S, Brynes R, et al: Rate of protamine administration: Its effect on heparin reversal and antithrombin recovery after coronary artery surgery. Anesth Analg 65:377, 1986
Address reprint requests to Robert N. Sladen, MB, ChB, MRCP, FRCPC College of Physicians and Surgeons of Columbia University 630 West 168th St, New York, NY 10032 e-mail: [email protected]
0889-8537/99 $8.00
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DRUGS TO PREVENT AND REVERSE ANTICOAGULATION Martin Franck, MD, and Robert N. Sladen, MB, ChB, MRCP, FRCP(C)
Bleeding or severe coagulopathy from inherited or iatrogenic coagulation defects can often be corrected by transfusion of specific factor deficiency. However, in some situations transfusional therapy can be augmented or avoided altogether by hemostatic drugs. Many hemostatic drugs have been evaluated, but only a few have proven clinical efficacy. This article will review the pharmacology and dosing of drugs commonly used for reversing anticoagulation and fibrinolysis. PROTAMINE Structure and Activity
Protamine is a strongly basic low molecular weight polycationic amine derived from the sperm or mature testes of salmon. Its alkalinity stems from the large proportion (over 65%)of its amino acid composition as arginine. Its primary indication is after cardiopulmonary bypass, when it is given to reverse the effects of heparin, a polyanionic mucopolysaccharide that produces anticoagulation via activation of antithrombin III. Protamine forms an ionic bond with heparin, and the stable complex neutralizes its anticoagulant effects.= The heparin-protamine complexes are ultimately removed by the reticuloendothelial system.
From the Department of Anesthesiology (MF, RNS) and Cardiothoracic-Surgical Intensive Care Unit (RNS), College of Physicians and Surgeons of Columbia University, New York, New York
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Neutralization of heparin requires an excess of protamine which competes with antithrombin I11 for binding with heparin.40Excess free protamine is broken down by an endogenous plasma protaminase, leading to instability of the heparin-protamine complex. The subsequent release of heparin restores its antithrombin activity, so-called heparin rebound.
Pharmacology and Dosage
Protamine is prepared as a powder or solution containing 250 mg in 25 mL (10 mg/mL). A number of dosing regimens have been developed for cardiopulmonary bypass in an effort to more precisely titrate the most appropriate reversal dose of protamine for a given dose of heparin. Difficulty arises because the neutralization ratio for protamine and heparin is different for different heparin sources. For example, 1 mg of protamine neutralizes 90 IU bovine lung heparin, and 110 IU porcine intestine heparin.23aThe most empiric approach is to administer 1 to 1.5 mg of protamine for every 100 IU of heparin, guided by the celite activated clotting time (ACT) measured 5 to 15 minutes after each dose. The end-point is to achieve correction of the ACT to pre-heparin baseline. Because heparin is rapidly metabolized, the amount of protamine required decreases with time after heparin administration. For example, if 30 to 60 minutes have elapsed, the protamine dose should be reduced to about 0.5 to 0.75 mg/100 IU heparin, and to about 0.25 mg/100 IU after 2 hours. The most established titration regimen is that of heparin response curves published by Bull et a1 in 1975.5The specific dose of protamine is calculated by in vitro titration of the patient's blood with protamine; approximately 1.3 mg/kg of protamine for each 100 IU of heparin present as calculated from the ACT. Weight-based heparin and protamine dosing strategies for cardiopulmonary bypass do not take into account wide interpatient variability. Despotis et a1 evaluated the Hepcon device in patients undergoing cardiopulmonary bypass who did not receive antifibrinolytic agents.1° The Hepcon is a whole blood hemostasis system that provides both ACT and heparin concentration measurements via an automated protamine titration method. Compared with a control method based on the ACT alone, patients in the Hepcon cohort received greater doses of heparin, had lower protamine-to-heparin ratios (0.71 versus 0.9:1), and received significantly fewer units of platelets, fresh frozen plasma, or cryoprecipitate. However, more recently, Shore-Lesserson et al4I found that an automated heparin and protamine titration system (Hepcon) did not result in a measurable improvement in perioperative hemostasis, although the predicted protamine dose could be lowered.
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Adverse Effects
Hypotension
Administration of protamine is frequently associated with acute, usually transient, hypotension as a result of histamine release, which induces vasodilation and myocardial depression. The response is quite predictable with rapid injection and can be attenuated or prevented by slow intravenous injection (i.e., a maximum rate of 5 mg/min). It has also been reported that reversal of heparin effect may be more complete when protamine is given as a 30-minute infusion rather than by bolus injection.46Attempts to induce pulmonary clearance of histamine by 32 or by the intra-arterial (intra-aortic or left atrial) admini~tration,2~, concomitant administration of intravenous calcium chloride, do not appear to prevent this phenomenon. It is suspected that vasodilator activity is blocked when protamine forms a complex with heparin. However, in an in vitro study Ordonez Fernandez et aI3O demonstrated that protamine induces endotheliumdependent systemic vasodilatation that is not blocked when protamine forms a complex with heparin in comparable concentrations of both drugs. Hypersensitivity Reactions
Protamine may induce a variety of allergic reactions, ranging from anaphylactoid-like symptoms (prolonged hypotension, dyspnea, bradycardia, flushing) through full-blown anaphylactic shock.'*, 21, 45 Patients who may be at risk include those with prior exposure to protarnine, NPH or protamine zinc ins~lin,'~ a history of fish allergy, or after vasectomy. The risk is greatest in individuals with antiprotamine IgG or IgE antibodies. The role of prophylaxis of hypersensitivity reactions in highrisk patients by corticosteroids and a combination of HI- and H2-blockers has not been established. The heparin-protamine complex may itself directly precipitate hemodynamic changes by complement activation via the classic pathway. Intense thromboxane release manifests as pulmonary vasoconstriction and bronchoconstriction.29This syndrome may be associated with acute right ventricular failure, shock, and/or noncardiogenic pulmonary edema. Protamine Overdose
Protamine administered in the absence of heparin interacts with platelets and proteins, including fibrinogen. These interactions may manifest as an anticoagulant effect of protamine and cause paradoxical bleeding by weakening formed clot and impairing adenosine diphosphate (ADP)-induced platelet aggregation. After cardiopulmonary bypass, bleeding associated with a prolonged ACT after protamine reversal
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of heparin could be misinterpreted as residual heparin anticoagulation. Additional protamine could further increase the ACT and exacerbate bleeding. In an in vitro study, Mochizuki et alZ8found that protamineto-heparin ratios of greater than 1.3:l significantly prolonged the ACT. This effect was either absent or attenuated by the use of alternate heparin antagonists (recombinant platelet factor 4 [rPF,], hexadimethrine). However, clinically significant alterations in coagulation parameters, such as prolonged activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) require protamine-heparin dose ratios which are at least 3-5:1, and as much as 100:l.33It is very unlikely that abnormal coagulation is induced by the doses of protamine routinely used after cardiopulmonary bypass. Heparin Rebound Heparin rebound implies the return of heparin antithrombin effect after initial neutralization of its activity by protamine after cardiopulmonary bypass. Its incidence is variable, and may occur within minutes or hours of protamine administration. The mechanisms are speculative but may include liberation of heparin from extravascular spaces or intravascular surfaces, or the breakdown of excess protamine by protaminase (discussed previously). Another potentially important mechanism is the administration of fresh frozen plasma after cardiopulmonary bypass because it contains antithrombin I11 and boosts heparin's antithrombin activity. Heparin rebound appears to be less likely to occur when an excess of protamine (i.e., a ratio of 1.5:l) has been administered. In contrast, the incidence is higher when the minimal amount of protamine required to neutralize heparin determined by titration methods is given.4O Alternatives to Protamine In an effort to avoid administration of protamine with its attendant complications, a number of substitutes have been or are being explored. Heparin substitutes, such as prostacyclin (PGI,) and Iloprost decrease (but do not replace) heparin requirements on cardiopulmonary bypass. Protamine substitutes with anti-heparin activity include heparinase I and hexadimethrine (polybrene), a synthetic quaternary ammonium salt.20Of these, the most promising is heparinase I (neutralase), a specific enzyme that inactivates heparin. Preliminary studies suggest that heparinase I is as effective as protamine in reversing the action of heparin, but lacks its hemodynamic or antiplatelet effects.', 26 An alternative is the use of a heparin removal device that separates plasma and adsorbs heparin on to ply-L-lysine. Although slower and less complete in heparin reversal than protamine, porcine studies suggest that it may provide sufficient clinical efficacyto be used in patients with known protamine hypersensiti~ity.~3
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DESMOPRESSIN Structure and Activity
Desmopressin acetate (DDAVP), 1-desamino-8-D-arginine vasopressin, is a synthetic vasopressin analogue. It is pharmacologically altered from naturally occurring vasopressin by deamination of hemicysteine at position one and substitution of D-arginine for L-arginine at position eight. These changes virtually eliminate vasopressor (V,-receptor agonist) activity, and enhance its antidiuretic (V2-receptor agonist) action. The antidiuretic-to-pressor potency ratio is increased from 1:l to 20004000:l. It also prolongs its duration of action from 2 to 6 hours to 6 to 36 by increasing resistance to enzymatic cleavage, delaying 24 absorption from the nasal mucosa, and enhancing generation of cyclic adenosine monophosphate (AMP) in the renal medulla.39Oxytocic activity is 4 to 75 times less than that of arginine vasopressin. Desmopressin is more potent than arginine vasopressin at the V2receptor in stimulating the endothelial release of factor VIII and von Willebrand factor into the plasma, where they form a complex with platelets and enhance their ability to aggregate. It has achieved a role in the preoperative prophylaxis of surgical bleeding in patients with mild certain forms of von Willebrand’s forms of hemophilia and in uremic thrombocytopathy.6 In hemophilia A, desmopressin decreases the aPTT but is ineffective if factor VII1:C levels are less than 5%. In the classic type I von Willebrand’s disease, desmopressin decreases the Ivy bleeding time, but in patients with type IIb it may actually induce thrombocytopenia by causing excess platelet aggregation.26If the type of von Willebrand’s disease has not been completely characterized, it is prudent to test the patient’s response to desmopressin about 2 weeks prior to elective surgery. Desmopressin enhances platelet function in uremic thrombocytopathy, but lack of effect may be encountered in critically ill patients on vasoactive drugs because catecholamines, such as epinephrine, also release factor VIII and von Willebrand’s factor from the endothelium. In these patients, it may be preferable to administer these factors directly in the form of ~ryoprecipitate.~~ In the mid-l980s, there was a flurry of interest in the hemostatic effect of desmopressin in patients undergoing cardiopulmonary bypass.3s However, the initial promise suggested by preliminary studies was never confirmed by larger trials. Its administration after cardiopulmonary bypass may exacerbate post-bypass hypotension.8*l2 Desmopressin also stimulates the endothelial release of plasminogen activator. Concomitant use of antifibrinolytic agents, such as epsilon-aminocaproic acid, may blunt its fibrinolytic effect and enhance thrombus formation.24 Dosage and Administration
Desmopressin was initially introduced for the treatment of chronic diabetes insipidus, for which it is given by nasal spray as 5 to 40 pg/d
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in divided doses. For acute diabetes insipidus (and in particular, donor preservation), it is given subcutaneously at 0.5 to 2 pg/d. For hemophilia A, von Willebrand’s disease, and uremic thrombocytopathy, desmopressin is given in a much larger dose, 0.3 pg/kg. Antidiuresis is not a concern because there is actually an inverse relationship between desmopressin dosage and its antidiuretic e f f e ~ tIt. ~is prepared in a concentration of 4 pg/mL, so, for example, an 80-kg patient should receive 24 pg (6 mL) diluted in 50 mL sterile saline and infused slowly over 15 to 30 minutes because of the risk of acute hypotension? Blood pressure and pulse should be closely monitored. Desmopressin is best given 30 minutes prior to the scheduled procedure because its beneficial effect on platelet function peaks at about 1 to 2 hours and lasts about 8 to 12 hours. Repeated administration within 48 hours usually results in tachyphylaxis, presumably because all available factor VIII and von Willebrand’s factor have been mobilized from the endothelium. Pharmacology
After intravenous injection, desmopressin has a distribution halflife of 7.8 minutes, and an elimination half-life of 2.5 to 4.4 ANTlFlBRlNOLYTlC AGENTS
Antifibrinolytic agents currently in use include synthetic lysine analogues, such as aminocaproic acid and tranexamic acid, and the naturally occurring kallikrein inhibitor, aprotinin. These compounds form a reversible complex with plasminogen and with the active protease, plasmin. They saturate the lysine-binding sites on plasminogen, and thereby displace plasminogen from the surface of fibrin and inhibit the proteolytic effect of plasmin. APROTlNlN
Structure and Activity
Aprotinin is a naturally occurring polypeptide inhibitor of proteolytic enzymes that is isolated from bovine lung.15It is known to inhibit human trypsin, plasmin, and tissue and plasma kallikrein by forming reversible enzyme-inhibitor complexes. Indications
Aprotinin is indicated for prophylaxis for perioperative blood loss during cardiopulmonary bypass (CPB).
DRUGS TO PREVENT AND REVERSE ANTICOAGULATION
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Pharmacology
Plasma aprotinin concentrations decrease rapidly after intravenous administration because of redistribution to peripheral tissues.23Aprotinin is rapidly eliminated from the circulation via glomerular filtration.
Dosage
The enzymatic activity of aprotinin is generally expressed in kallikrein inactivator units (KIU), with 1 KIU defined as the amount of aprotinin that decreases the activity of two biologic kallikrein units by 50%. One milligram of aprotinin is equivalent to 7143 KIU. Hemostatically effective plasmin inhibition requires a plasma aprotinin concentration of greater than 50 KIU/mL.23A 2-million KIU dose is needed to achieve the higher plasma concentrations necessary to inhibit kallikrein. The Celite ACT does not reliably monitor heparin effect in the presence of aprotinin. The kaolin ACT should be substituted. Standard Dosing for Cardiac Surgery with Cardiopulmonary Bypass
Aprotinin should be administered exclusively through a central venous catheter; no other drugs should be administered using the same line. Because of the potential for anaphylaxis (1%-2% risk in patients exposed to aprotinin within the previous 6 months), a test dose of 1 mL aprotinin (10,000 KIU) is administered intravenously at least 10 minutes prior to the loading dose. Signs of an allergic reaction (tachycardia, flushing, hypotension, bronchospasm) should be closely monitored prior to further dosing. After the induction of anesthesia, but prior to sternotomy, a loading dose of 2 million KIU is given over 20 to 30 minutes. An additional 2 million KIU of aprotinin is added to the priming fluid of the cardiopulmonary bypass pump. After the loading dose is given, a constant infusion of 0.5 million KIU/h is begun and continued until the patient leaves the operating room. Because of the high cost of the aprotinin regimen described above (about $1200 per case), an alternative reduced-dosage regimen has been advocated as being comparably effective in decreasing perioperative blood loss and transfusion requirements in patients undergoing coronary revascularization procedures. The dosing regimen is identical except that the doses have been halved-after a test dose, a loading dose of 1 million KIU of aprotinin is given, 1 million KIU is added to the pump prime, and a continuous infusion of 0.25 million KIU/h is run through the rest of the case.
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Adverse Effects
The major concern with aprotinin is the risk of a hypersensitivity reaction. With first-time exposure, the risk of anaphylaxis is estimated to be about 0.1%, but this increases to 1% to 2% with a history of exposure within the previous 6 month^.^ Aprotinin is renally eliminated and has the potential for nephrotoxic injury, producing dose-related increases in serum creatinine. AMINOCAPROIC ACID Structure and Activity
Epsilon-aminocaproic acid, an analogue of lysine, is a 6-aminohexanoic acid. Aminocaproic acid appears to inhibit fibrinolysis by inhibiting plasminogen activators and, to a lesser degree, by its antiplasmin activity. The fibrinolytic system consists of plasminogen activators (streptokinase, urokinase, tissue activators), plasminogen (profibrinolysin), and plasmin (fibrinolysin). Plasminogen activators convert plasminogen to plasmin, a proteolytic enzyme responsible for the degradation of thrombi. Excess plasminogen activation results in increased fibrinolysis and dysfunction of fibrinogen, fibrin, and other clotting components. Severe hemorrhage may result. Aminocaproic acid is a competitive inhibitor of plasminogen activators and inhibits plasmin to a lesser extent (at higher doses). Indications
Aminocaproic acid can potentially enhance hemostasis when fibrinolysis contributes to bleeding. It is specifically indicated as an antifibrinolytic agent in the treatment of bleeding resulting from systemic fibrinolysis and urinary fibrinolysis. Aminocaproic acid should not be used when there is evidence of an active intravascular clotting process. It is appropriate to use in primary fibrinolysis (hyperplasminemia), but may exacerbate intravascular clot formation in disseminated intravascular coagulation (DIC). Pharmacology
Aminocaproic acid is largely eliminated unchanged by renal excretion (65%),but about 35% undergoes hepatic metabolism to the metabolite, adipic acid, which also appears in the urine. The renal clearance (116 mL/min) approximates endogenous creatinine clearance, and total body clearance is 169 m L / m i ~ ~The . ~ l terminal elimination half-life for aminocaproic acid is approximately 1 to 2 hours.
DRUGS TO PREVENT AND REVERSE ANTICOAGULATION
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Dosage
The initial loading dose in an adult patient is 5 g administered over 15 to 20 minutes. Rapid intravenous administration may induce acute h y p o t e n s i ~ nThis . ~ ~ is followed by a continuous infusion at the rate of 1 g/h, for 5 to 8 hours or until the bleeding situation has been controlled. The dose of aminocaproic acid should be reduced by 15% to 25% in patients with renal disease or oliguria. Adverse Effects
The most common acute side effect is hypotension, associated with rapid intravenous administration. Other reported adverse effects are occasionally encountered with longer-term administration and include rash, nausea and vomiting, weakness, retrograde ejaculation, myopathy, and even rhabdomy~lysis.~~ TRANEXAMIC ACID Structure and Activity
Tranexamic acid (trans-4-aminomethyl-cyclohexanecarboxylic acid) is a competitive inhibitor of plasminogen activation, and, at much higher concentrations, a noncompetitive inhibitor of plasmin. Its actions are similar to those of aminocaproic acid, but tranexamic acid is about 10 times more potent in vitro, with higher and more sustained antifibrinolytic activity.2,44 However, there appears to be little difference in their therapeutic or adverse effects. Aminocaproic acid has been preferred in the treatment of subarachnoid hemorrhage, because the use of tranexamic acid has been associated with an unacceptable incidence of ischemic complications.'l Mechanism of Action
Tranexamic acid exerts its antifibrinolytic activity by occupying the lysine-binding sites of human plasminogen. This displaces it from the fibrin clot surface of cloti9 Plasmin-induced fibrinolysis is inhibited regardless of the rate of plasmin formation because tranexamic acid prevents it from binding to fibrinogen or fibrin monomers and exerting its proteolytic action at the serine-histidine enzyme site.44Tranexamic acid blocks the lysine binding sites of plasmin, making inactivation by alpha-2-antiplasmin impossible, and further inhibiting its proteolytic activity. Tranexamic acid may also provide a hemostatic benefit in recurrent or excessive bleeding by stabilizing fibrin structures and preventing
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fibrin dissolution, especially when fibrin formation is defective. Its effect in preserving the fibrin matrix may also enhance collagen synthesis and tensile strength in granulation tissue.22
Indications and Limitations Tranexamic acid is indicated to treat bleeding associated with primary fibrinolysis. This should be differentiated from DIC because, in the latter, it may increase intravascular thrombosis, unless low-dose heparin is given concomitantly. Tranexamic acid has been fairly widely used to prevent or treat bleeding with associated fibrinolysis during teeth extraction in hemophiliacs, recurrent epistaxis, upper gastrointestinal bleeding, or menorrhagia. It also appears to reduce the frequency of attacks of hereditary and nonheriditary angioneurotic edema. There are a number of clinical studies that attest to its effectiveness in decreasing blood loss and transfusion requirement after cardiopulmonary bypass. There is some evidence that it may be effective in surgical procedures such as total knee arthroplasty, but it is contraindicated for transurethral prostatectomy because of the risk of intravesicular clotting.
Pharmacology Only a small fraction of administered tranexamic acid is metabolized; the majority is excreted unchanged by the kidney. The dose must be substantially decreased in renal impairment: by about 50% with serum creatinine, 1 to 2 mg/dL; a further 50% with serum creatinine, 2 to 4 mg/dL; and a further 50% with serum creatinine greater than 4 mg/dL. Dosing adjustment is not necessary with liver disease. Pharmacokinetic studies have revealed that tranexamic acid has a volume of distribution of 9 to 12 L and an elimination half-life of about 2
Dosage
A wide range of dosage is used. In most instances, the single intravenous dose of tranexamic acid is 10 to 15 mg/kg. During cardiac surgery, a loading dose of 15 mg/kg is given prior to cardiopulmonary bypass, followed by a continuous infusion of 1 mg/kg/h for 5 to 8 hours. However, some studies have used doses as high as 100 to 150 mg/kg as a single load prior to cardiopulmonary bypass.
DRUGS TO PREVENT AND REVERSE ANTICOAGULATION
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Adverse Effects
Hypotension may be caused by rapid intravenous injection. As with aminocaproic acid, the major concerns have related to the potential for increasing the perioperative risk of thromboembolism, arterial thrombosis, myocardial infarction, and pulmonary embolism, which, although rare, have been reported with long-term therapy or with high doses in subarachnoid hemorrhage.”,
References 1. Ammar T, Fisher C F The effects of heparinase 1 and protamine on platelet reactivity. Anesthesiology 861382,1997 2. Andersson L, Nilsson IM, Colleen S, et a1 Role or urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann NY Acad Sci 146642,1968 3. Ariano RE, Seymour B: Inverse relationship between desmopressin dosage and antidiuresis. Clin Pharm 10912, 1991 4. Bichet DG, Razi M, Lonergan M, et a1 1-Desamino (8-D arginine) vasopressin (dDAVP) decreases blood pressure and increases pulse rate in normal individuals. Thromb Haemost 60348, 1988 5. Bull BS, Huse WM, Brauer FS, et al: Heparin therapy during extracorporeal circulation. 11. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69:785, 1975 6. Canavese C, Salomone M, Pacitti A, et al: Reduced response of uraemic bleeding time to repeated doses of desmopressin. Lancet 1:867, 1985 7. Cobb WE, Spare S, Reichlin S Neurogenic diabetes insipidus: Management with DDAVP(r) (1-Desamino-8-D Arginine Vasopressin). Ann Intern Med 88:183, 1978 8. DAlauro FS, Johns RA: Hypotension related to desmopressin administration following cardiopulmonary bypass. Anesthesiology 69:962, 1988 9. DAmbra MN, Risk SC: Aprotinin, erythropoietin and blood substitutes. Int Anesthesiol Clin 28:237, 1990 10. Despotis GJ, Joist JH, Hogue CWJ, et a1 The impact of heparin concentration and activated clotting time monitoring on blood conservation: A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 11046, 1995 11. Fodstad H, Forssell A, Liliequist B, et al: Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: A consecutive controlled clinical trial. Neurosurgery 8:158, 1981 12. Frankville DD, Harper GB, Lake CL, et al: Hemodynamic consequences of desmopressin administration after cardiopulmonary bypass. Anesthesiology 74988, 1991 13. Gupta SK, Veith FJ, Ascer E, et al: Anaphylactoid reactions to protamine: An often lethal complication in insulin-dependent diabetic patients undergoing vascular surgery. J Vasc Surg 9:342, 1988 15. Hardy JF, Desroches J: Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 73:395, 1994 16. Holmberg L, Nilsson IM, Borge L Platelet aggregation induced by l-desamino-8-Darginine vasopressin (DDAVP) in type IIB von Willebrand’s disease. N Engl J Med 3092316, 1983 17. Horrow JC: Desmopressin and antifibrinolytics. Int Anesthesiol Clin 28:230, 1990 18. Horrow JC: Protamine: A review of its toxicity. Anesth Analg 6 4 9 8 , 1985 19. Hoylaerts M, Lijnen HR, Colien D Studies on the mechanism of antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 67375, 1981
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20. Kikura M, Lee MK, Levy JH: Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. Anesth Analg 83:223, 1996 21. Konstadt SN. Protamine administration: Untoward responses and their mechanisms. Mt Sinai J Med 54:297, 1987 22. Kwaan HC, Astrup T Tissue repair in presence of locally applied inhibitors of fibrinolysis. Exp Mol Pathol 11232, 1969 23. Levy JH, Bailey JM, Salmenpera M Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 80:1013, 1994 23a. Majerus PW, Broze GJ, Miletich JP, et a1 Anticoagulants, thrombolytic, and antiplatelet drugs. In Hardman JG, Limbird LE, Molinoff PB, et a1 (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 1996, pp 13411360 24. Mannucci PM, Lusher JM: Desmopressin and thrombosis [letter]. Lancet 2:675, 1989 25. Mannucci P M Hemostatic drugs. N Engl J Med 339:245, 1998 26. Michelsen LG, Kikura M, Levy JH, et al: Heparinase I (neutralase) reversal of systemic anticoagulation. Anesthesiology 85:339, 1996 27. Milne B, Rogers K, Cervenko F, et al: The haemodynamic effects of intraaortic versus intravenous administration of protamine for reversal of heparin in man. Can Anaesth SOCJ 30:347, 1983 28. Mochizuki T, Olson PJ, Szlam F, et a1 Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 87781, 1998 29. Morel DR, Zapol WM, Thomas SJ, et al: C5 and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology 66:597, 1987 30. Ordonez Fernandez A, Hernandez Fernandez A, Borrego Dominguez JM, et al: The systemic vasodilatory action of protamine: Is it inhibited or mediated by heparin? Res Exp Med (Berl) 197:337,1998 31. Pagliaro LA, Benet LZ: Pharmacokinetic Data. J Pharmacokinet Biopharm 3:333, 1975 32. Pauca AL, Graham JE, Hudspeth AS Hemodynamic effects of intraaortic administration of protamine. Ann Thorac Surg 35:637, 1983 33. Perkash A: A comparison of the quantitative action of protamine and heparin on blood coagulation: Significance in clinical and laboratory usage. Am J Clin Pathol 73:767, 1980 34. Puigdellivol E, Carral ME, Moreno J, et al: Pharmacokinetics and absolute bioavailability of intramuscular tranexamic acid in man. Int J Clin Pharmacol Ther Toxic01 23:298, 1985 35. Rizza RA, Sclonick S, Conley C L Myoglobinuria following aminocaproic acid administration. JAMA 236:1845, 1976 36. Robinson AG: DDAVP(r) in the treatment of central diabetes insipidus. N Engl J Med 294:507, 1976 37. Salva KM, Kim HC, Nahum K, et al: DDAVP in the treatment of bleeding disorders. Pharmacotherapy 8:94, 1988 38. Salzman EW, Weinstein MJ, Weintraub RM, et al: Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 3141402, 1986 39. Seif SM, Zenser TV, Ciarochi FF, et al: DDAVPB (1-Desamino-8-Arginine Vasopressin) treatment of central diabetes insipidus: Mechanism of prolonged antidiuresis. J Clin Endocrinol Metab 46:381, 1978 40. Shanberge JN, Murato M, Quattrociocchi-Longe T, et al: Heparin-protamine complexes in the production of heparin rebound and other complications of extracorporeal bypass procedures. Am J Clin Pathol 87210, 1987 41. Shore-Lesserson L, Reich DL, DePerio M Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth 45:10, 1998 42. Swartz C, Onesti G, Ramirez 0, et al: Cardiac and renal hemodynamic effects of the antifibrinolytic agents, epsilon aminocaproic acid. Curr Ther Res 8:336, 1966 43. Tao W, Deyo DJ, Brunston RLJ, et al: Efficacy of a heparin removal device in comparison with protamine after hypothermic cardiopulmonary bypass. ASAIO J 43M825, 1997
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44. Verstraete M Clinical application of inhibitors of fibrinolysis. Drugs 29:236, 1985 45. Weiler JM, Freiman P, Sharath MD, et al: Serious adverse reactions to protamine sulfate: Are alternatives needed? J Allergy Clin Immunol 75:297, 1985 46. Zaidan JR, Johnson S, Brynes R, et al: Rate of protamine administration: Its effect on heparin reversal and antithrombin recovery after coronary artery surgery. Anesth Analg 65:377, 1986
Address reprint requests to Robert N. Sladen, MB, ChB, MRCP, FRCPC College of Physicians and Surgeons of Columbia University 630 West 168th St, New York, NY 10032 e-mail: [email protected]