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Acute heparin-induced thrombocytopenia type II during cardiopulmonary bypass
CASE REPORTS
Acute Heparin-Induced Thrombocytopenia Type II During Cardiopulmonary Bypass Andreas Koster, MD, George J. Crystal, PhD, Herrmann Kuppe, MD, PhD, and Fritz Mertzlufft, MD, PhD
H
EPARIN-INDUCED THROMBOCYTOPENIA TYPE II (HIT II) is a potentially lethal complication, associated most frequently with unfractionated heparins. The incidence varies from approximately 1% to more than 30% of surgical patients, and 35% of these experience devastating outcomes.1,2 In cardiac surgery, the condition was associated with a complication rate of 51% and a mortality of 37%.3 If HIT II is either diagnosed or suspected, any form of heparin administration should be stopped immediately, and therapy with alternative anticoagulants should be instituted. In patients with HIT II, an immune response induces the formation of antibodies against heparin–platelet factor 4 complexes. The antigen-antibody complex stimulates platelet aggregation, which can result in arterial or venous thromboembolic events, often associated with a decrease in platelet count.1,4,5 Additional clinical signs may include stroke, myocardial infarction, or thromboembolism in the lungs, mesentery, or extremities. HIT II usually occurs after 2 to 14 days of exposure to heparin, but it can develop within hours in cases of reexposure to heparins.1,4 To date, HIT II has not been described to develop acutely under the condition of high-dose heparinization during cardiopulmonary bypass (CPB). Two cases in which HIT II developed immediately after institution of CPB are described. CASE REPORTS
First Patient In another hospital, a 69-year-old man (weight, 65 kg; height, 165 cm) exhibiting unstable angina with chest pain had received 5,000 IU of unfractionated heparin at catheterization of the left side of the heart with subsequent heparin therapy over 5 days followed by salicylic acid over the ensuing weeks. The antiplatelet therapy with salicylic acid had been terminated 2 weeks before his scheduled cardiac surgery in this hospital for the
From the Department of Anesthesia, German Heart Institute Berlin, Berlin, Germany; Department of Anesthesiology, Illinois Masonic Medical Center; and Departments of Anesthesiology and Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL; and Department of Anesthesiology and Critical Care Medicine, University Hospital, Homburg-Saar, Germany. Address reprint requests to Fritz Mertzlufft, MD, PhD, Klinik fuer Anaesthesiologie und Intensivmedizin, Universitaetskliniken des Saarlandes, D-66421 Homburg-Saar, Germany. Copyright r 2000 by W.B. Saunders Company 1053-0770/00/1403-0014$10.00/0 doi:10.1053/cr.2000.5847 Key words: white clots, recombinant hirudin, ecarin clotting time, protamine 300
revascularization of single-vessel coronary artery disease. On admission to the hospital, the patient received no preoperative, prophylactic heparin because of his ambulatory status. Induction and maintenance of anesthesia were performed using a standard balanced intravenous technique. After preparation of the left thoracic artery, unfractionated heparin (Liquemin, Hoffman-LaRoche, Grenzach-Wyhlen, Germany) was administered based on the automated heparin dose-response assay (HepconHMS; Medtronic HemoTec, Parker, CO). According to departmental standard, a kaolin activated coagulation time (ACT) value of 440 seconds was the predetermined target. The necessary individual heparin concentration of 4.2 IU/mL was calculated by means of the heparin titration cartridge of the HepconHMS, which increased the ACT (drawn from the CPB circuit) to a level (460 seconds) sufficient to establish CPB. During CPB, the heparin concentration was adjusted to the individual target according to the calculations of the HepconHMS device. After clamping of the aorta, the venous reservoir of the heart-lung machine collapsed because of clots. Clot formation resulting from cold agglutinins (hypothermia during cooling causes a blood temperature of about ,30°C) was ruled out on the basis of a routine prior analysis. The reservoir of the CPB system (non–heparin-bonded roller pump with membrane oxygenator; Medtronic, Parker, CO) was immediately bypassed with a Y-connector, and a bolus of heparin (20,000 IU) was given. This bolus produced a blood heparin concentration of 5.5 IU/mL (HepconHMS) and a corresponding kaolin ACT value of greater than 800 seconds (drawn from the CPB circuit) obtained by the HepconHMS (Medtronic, Parker, CO) and Hemochron (International Technidyne Corp, Edison, NJ) procedures in parallel. The remainder of the operation proceeded uneventfully. The CPB system revealed clot formation (typical white clots) in the oxygenator (Fig 1), the arterial filter, and the arterial and venous reservoirs. During the immediate postoperative period, the platelet count decreased from 329 3 103/mL to 46 3 103/mL and did not recover over the ensuing 12 hours (measured in 2-hour intervals). The suspicion of HIT II and the need for postoperative anticoagulation prompted the administration of a 10-mg bolus of recombinant hirudin (r-hirudin) (Refludan, Hoechst, Frankfurt, Germany) for anticoagulation followed by a continuous infusion of r-hirudin, which was titrated to achieve an activated partial thromboplastin time (aPTT) value of 60 to 80 seconds,6,7 and the performance of the heparin-induced platelet aggregation assay (HIPAA). A positive finding in the HIPAA (agglutination in three of four chambers containing 0.2 IU/mL heparin and a negative result in the buffer and the 100-IU/mL heparin chamber) confirmed the development of
Journal of Cardiothoracic and Vascular Anesthesia, Vol 14, No 3 (June), 2000: pp 300-303
ACUTE HIT II DURING CPB
301
Fig 1. Clot formation in the oxygenator of the cardiopulmonary bypass system observed after administration of unfractionated heparin (4.2 IU/mL calculated according to the HepconHMS; kaolin activated coagulation time, 460 sec) and clamping of the aorta. These typical white clots were composed entirely of platelets, and they were a sign of acute heparin-induced thrombocytopenia type II (HIT II).
HIT II. Platelet count increased to 86 3 103/mL during the course of the day, and infusion of r-hirudin was maintained to provide time for oral anticoagulation with coumadin to take effect. The patient recovered uneventfully and left the hospital 3 days later. Second Patient A 74-year-old man (weight, 95 kg; height, 185 cm) with a history of multiple surgical procedures was admitted to this hospital for urgent coronary artery bypass graft surgery involving three vessels. On admission, low-dose anticoagulation was initiated with an injection of 2,850 anti–factor Xa units of the
low-molecular-weight heparin nadroparin (Fraxiparin; SanofiWinthrop, Mu¨nchen, Germany). Surgery was performed the following day. Induction and maintenance of anesthesia were achieved using a standard balanced intravenous technique. After preparation of the left thoracic artery, unfractionated heparin was given based on the HepconHMS. The predetermined target kaolin ACT value of 440 seconds resulted in a corresponding heparin concentration of 3.4 IU/mL (HepconHMS). This concentration produced a kaolin ACT value (drawn from the CPB circuit) of 560 seconds provided by the HepconHMS. The collapsible venous reservoir clotted within seconds of initiating CPB (non–heparin-bonded roller pump
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with membrane oxygenator; Medtronic, Parker, CO), which required that a bypass be installed using a Y-connector. The experience with the first patient (see previously) a few days earlier and the routine preoperative test results ruling out other causes, including cold agglutinins, raised the suspicion that this patient was also suffering from HIT II. Additional evidence for HIT II was a precipitous decrease in platelet count from 200 3 103/mL to 40 3 103/mL. These clinical findings prompted an immediate 50-mg (approximately 0.5 mg/kg) injection of r-hirudin into the CPB system. This dose of r-hirudin was based on published recommendations (ie, 0.2 mg/kg added to the prime and 0.25 mg/kg given to the patient).6-8 During CPB, the adequacy of the level of r-hirudin was assessed on-line using the ecarin clotting time (ECT) 7,8 obtained with the TAS analyzer6,9 (Thrombolytic Assessment System; Cardiovascular Diagnostics Inc, Raleigh, NC) in parallel. By the end of CPB, the r-hirudin blood concentration had decreased from 4 µg/mL to 2 µg/mL, and the remainder of the operation was uneventful. After the cessation of CPB, protamine was administered according to approximately one third of the initial heparin dose (100-mg intravenous bolus injection followed by a continuous infusion at 10 mg/hr for 6 hours for prevention of possible heparin rebound). The extracorporeal system was emptied by modified zero-balanced ultrafiltration.6 Elimination of r-hirudin was enhanced further by forced diuresis using 200 mL of mannitol (20%) and furosemide (40 mg).6 The initial postoperative r-hirudin level was 1.5 µg/mL, and the platelet count was 35 3 103/mL. During the first 24 hours postoperatively, r-hirudin was infused continuously to achieve aPTT values of 80 to 100 seconds, and thereafter the dose was reduced until aPTT values remained in the range of 40 to 60 seconds6 (to provide time for oral anticoagulation to take effect). Postoperative drainage was to 450 mL. The diagnosis of HIT II was confirmed using the HIPAA (positive result in three of the four chambers containing 0.2 IU/mL heparin and a negative result in the buffer and the 100-IU/mL heparin chamber). Contrary to the first patient, no further clot formation was evident in the CPB system of this patient. The patient recovered uneventfully and was discharged after 3 days. DISCUSSION
These reports provide convincing evidence that HIT II can develop acutely during the early period of CPB. In keeping with the literature in diagnosing HIT II,1,4,7 the typical clinical signs (thromboembolic events and concomitant decrease in platelet count) were supported by the sensitive HIPAA results.10 If coagulation is observed in the CPB system in the presence of either a sufficient kaolin ACT value or heparin concentration, HIT II should be considered as a potential diagnosis. In the first patient, thrombosis or embolism remained limited to the CPB system. This is in agreement with the literature1 reporting that HIT II does not necessarily cause sequelae, particularly if the fibrinolytic capacity of the patient remained sufficient. The use of r-hirudin during the postoperative period avoided a further consumption of platelets and the concomitant occurrence of systemic or regional thromboembolic complications. In the second patient, a single bolus injection of r-hirudin (0.5 mg/kg), administered after acute coagulation within the CPB system
was observed, increased r-hirudin blood concentration to the recommended level of 4 µg/mL.6-9 By the end of CPB (after 75 minutes), blood r-hirudin concentration had decreased to 2.0 µg/mL, which is below the level (2.5 µg/mL) at which CPB can be performed safely using only r-hirudin as anticoagulant.6,8 The decision to administer r-hirudin in these patients requires explanation. In the first patient, HIT II was suspected in the postoperative period, and r-hirudin was administered to minimize the potential for the lethal postoperative complications associated with HIT II. In the second patient, r-hirudin was used as an acute replacement for heparin during CPB and as a treatment for HIT II–associated complications. Its choice was based on advantages it has over the other options for anticoagulation.6 The heparinoid orgaran has cross-reactivity with heparin in almost 30% of the patients9,11 (which cannot be diagnosed instantaneously by the HIPAA). The prostaglandins are considered inappropriate in cases with preexisting thrombocytopenia (including serious coagulation disorders), in cases with absence of a reversal agent, and in cases in which the administration of platelets is contraindicated. Defibrinogenation with ancrod requires several hours to take effect. r-Hirudin does not cross-react with heparin-induced antibodies because of its protein structure,6,8 and it has an immediate anticoagulant effect.6,7,9 Thrombin seems to play an important role in the development of thromboembolic complications associated with the HIT II reaction.12 r-Hirudin is the most potent direct thrombin inhibitor. It inhibits the plasmatic thrombin and the platelet-bound and clot-bound thrombin as well,7,13 which efficiently promotes thrombolysis. r-Hirudin inhibits major sequences of the HIT II cascade effectively,12-14 while providing safe anticoagulation. Finally, r-hirudin is rapidly eliminated by the kidneys (40 to 60 minutes) so that restoration of coagulation occurs.6,9 The measurement of the ECT is necessary for on-line monitoring of r-hirudin during CPB6-9 (if provided within the operating room, it allows for minute-by-minute testing of the r-hirudin concentration6,9 ). The ECT measurement is based on the conversion of prothrombin to meizothrombin, and it provides reliable results even in the present case of coexisting heparinization.8 In the second patient, the effects of heparin were not immediately reversed with protamine after the administration of the r-hirudin bolus. Protamine was not given during CPB but after cessation of CPB, which immediately restored coagulation and avoided excessive bleeding. The dose was arbitrary (about one third of the initial heparin dose), however, because heparin concentration cannot be obtained in a whole blood test in the presence of r-hirudin. The indirect (qualitative) measurement by heparinase ACT is not provided by the HepconHMS device and was not available in the acute situation. The rationale for this approach was as follows. After CPB, coagulation had to be restored. The development of HIT II, however, contraindicated a transfusion of platelets, particularly because the half-life and elimination of the heparin and heparin–antibody platelet factor 4 complexes are unknown. Despite the rapid renal elimination of r-hirudin, there exists no specific reversal agent for r-hirudin (which would contribute a major threat in case of bleeding). The anticoagulant effect of residual heparin permitted a reduction in
ACUTE HIT II DURING CPB
303
r-hirudin concentration before termination of CPB without risking further clotting and postoperative bleeding. A delay in the protamine-induced reversal of heparin was possible because (1) r-hirudin is the most potent thrombin inhibitor known,15 including plasmatic thrombin as well as plateletbound and clot-bound thrombin13; (2) r-hirudin directly inhibits the major sequences of the HIT II reaction cascade12-14; and (3) thrombin itself is a major stimulator of platelet aggregation,14 and r-hirudin has an additional indirect antiplatelet effect, which should also contribute to inhibition of the HIT II reaction.
The present cases indicate that the use of CPB with unfractionated heparins may acutely induce HIT II. A bolus administration of r-hirudin (10 mg) given postoperatively and a bolus given immediately after the occurrence of clot formation in the CPB system (0.5 mg/kg), with a decrease in r-hirudin blood concentration to 2 µg/mL (as assessed on-line with the ECT), proved a safe and effective management. This approach avoided the potentially life-threatening complications associated with HIT II, while allowing for protamine-induced heparin reversal after CPB, which rapidly restored coagulation and prevented bleeding.
REFERENCES 1. Slaughter TF, Greenberg CS: Heparin-associated thrombocytopenia and thrombosis—implications for perioperative management. Anesthesiology 87:667-675, 1997 2. Blakeman B: Management of heparin-induced thrombocytopenia: A cardiovascular surgeon’s perspective. Semin Hematol 36:37-41, 1999 (suppl 1) 3. Bauer TL, Arepaly G, Konkele BA, et al: Prevalence of heparinassociated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 95:1242-1246, 1997 4. Shorten GD, Comunale ME: Heparin-induced thrombocytopenia. J Cardiothorac Vasc Anesth 10:521-530, 1996 5. Warkentin TE, Kelton JG: A 14-year study of heparin-induced thrombocytopenia. Am J Med 101:502-507, 1996 6. Koster A, Kuppe H, Hetzer R, et al: Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology 89:777-780, 1998 7. Greinacher A, Vo¨lpel H, Janssens U, et al: Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: A prospective study. Circulation 99:73-80, 1999 8. Po¨tzsch B, Hund S, Madlener K, et al: Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass—assessment of the whole blood ecarin clotting time. Thromb Haemost 77:920-925, 1997 9. Koster A, Kuppe H, Mertzlufft F: Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A synopsis of 19 cases. Br J Anaesth 82:35(A.116), 1999 (suppl 1)
10. Greinacher A, Amiral J, Dummel V, et al: Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion 34:381-385, 1994 11. Newman PM, Swanson RL, Chong BH: Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low-molecular-weight heparin and heparinoid. Thromb Haemost 80:292-297, 1998 12. Warkentin TE: Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transfus Med Rev 10:249-258, 1996 13. Weitz JI, Hudoba M, Massel D, et al: Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86:385-391, 1990 14. Warkentin TE, Hayward CPM, Boshkov LK, et al: Sera from patients with heparin-induced thrombocytopenia generate plateletderived microparticles with procoagulant activity: An explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 84:3691-3699, 1994 15. Bang NU: Hirudin and hirudin-mimetic peptides: A promising group of antithrombotic agents. Am Coll Cardiol Curr J Rev 2:43-45, 1993
Acute Heparin-Induced Thrombocytopenia Type II During Cardiopulmonary Bypass Andreas Koster, MD, George J. Crystal, PhD, Herrmann Kuppe, MD, PhD, and Fritz Mertzlufft, MD, PhD
H
EPARIN-INDUCED THROMBOCYTOPENIA TYPE II (HIT II) is a potentially lethal complication, associated most frequently with unfractionated heparins. The incidence varies from approximately 1% to more than 30% of surgical patients, and 35% of these experience devastating outcomes.1,2 In cardiac surgery, the condition was associated with a complication rate of 51% and a mortality of 37%.3 If HIT II is either diagnosed or suspected, any form of heparin administration should be stopped immediately, and therapy with alternative anticoagulants should be instituted. In patients with HIT II, an immune response induces the formation of antibodies against heparin–platelet factor 4 complexes. The antigen-antibody complex stimulates platelet aggregation, which can result in arterial or venous thromboembolic events, often associated with a decrease in platelet count.1,4,5 Additional clinical signs may include stroke, myocardial infarction, or thromboembolism in the lungs, mesentery, or extremities. HIT II usually occurs after 2 to 14 days of exposure to heparin, but it can develop within hours in cases of reexposure to heparins.1,4 To date, HIT II has not been described to develop acutely under the condition of high-dose heparinization during cardiopulmonary bypass (CPB). Two cases in which HIT II developed immediately after institution of CPB are described. CASE REPORTS
First Patient In another hospital, a 69-year-old man (weight, 65 kg; height, 165 cm) exhibiting unstable angina with chest pain had received 5,000 IU of unfractionated heparin at catheterization of the left side of the heart with subsequent heparin therapy over 5 days followed by salicylic acid over the ensuing weeks. The antiplatelet therapy with salicylic acid had been terminated 2 weeks before his scheduled cardiac surgery in this hospital for the
From the Department of Anesthesia, German Heart Institute Berlin, Berlin, Germany; Department of Anesthesiology, Illinois Masonic Medical Center; and Departments of Anesthesiology and Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL; and Department of Anesthesiology and Critical Care Medicine, University Hospital, Homburg-Saar, Germany. Address reprint requests to Fritz Mertzlufft, MD, PhD, Klinik fuer Anaesthesiologie und Intensivmedizin, Universitaetskliniken des Saarlandes, D-66421 Homburg-Saar, Germany. Copyright r 2000 by W.B. Saunders Company 1053-0770/00/1403-0014$10.00/0 doi:10.1053/cr.2000.5847 Key words: white clots, recombinant hirudin, ecarin clotting time, protamine 300
revascularization of single-vessel coronary artery disease. On admission to the hospital, the patient received no preoperative, prophylactic heparin because of his ambulatory status. Induction and maintenance of anesthesia were performed using a standard balanced intravenous technique. After preparation of the left thoracic artery, unfractionated heparin (Liquemin, Hoffman-LaRoche, Grenzach-Wyhlen, Germany) was administered based on the automated heparin dose-response assay (HepconHMS; Medtronic HemoTec, Parker, CO). According to departmental standard, a kaolin activated coagulation time (ACT) value of 440 seconds was the predetermined target. The necessary individual heparin concentration of 4.2 IU/mL was calculated by means of the heparin titration cartridge of the HepconHMS, which increased the ACT (drawn from the CPB circuit) to a level (460 seconds) sufficient to establish CPB. During CPB, the heparin concentration was adjusted to the individual target according to the calculations of the HepconHMS device. After clamping of the aorta, the venous reservoir of the heart-lung machine collapsed because of clots. Clot formation resulting from cold agglutinins (hypothermia during cooling causes a blood temperature of about ,30°C) was ruled out on the basis of a routine prior analysis. The reservoir of the CPB system (non–heparin-bonded roller pump with membrane oxygenator; Medtronic, Parker, CO) was immediately bypassed with a Y-connector, and a bolus of heparin (20,000 IU) was given. This bolus produced a blood heparin concentration of 5.5 IU/mL (HepconHMS) and a corresponding kaolin ACT value of greater than 800 seconds (drawn from the CPB circuit) obtained by the HepconHMS (Medtronic, Parker, CO) and Hemochron (International Technidyne Corp, Edison, NJ) procedures in parallel. The remainder of the operation proceeded uneventfully. The CPB system revealed clot formation (typical white clots) in the oxygenator (Fig 1), the arterial filter, and the arterial and venous reservoirs. During the immediate postoperative period, the platelet count decreased from 329 3 103/mL to 46 3 103/mL and did not recover over the ensuing 12 hours (measured in 2-hour intervals). The suspicion of HIT II and the need for postoperative anticoagulation prompted the administration of a 10-mg bolus of recombinant hirudin (r-hirudin) (Refludan, Hoechst, Frankfurt, Germany) for anticoagulation followed by a continuous infusion of r-hirudin, which was titrated to achieve an activated partial thromboplastin time (aPTT) value of 60 to 80 seconds,6,7 and the performance of the heparin-induced platelet aggregation assay (HIPAA). A positive finding in the HIPAA (agglutination in three of four chambers containing 0.2 IU/mL heparin and a negative result in the buffer and the 100-IU/mL heparin chamber) confirmed the development of
Journal of Cardiothoracic and Vascular Anesthesia, Vol 14, No 3 (June), 2000: pp 300-303
ACUTE HIT II DURING CPB
301
Fig 1. Clot formation in the oxygenator of the cardiopulmonary bypass system observed after administration of unfractionated heparin (4.2 IU/mL calculated according to the HepconHMS; kaolin activated coagulation time, 460 sec) and clamping of the aorta. These typical white clots were composed entirely of platelets, and they were a sign of acute heparin-induced thrombocytopenia type II (HIT II).
HIT II. Platelet count increased to 86 3 103/mL during the course of the day, and infusion of r-hirudin was maintained to provide time for oral anticoagulation with coumadin to take effect. The patient recovered uneventfully and left the hospital 3 days later. Second Patient A 74-year-old man (weight, 95 kg; height, 185 cm) with a history of multiple surgical procedures was admitted to this hospital for urgent coronary artery bypass graft surgery involving three vessels. On admission, low-dose anticoagulation was initiated with an injection of 2,850 anti–factor Xa units of the
low-molecular-weight heparin nadroparin (Fraxiparin; SanofiWinthrop, Mu¨nchen, Germany). Surgery was performed the following day. Induction and maintenance of anesthesia were achieved using a standard balanced intravenous technique. After preparation of the left thoracic artery, unfractionated heparin was given based on the HepconHMS. The predetermined target kaolin ACT value of 440 seconds resulted in a corresponding heparin concentration of 3.4 IU/mL (HepconHMS). This concentration produced a kaolin ACT value (drawn from the CPB circuit) of 560 seconds provided by the HepconHMS. The collapsible venous reservoir clotted within seconds of initiating CPB (non–heparin-bonded roller pump
302
KOSTER ET AL
with membrane oxygenator; Medtronic, Parker, CO), which required that a bypass be installed using a Y-connector. The experience with the first patient (see previously) a few days earlier and the routine preoperative test results ruling out other causes, including cold agglutinins, raised the suspicion that this patient was also suffering from HIT II. Additional evidence for HIT II was a precipitous decrease in platelet count from 200 3 103/mL to 40 3 103/mL. These clinical findings prompted an immediate 50-mg (approximately 0.5 mg/kg) injection of r-hirudin into the CPB system. This dose of r-hirudin was based on published recommendations (ie, 0.2 mg/kg added to the prime and 0.25 mg/kg given to the patient).6-8 During CPB, the adequacy of the level of r-hirudin was assessed on-line using the ecarin clotting time (ECT) 7,8 obtained with the TAS analyzer6,9 (Thrombolytic Assessment System; Cardiovascular Diagnostics Inc, Raleigh, NC) in parallel. By the end of CPB, the r-hirudin blood concentration had decreased from 4 µg/mL to 2 µg/mL, and the remainder of the operation was uneventful. After the cessation of CPB, protamine was administered according to approximately one third of the initial heparin dose (100-mg intravenous bolus injection followed by a continuous infusion at 10 mg/hr for 6 hours for prevention of possible heparin rebound). The extracorporeal system was emptied by modified zero-balanced ultrafiltration.6 Elimination of r-hirudin was enhanced further by forced diuresis using 200 mL of mannitol (20%) and furosemide (40 mg).6 The initial postoperative r-hirudin level was 1.5 µg/mL, and the platelet count was 35 3 103/mL. During the first 24 hours postoperatively, r-hirudin was infused continuously to achieve aPTT values of 80 to 100 seconds, and thereafter the dose was reduced until aPTT values remained in the range of 40 to 60 seconds6 (to provide time for oral anticoagulation to take effect). Postoperative drainage was to 450 mL. The diagnosis of HIT II was confirmed using the HIPAA (positive result in three of the four chambers containing 0.2 IU/mL heparin and a negative result in the buffer and the 100-IU/mL heparin chamber). Contrary to the first patient, no further clot formation was evident in the CPB system of this patient. The patient recovered uneventfully and was discharged after 3 days. DISCUSSION
These reports provide convincing evidence that HIT II can develop acutely during the early period of CPB. In keeping with the literature in diagnosing HIT II,1,4,7 the typical clinical signs (thromboembolic events and concomitant decrease in platelet count) were supported by the sensitive HIPAA results.10 If coagulation is observed in the CPB system in the presence of either a sufficient kaolin ACT value or heparin concentration, HIT II should be considered as a potential diagnosis. In the first patient, thrombosis or embolism remained limited to the CPB system. This is in agreement with the literature1 reporting that HIT II does not necessarily cause sequelae, particularly if the fibrinolytic capacity of the patient remained sufficient. The use of r-hirudin during the postoperative period avoided a further consumption of platelets and the concomitant occurrence of systemic or regional thromboembolic complications. In the second patient, a single bolus injection of r-hirudin (0.5 mg/kg), administered after acute coagulation within the CPB system
was observed, increased r-hirudin blood concentration to the recommended level of 4 µg/mL.6-9 By the end of CPB (after 75 minutes), blood r-hirudin concentration had decreased to 2.0 µg/mL, which is below the level (2.5 µg/mL) at which CPB can be performed safely using only r-hirudin as anticoagulant.6,8 The decision to administer r-hirudin in these patients requires explanation. In the first patient, HIT II was suspected in the postoperative period, and r-hirudin was administered to minimize the potential for the lethal postoperative complications associated with HIT II. In the second patient, r-hirudin was used as an acute replacement for heparin during CPB and as a treatment for HIT II–associated complications. Its choice was based on advantages it has over the other options for anticoagulation.6 The heparinoid orgaran has cross-reactivity with heparin in almost 30% of the patients9,11 (which cannot be diagnosed instantaneously by the HIPAA). The prostaglandins are considered inappropriate in cases with preexisting thrombocytopenia (including serious coagulation disorders), in cases with absence of a reversal agent, and in cases in which the administration of platelets is contraindicated. Defibrinogenation with ancrod requires several hours to take effect. r-Hirudin does not cross-react with heparin-induced antibodies because of its protein structure,6,8 and it has an immediate anticoagulant effect.6,7,9 Thrombin seems to play an important role in the development of thromboembolic complications associated with the HIT II reaction.12 r-Hirudin is the most potent direct thrombin inhibitor. It inhibits the plasmatic thrombin and the platelet-bound and clot-bound thrombin as well,7,13 which efficiently promotes thrombolysis. r-Hirudin inhibits major sequences of the HIT II cascade effectively,12-14 while providing safe anticoagulation. Finally, r-hirudin is rapidly eliminated by the kidneys (40 to 60 minutes) so that restoration of coagulation occurs.6,9 The measurement of the ECT is necessary for on-line monitoring of r-hirudin during CPB6-9 (if provided within the operating room, it allows for minute-by-minute testing of the r-hirudin concentration6,9 ). The ECT measurement is based on the conversion of prothrombin to meizothrombin, and it provides reliable results even in the present case of coexisting heparinization.8 In the second patient, the effects of heparin were not immediately reversed with protamine after the administration of the r-hirudin bolus. Protamine was not given during CPB but after cessation of CPB, which immediately restored coagulation and avoided excessive bleeding. The dose was arbitrary (about one third of the initial heparin dose), however, because heparin concentration cannot be obtained in a whole blood test in the presence of r-hirudin. The indirect (qualitative) measurement by heparinase ACT is not provided by the HepconHMS device and was not available in the acute situation. The rationale for this approach was as follows. After CPB, coagulation had to be restored. The development of HIT II, however, contraindicated a transfusion of platelets, particularly because the half-life and elimination of the heparin and heparin–antibody platelet factor 4 complexes are unknown. Despite the rapid renal elimination of r-hirudin, there exists no specific reversal agent for r-hirudin (which would contribute a major threat in case of bleeding). The anticoagulant effect of residual heparin permitted a reduction in
ACUTE HIT II DURING CPB
303
r-hirudin concentration before termination of CPB without risking further clotting and postoperative bleeding. A delay in the protamine-induced reversal of heparin was possible because (1) r-hirudin is the most potent thrombin inhibitor known,15 including plasmatic thrombin as well as plateletbound and clot-bound thrombin13; (2) r-hirudin directly inhibits the major sequences of the HIT II reaction cascade12-14; and (3) thrombin itself is a major stimulator of platelet aggregation,14 and r-hirudin has an additional indirect antiplatelet effect, which should also contribute to inhibition of the HIT II reaction.
The present cases indicate that the use of CPB with unfractionated heparins may acutely induce HIT II. A bolus administration of r-hirudin (10 mg) given postoperatively and a bolus given immediately after the occurrence of clot formation in the CPB system (0.5 mg/kg), with a decrease in r-hirudin blood concentration to 2 µg/mL (as assessed on-line with the ECT), proved a safe and effective management. This approach avoided the potentially life-threatening complications associated with HIT II, while allowing for protamine-induced heparin reversal after CPB, which rapidly restored coagulation and prevented bleeding.
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