Management of Bleeding Complications in Redo Cardiac Operations

Management of Bleeding Complications in Redo Cardiac Operations Craig R. Smith, MD Division of Cardiothoracic Surgery, Columbia-Presbyterian Medical Center, New York, New York

Bleeding remains a complication of certain complex surgical procedures, particularly those cardiac operations associated with long bypass times and profound hypothermia. Clinical and novel experimental strategies to reduce bleeding and the need for blood and bloodproduct transfusions are the focus of this review. Preoperative assessment of the patient will identify druginduced, acquired, or inherited coagulation defects that may contribute to this problem. The main attention is directed to the perioperative period, and broad areas discussed include the preoperative use of erythropoietin to increase red blood cell mass, autologous donation either preoperatively or before bypass, autotransfusion/ hemofiltration, and acceptance of relative anemia both during the operation and into the postoperative period. A further, often overlooked, management strategy in treating major coagulopathies is the consideration of the cost and half-lives of the coagulation factors in individual blood components. Prevention of bleeding has become possible both by manipulation of the control of coagulation and inflammatory processes and by the introduction of pharmacologic agents such as aprotinin. Aprotinin is widely used and has proven efficacy in the management of excess bleeding. It is a serine protease inhibitor and

has several possible mechanisms of action, including inhibition of the plasma enzyme systems activated by contact with the foreign surface of the bypass circuit and preservation of platelet function. Safety issues include the possibility of hypersensitivity and anaphylactic reaction on a second exposure. Concerns that aprotinin may induce a prothrombotic or coagulant state have no basis in theory or any good evidence in the current literature. A recent study specifically sought to identify the presence of disseminated microvascular platelet-fibrin thrombi present at autopsy in patients who had received aprotinin therapy. The study concluded that diffuse plateletfibrin thrombi were not a direct complication of aprotinin therapy. Finally, modern molecular biology has led to the recent development of an inhibitor for factor IXa that competitively replaced IXa in the intrinsic complex and blocked the conversion of factor X to factor Xa. This compound is under investigation in animal studies. These have so far shown efficacy in reducing blood loss after bypass in comparison with standard heparin anticoagulation.

T

should be to minimize bleeding; the second should be to minimize transfusion requirements.

he risk factors associated with increased perioperative bleeding in patients undergoing cardiac operations are well known. Although the majority of operations can be performed with no or minimal use of blood and blood products, procedures such as heart-lung or double-lung transplantations, aortic dissection repair, insertion of left ventricular assist devices (LVADs), and, of course, reoperations have all been associated with hemostatic problems. Prolonged bypass times and hypothermic circulatory arrest in certain of these patient populations compound the problem. This presentation will extend the debate beyond the technical factors that influence the need for bloodproduct transfusion and examine a more global view of the management of bleeding complications and ways of optimizing hemostasis in redo patients. The first priority of any blood-conservation program Presented at the Second International Symposium on Redo Cardiac Surgery in Adults, Washington, DC, May 2, 1997. Address reprint requests to Dr Smith, Department of Cardiothoracic Surgery, Columbia Presbyterian Medical Center, Milstein Hospital Bldg, 177 Ft Washington Ave, New York, NY 10032.

© 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

(Ann Thorac Surg 1998;65:S2– 8) © 1998 by The Society of Thoracic Surgeons

Technical Strategies to Minimize Bleeding Meticulous technique, patience, and good patient selection all contribute significantly to minimizing bleeding in high-risk patients. The use of topical agents to control hemostasis is well established, although commonly used agents such as Surgicel (Johnson & Johnson Medical, Arlington, TX), thrombin-soaked gel, and fibrin glue have little efficacy in the face of significant bleeding, particularly if clot formation is impaired. Cardiopulmonary bypass (CPB) has many actions on homeostatic mechanisms. It is important not to overlook the influence of bypass techniques on coagulation. Exposure of the blood to the foreign surface of the extracorporeal circuit results in a largely unwanted stimulus to circulating platelets. Comparison between platelet counts before and after bypass shows a dramatic reduction in numbers [1–3], and bleeding time as a measure of impaired hemostasis has a strong linear correlation with the length of bypass [4]. Another important factor in 0003-4975/98/$19.00 PII S0003-4975(98)00070-8

Ann Thorac Surg 1998;65:S2– 8

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

S3

relation to bypass procedures is the effect of temperature on clot-forming ability. Although there is less tendency these days to cool patients significantly, there is still a steep relationship between prothrombin time or activated partial thromboplastin time and temperature [5]; where possible, temperatures should not fall to less than 32°C. Elective redo operation allows preoperative assessment of the patient to identify drug-induced, acquired, or inherited coagulation defects: Drug-induced Aspirin Warfarin Heparin Nonsteroidal antiinflammatory drug Acquired Liver dysfunction Sepsis Shock Thrombocytopenia Fibrinolysis Disseminated intravascular coagulation Inherited Factor deficits Platelet dysfunction Discontinuation or reversal of anticoagulant medications is an important luxury not available for emergency procedures.

Pharmacologic Strategies to Minimize Bleeding Use of one or more pharmacologic agents is the most widespread blood-conservation method available today: Erythropoietin Blood substitutes Tranexamic acid DDAVP (desmopressin) Prostaglandin I2 analogue (iloprost) Nafamostat mesilate e-Aminocaproic acid Aprotinin (Trasylol; Bayer, West Haven, CT)

Fig 1. Possible mechanisms of action of aprotinin. (CPB 5 cardiopulmonary bypass; TPA 5 tissue plasminogen activator.)

platelet surface glycoproteins, resulting in deranged platelet adhesion and aggregation [10, 11]. A number of studies have shown that aprotinin is able to inhibit platelet activation and to preserve certain platelet functions [5, 6, 12], although whether this is related to aprotinin’s action to reduce bleeding has yet to be proved. efficacy. The efficacy of aprotinin in reducing bleeding and the need for donor-blood transfusion is documented in a large number of randomized, double-blind, placebocontrolled studies performed in Europe and the United States [13, 14]. Two recent studies evaluated the efficacy and safety of aprotinin in a United States population of patients undergoing reoperative coronary artery bypass grafting [15, 16]. The number of units of blood and blood products transfused in the perioperative period was significantly reduced with aprotinin therapy in both study populations (Fig 2). Aprotinin use also was associated with decreases in transfusion of individual bloodproduct components, with significantly less packed red blood cells, fresh-frozen plasma, and platelet concentrates administered (Fig 3). hypersensitivity reactions. Because aprotinin is a polybasic polypeptide derived from bovine organs, there is always the possibility of an adverse reaction to the drug.

Aprotinin Aprotinin is widely used to improve hemostasis in patients undergoing cardiac operations. It is a serine protease inhibitor and has several possible mechanisms of action to reduce perioperative bleeding and the need for transfusion of blood and blood products (Fig 1). The foreign surface of the bypass machine triggers activation of a number of inflammatory cascades. These plasma enzyme systems result in the generation of plasmin and kallikrein. Inhibition of these serine proteases by aprotinin will have effects on fibrinolysis and also will reduce the inflammatory actions of kallikrein and the subsequent involvement of the complement system and whitecell activation [6 –9]. Contact activation of platelets during bypass produces expression and subsequent loss of

Fig 2. Mean units of blood and blood products transfused in the perioperative period in two recent United States clinical trials investigating the efficacy of aprotinin therapy. (Study 1, Lemmer et al [15]; study 2, Levy et al [16].)

S4

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

Ann Thorac Surg 1998;65:S2– 8

samples to detect immunoglobulin E antibodies resulting from prior exposure to the drug. However, the relationship between antibody levels and the likelihood of an adverse reaction to a second administration of aprotinin is not well documented at present and need to be the focus of future investigation [17, 18].

Fig 3. Mean units of individual blood components transfused in the perioperative period in a recent United States clinical trial investigating the efficacy of aprotinin therapy [15]. (Cryo 5 cryoprecipitate; FFP 5 fresh-frozen plasma; PRBCs 5 packed red blood cells.)

Hypersensitivity reactions may range from mild skin rashes and urticaria to anaphylaxis and circulatory collapse. True anaphylactic reactions require previous exposure to the drug and the generation of specific immunoglobulin E. Based on an analysis of the currently available literature, hypersensitivity reactions are rarely reported in patients with no prior exposure to aprotinin (Table 1). Patients who have been previously treated with the drug appear to be at increased risk. The number of patients undergoing reoperations is increasing, and physicians who use aprotinin in their practice should be aware of the potential risk of anaphylaxis in this group of patients. In view of the potential for hypersensitivity reactions to aprotinin, all patients should receive a test dose of 1 mL before administration of the full loading dose. In a patient with a history of prior exposure, administration of a test dose and loading dose should be delayed until conditions for rapid cannulation are present. A skin test may detect the presence of antiaprotinin antibodies, and there are several laboratories that can analyze blood Table 1. Anaphylaxis Risk With Exposure to Aprotinina No Prior Exposure Studies US controlled studies Foreign controlled studies US open studies Foreign open studies Foreign postmarketing surveillance data a

Total

Prior Exposure

Fatalities

Total

Fatalities

0/398

0/398

0/0

0/0

7/1996

1/1996

0/0

0/0

0/299 3/1873

0/299 1/1873

1/6 1/6 1 patient treated 0/0 second time 5/140,000 1/140,000 13/7000 4/7000

Data available from Bayer Pharmaceutical Co.

thromboembolic complications. Aprotinin’s action to prevent bleeding has raised concerns that this action may induce a prothrombotic or coagulant state. There is no basis in theory or any good evidence in the current literature that this is the case. A study recently completed at Columbia-Presbyterian Medical Center specifically investigated whether aprotinin could induce a hypercoagulable state (Goldstein DJ, DeRosa C, Fisher PA, Smith CR; unpublished results). The patient population comprised 20 aprotinin recipients dying within 4 weeks of operation who underwent postmortem examination. Surgical procedures included heart transplantations, insertion of LVADs, and complex reoperations. The activated clotting time in all patients was maintained greater than 500 seconds if kaolin was the activator and greater than 750 seconds for celite activation, in accordance with the recommendations for use of these tests in the presence of aprotinin. At autopsy, each patient underwent an extensive pathologic investigation to specifically identify the presence of disseminated microvascular platelet-fibrin thrombi. Seven organs were examined including kidney, spleen, heart, lung, and liver. Ten patients (50%) had no evidence of platelet-fibrin thrombi in any organ. Five patients (25%) had lesions involving a single organ, and 3 patients (15%) had focal platelet-fibrin thrombi involving multiple organs. Focal platelet-fibrin thrombi were defined as those occurring in one or two blood vessels. Five of these 8 patients had preoperative evidence of thromboembolic problems. Two patients had evidence of diffuse platelet-fibrin thrombi. Before death both of these patients were on extracorporeal membrane oxygenation, a treatment well known to produce thrombotic complications. This study concluded that diffuse platelet-fibrin thrombosis is not a direct complication of aprotinin therapy.

Optimizing Hemostasis in Patients With Left Ventricular Assist Devices Insertion of an LVAD as a “bridging” device to cardiac transplantation can potentially lead to impaired hemostasis, with either excessive bleeding or the risk of thrombosis. The newer devices, for example, the HeartMate LVAD developed by Thermo Cardiosystems Inc (Woburn, MA), are now designed with a textured bloodcontacting surface to minimize this risk [19, 20]. Clinical experience with the HeartMate LVAD has been encouraging despite the absence of anticoagulation [21]. However, recently published data from ColumbiaPresbyterian [22] indicate that despite “normal” screening values of routine hemostatic parameters such as prothrombin time, activated partial thromboplastin time, and platelet count, patients with LVADs had significant activation of coagulation with secondary fibrinolysis.

Ann Thorac Surg 1998;65:S2– 8

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

S5

Fig 4. Assessment of thrombin generation in patients with left ventricular assist devices (LVADs) and in patients with end-stage heart failure (ESHF). Mean values 1 standard deviation are shown. (Reprinted with permission from Spanier T, Oz M, Levin H, et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112:1090 –7.)

Measurement of thrombin antithrombin-III complexes and prothrombin activation peptide levels in 20 patients supported with an LVAD for between 5 days and 335 days provided strong evidence of thrombin generation when compared either with a control population or with patients with end-stage heart failure (Fig 4). Enhanced fibrinolysis accompanied this activation of the procoagulant pathway, with significantly higher levels of d-dimers and fibrin degradation products found in the LVAD patients in comparison with the control groups (Fig 5). Endothelial cell perturbation consequent to the presence of the LVADs also was indicated by increased levels of soluble thrombomodulin. These patients were stable and not bleeding despite a biochemical profile characteristic of a low-grade disseminated intravascular coagulation. From a clinical standpoint, the potential for exacerbation of bleeding or clotting complications when the patient eventually undergoes transplantation or is returned to the operating room for other procedures should not be ignored. Aprotinin is a logical choice to minimize the possibility of bleeding in this high-risk group of patients. Its efficacy and safety have been demonstrated by a multicenter,

retrospective analysis of LVAD recipients who underwent operations between 1986 and 1993 [23]. Forty-two patients received aprotinin, and the results in respect to bleeding and transfusion were compared with those of 10 patients operated on without aprotinin. Chest-tube drainage in the control group was 4,017 6 6,630 mL/24 h compared with 1,531 6 1,326 mL/24 h in the aprotinin group. These differences were reflected in the amount of blood and blood products transfused, with aprotinintreated patients receiving an average of 13.8 6 14.9 units compared with 22.2 6 22.6 units for nontreated patients. There were no reported incidents of anaphylaxis, and major adverse events were not clustered in the aprotinintreated patients. In fact, the data suggested a tendency for reduced 7-day mortality, fewer thromboembolic complications, and lower need for right ventricular assist device insertion with aprotinin therapy, possibly related to the significant reductions in transfusion volumes.

Optimizing Blood and Blood-Product Transfusion A number of strategies are in widespread use to minimize the need for transfusion in the perioperative period.

Fig 5. Assessment of activation of fibrinolysis in patients with left ventricular assist devices (LVADs) and in patients with end-stage heart failure (ESHF). Mean values 1 standard deviation are shown. (Reprinted with permission from Spanier T, Oz M, Levin H, et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112:1090 –7.)

S6

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

Ann Thorac Surg 1998;65:S2– 8

Table 2. Coagulation Factor Concentrations in Blood Products Blood Product

Vol (mL)

Factors

Fibrinogen

Cost/U

Cost/Standard Treatmenta

Cryoprecipitate Liquid plasmab Fresh-frozen plasma Plateletsb

15 180 –300 180 –300 20 –30

5U/mL 1U/mL 1U/mL 2U/mL

10 mg/mL 2– 4 mg/mL 2– 4 mg/mL 4 – 8 mg/mL

$75 $75 $75 $55

$750 (10 U) $450 (6 U) $450 (6 U) $330 (6 U)

a

Typical cost of treatment of major coagulopathies.

b

Except labile factors (VIII, V).

These include the preoperative use of erythropoietin to increase red blood cell mass, autologous donation either preoperatively or before bypass, autotransfusion/hemofiltration, and acceptance of relative anemia both during the operation and into the postoperative period. In treating major coagulopathies with ongoing transfusion of blood and blood products, it is important to remember that the half-lives of the coagulation factors are variable and very short in some cases: factor VII, 18 to 35 minutes; factor VIII, 3.8 hours; and factor V, 12 to 15 hours. Patients with persistent bleeding will run out of these substances rapidly, and transfusion with packed red blood cells alone obviously will not replace them.

Analysis of the factor concentrations per unit volume of individual blood components suggests that management should start with platelet concentrate transfusions (Table 2). Fibrinogen levels are twice those of fresh-frozen plasma on a volume basis, and the clotting factors are present in reasonable concentrations. Fresh-frozen plasma and cryoprecipitate can be withheld until needed. Factor transfusion is a fairly costly procedure, with a standard treatment to manage major coagulopathies requiring 28 units or more of blood products at a cost approaching $2,000. Factor IX complex (Konyne 80; Bayer Inc, West Haven, CT) is another option for the management of patients with intractable hemorrhage. This is a lyophilized product derived from human plasma. The 40-mL volume contains factors II (1,500 IU), VII (180 IU), and X (1,500 IU), in addition to 1,000 IU of factor IX. It is not widely used, probably because of some older, unconfirmed reports of a hepatitis risk. Our group at ColumbiaPresbyterian recently reported Konyne 80 infusion to be effective in treating progressive consumptive coagulopathy in several LVAD patients when traditional factor replacement failed [24].

Active-Site Blocked Factor IXa: A Novel Anticoagulant

Fig 6. Generation of thrombin activated via either the contact system or the extrinsic release of tissue factor (F). In the setting of cardiopulmonary bypass, the surfaces of the extracorporeal circuit have been hypothesized to provide a substrate for activation of the contact system: factor XII activates prekallikrein and factor XI in close relation to the artificial surface, and factor XIa then, in turn, activates factor IX, producing factor IXa, the latter together with factor VIIIa activating factor Xa, which feeds into the final common pathway, ie, the propagation phase of coagulation. In the extravascular space (such as in soft tissue wounds), an abundance of tissue factor is present in the interstitial and subcutaneous tissues (which express the procoagulant cofactor, tissue factor, constitutively), resulting in effective tissue factor–factor VIIa-mediated activation of factor X. Direct activation of factor X by factor VIIa–tissue factor underlies the hemostatic response. In the intravascular space (where low amounts of tissue factor are constitutively expressed), direct activation of factor IX by factor VIIa occurs, likely accounting for the low baseline levels of products of the procoagulant pathway (thrombin generation) observed normally under homeostatic conditions.

The ultimate goal of therapeutic intervention in the coagulation mechanism during CPB is to effectively prevent thrombosis and at the same time minimize the impairment of hemostasis. The surface-mediated activation of the intrinsic system of coagulation involves an interaction between kallikrein and factor XII. The generation of factor XIIa starts an amplifying cascade to generate active enzymes from inactive precursors that result in thrombin formation (Fig 6). Inhibition of one or more of these enzymes would prevent thrombin and hence fibrin generation but would leave activation of the extrinsic system by tissue factor release from traumatized endothelium largely unaffected. Thus normal hemostasis would be preserved and the unwanted effects of CPB on coagulation eliminated. Collaboration between the Physiology and Cardiovascular Surgery Departments at Columbia-Presbyterian has resulted in the development of an inhibitor for factor IXa [25–29]. Factor IXai has no enzymatic activity, but binding to platelets and endothelial cells is comparable with that of the active factor IXa. It will competitively replace IXa in the intrinsic complex and block the conversion of factor X to factor Xa (Fig 7).

Ann Thorac Surg 1998;65:S2– 8

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

S7

extracorporeal membrane oxygenation, hemodialysis, and continuous venovenous hemofiltration.

Case Report on Use of Factor IXai

Fig 7. Active site-blocked IXa (IXai) can effectively replace IXa in the factor X activation complex to prevent the generation of thrombin. Factor IXa expresses its coagulant activity after interaction with its cofactor, factor VIIIa, and a cellular surface (for example, platelets or endothelium). The presence of excess IXai can competitively replace native factor IXa in the activation complex, thereby blocking intrinsic factor X activation.

Permission was obtained to use factor IXai on a compassionate basis in a 28-year-old woman with fulminant idiopathic myocarditis/cardiogenic shock. The patient had right and left ventricular assist devices, was on extracorporeal membrane oxygenation and continuous venovenous hemofiltration, and required massive transfusions for uncontrollable bleeding. She was given factor IXai (460 mg/kg IV every 6 hours), and heparin administration was stopped. Over a 24-hour period, the activated clotting time fell from 835 seconds to 169 seconds, chesttube drainage was significantly reduced, and the number of units of blood products transfused was decreased. Measurement of thrombin antithrombin-III complexes and prothrombin activation peptide suggested an attenuation of thrombin formation (Fig 8). The significance of these data, however, is unclear as they may merely have reflected a total loss of coagulation factors as the patient bled to death.

Experimental Studies With Factor IXai Histologic examination of various organs in dogs has shown no evidence of increased thrombosis after a 3-hour bypass run with factor IXai in comparison with standard anticoagulation with heparin. Deposition of platelets and other debris was also indistinguishable from heparin. A dose-dependent effect on blood loss was observed with a significant reduction at doses between 360 and 460 mg/kg, with higher doses having less efficacy. The coagulation profile differs from that with heparin anticoagulation. Factor IXai has no effect on the prothrombin time and the activated partial thromboplastin time, and activated clotting times are not elevated. It has been necessary to develop a means to monitor the adequacy of this anticoagulant during bypass, and a cephalin-based assay has proved to be a rapid and reproducible substitute for the activated clotting time. Similar reductions in bleeding have been obtained in baboons, suggesting that efficacy in humans could be anticipated. Future applications in patients might include

Fig 8. Progressive decline in thrombin generation as evidenced by decreasing levels of thrombin-antithrombin complex (TAT) and prothrombin activation peptide (F112) over the time course of systemic anticoagulant therapy with factor IXai.

Conclusion Cardiopulmonary bypass using active site-blocked factor IXa represents a single-agent antithrombotic strategy in which hemostasis in the surgical wound is selectively preserved in the absence of intravascular/extracorporeal circuit thrombosis. The ability to perform CPB without heparin, protamine, or other pharmacologic reversal identifies IXai as a means by which to perform safe, effective heparinless CPB.

References 1. Ray MJ, Marsh NA, Hawson GA. Relationship of fibrinolysis and platelet function to bleeding after cardiopulmonary bypass. Blood Coag Fibrinol 1984;5:679– 85. 2. Jung G, Razafindranaibe F, Elkouby A, Durashel P, Penes F, Monassier JP. Modification in platelet shape and change in ATP release during CPB. Haemostasis 1995;25:149–57. 3. Wahba A, Rothe G, Schmitz G, Birnbaum DE. Heparin effect on platelets and fibrinolysis. Ann Thorac Surg 1996;61: 1590–1. 4. Bertolino G, Locatelli A, Noris P, et al. Platelet composition and function in patients undergoing CPB for heart surgery. Haemotologica 1996;81:116–20. 5. Boldt J, Knothe C, Welters I, Dapper FL, Hemplemann G. Normothermic versus hypothermic cardiopulmonary bypass: do changes in coagulation differ? Ann Thorac Surg 1996;62:130–5. 6. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119–26. 7. Blauhut B, Gross C, Necek S, Doran JE, Spath P, Lundsgaard-Hansen P. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958– 67. 8. Lu H, Soria C, Commin PL, et al. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991;66:633–7.

S8

PATIENT MANAGEMENT SMITH MANAGEMENT OF BLEEDING COMPLICATIONS

9. Royston D. Preventing the inflammatory response to openheart surgery: the role of aprotinin and other protease inhibitors. Int J Cardiol 1996;53:S11–37. 10. Musial J, Niewiarowski S, Hershock D, et al. Loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation. J Lab Clin Med 1985;105:514–22. 11. Adelman B, Michelson AD, Greenberg J, Handin RI. Proteolysis of platelet glycoprotein Ib by plasmin is facilitated by plasmin lysine-binding regions. Blood 1986;68:1280– 4. 12. Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788–96. 13. Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth 1992;6: 76 –100. 14. Davis R, Whittington R. Aprotinin: a review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995;49:954– 83. 15. Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994;107:543–51. 16. Levy JH, Pifarre´ R, Schaff HV, et al. A multicenter, doubleblind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236– 44. 17. Freeman JG, Turner GA, Venavbles LW, Latner AL. Serial use of aprotinin and incidence of allergic reactions. Curr Med Res Opin 1983;8:559– 61. 18. LaFerla GA, Murray WR. Anaphylactic reaction to aprotinin despite negative ocular sensitivity. Br Med J (Clin Res Ed) 1984;289:1176–7. 19. Rose EA, Levin HR, Oz MC, et al. Artificial circulatory support with textured interior surfaces: a counterintuitive approach to minimizing thromboembolism. Circulation 1994;90(Suppl 2):87–91.

Ann Thorac Surg 1998;65:S2– 8

20. Graham TR, Dasse K, Coumbe A, et al. Neo-intimal development on textured biomaterial surfaces during clinical use of an implantable left ventricular assist device. Eur J Cardiothorac Surg 1990;4:182–90. 21. Slater JP, Rose EA, Levin HL, et al. Low thromboembolic risk without anticoagulation using advanced design left ventricular assist devices. Ann Thorac Surg 1996;62:132–7. 22. Spanier T, Oz M, Levin H, et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112:1090–7. 23. Goldstein DJ, Seldomridge JA, Chen JM, et al. Use of aprotinin in LVAD recipients reduces blood loss, blood use, and perioperative mortality. Ann Thorac Surg 1995;59: 1063–7. 24. Sun BC, Spanier TB, Choudhri AF, Oz MC. Factor IX concentrates initiate hemostasis in LVAD patients with intractable postoperative hemorrhage. J Heart Lung Transplant 1997;16:95. 25. Osterurd B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci 1977;74:5260– 4. 26. Lollar P, Fass DN. Inhibition of activation porcine factor IX by dansyl-glutamyl-glycl-arginyl-chloromethylketone. Arch Biochem Biophys 1984;233:438– 46. 27. Braunstein KM, Noyes CM, Griffith MJ, Lundblad RL, Roberts HR. Characterization of the defect in activation of factor IX Chapel Hill by human factor XIa. J Clin Invest 1981;68: 1420– 6. 28. Benedict CR, Ryan J, Wolitzky B, et al. Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model. J Clin Invest 1991;88: 1760–5. 29. Spanier TB, Oz MC, Minanov O, Stern D, Rose E, Schmidt AM. Active site blocked factor IXa (IXai): a novel selective anticoagulant for use in CPB. Presented at the 83rd Clinical Congress of the American College of Surgeons, Chicago, IL, Oct 12–17, 1997.