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  1. 1. CASE REPORTSBivalirudin for Anticoagulation During HypothermicCardiopulmonary Bypass and Recombinant Factor VIIa forIatrogenic CoagulopathyErin L Nagle, Laura V Tsu, and William E Dager ardiac surgeries requiring continu-C ous anticoagulation predominatelyuse unfractionated heparin, as there is OBJECTIVE: To describe management of anticoagulation with a decreased dose requirement of bivalirudin during cardiopulmonary bypass using deep hypo-extensive experience, rapid onset of ac- thermic circulatory arrest (DHCA) and the reversal of the ensuing coagulopathy with recombinant factor VIIa (rFVIIa).tion, point of care monitoring, and avail- CASE SUMMARY: A 48-year-old male developed chest pain, hypertension, and anability to rapidly reverse its effect using aortic aneurysm requiring urgent surgical repair. At the time of surgery, the patientprotamine.1 Furthermore, the short half- reported an allergy to heparin, so bivalirudin was used for anticoagulation (1life and ability to rapidly titrate to effect mg/kg loading dose, followed by intermittent infusions of 1.25-2.5 mg/kg/h overmake unfractionated heparin an attrac- the 5 hours of cardiopulmonary bypass). When the cooling process was initiated,tive anticoagulant during cardiopul- bivalirudin was stopped in anticipation of loss of the clotting cascade function and potential slowing of drug elimination. Bivalirudin was restarted for 45 minutesmonary bypass (CPB). In situations during the rewarming period because of concern for potential clot formation in thewhen heparin should be avoided, as is bypass circuit with recovery of hemostasis; it was again stopped due to thethe case in patients with suspected or patient’s activated clotting time (ACT) of 504 seconds. Despite this measure,confirmed heparin-induced thrombocy- diffuse and severe coagulopathy was observed upon rewarming, with ACTstopenia (HIT) or heparin allergy, an al- longer than 999 seconds. Although multiple blood products were administered, visualization of a clot in the surgical field was not notable. A total dose of rFVIIaternative anticoagulant must be used.2 20 µg/kg was administered, resulting in visual clot formation within 4 minutes. On Bivalirudin is a parenterally adminis- postsurgical day 6, bilateral asymptomatic distal deep vein thromboses weretered direct thrombin inhibitor (DTI) that noted on imaging; on postsurgical day 8, fondaparinux 2.5 mg subcutaneouslyis an alternative to unfractionated hep- was administered daily to prevent clot extension. The patient was discharged onarin in cardiac surgery. It has gained in- postoperative day 23 with no acute issues and no further anticoagulants.terest due to its short half-life of 25 min- DISCUSSION: Alternative anticoagulation agents such as bivalirudin are used inutes and proteolytic degradation largely patients who have an allergy or contraindication to heparin. We propose that prolonged coagulopathy after the induction of hypothermia is due to decreasedindependent of hepatic and renal func- clotting cascade function as well as slowing of protease activity resulting intion.3 Prospective studies have evaluated decreased bivalirudin elimination. We observed a positive response to low-dosethe efficacy of bivalirudin during CPB.3,4 rFVIIa, which could be due to activation of the extrinsic pathway and/or aArgatroban and lepirudin use during thrombin burst, resulting in hemostasis. Currently, there is limited evidence supporting reversal of direct thrombin inhibitors with rFVIIa.CPB has been described in case re- CONCLUSIONS: In the setting of DHCA, bivalirudin should be used cautiously, withports.5,6 Dosing of DTIs can be adjusted frequent monitoring of the ACTs and potential cessation of the infusion inby monitoring the activated clotting time anticipation of prolonged drug effect with subsequent potential coagulopathy. If(ACT) during cardiac surgery, typically coagulopathy ensues, use of low-dose rFVIIa may be an option to initiatetargeting a value of 2.5 times baseline hemostasis. When using rFVIIa, it is important to consider the risk of thrombosiswhen renal function is normal.3,4,7 Criti- and monitor patients concerns associated with the use of KEY WORDS: aortic aneurysm, bivalirudin, cardiopulmonary bypass, hypothermia,any anticoagulant in CPB are thrombosis rFVIIa.of the circuit and excessive bleeding dur- Ann Pharmacother 2011;45:e47. Published Online, 23 Aug 2011,, DOI 10.1345/aph.1P785Author information provided at end of The Annals of Pharmacotherapy I 2011 September, Volume 45 I e47
  2. 2. EL Nagle et surgery or closing after going off the bypass circuit. No This allergy was subsequently confirmed from outsidesafe means to rapidly reverse bivalirudin has been estab- hospital records, although information on the reaction waslished; thus, the bivalirudin infusion is typically stopped neither available nor well defined. After thoracotomy andprior to taking the patient off bypass. Balancing the risk of upon inspection, there was a 7-cm diameter thoracic aorticthrombosis and hemorrhage is a challenging process dur- aneurysm extending just distal to the left subclavian to ap-ing surgery, and multiple patient-specific factors must be proximately two thirds of the way down to the T8 level.considered to determine the optimal time to stop the bi- This area of the thoracic aorta was replaced with a #32valirudin infusion. Dacron interposition graft with fenestration of the dissec- Recombinant factor VIIa (rFVIIa) is Food and Drug tion flap distally.Administration (FDA)–approved for bleeding in patients Anticoagulation during CPB was managed with the DTIwith hemophilia or factor VII deficiency, and has gained on the hospital formulary, bivalirudin. Anecdotal experi-some interest as an off-label adjunct for management of ence with bivalirudin in similar surgical settings was posi-acute bleeding during cardiac surgery.8 Case reports have tive, and there is greater evidence for bivalirudin use in thiscited the use of rFVIIa for postoperative bleeding sec- setting compared with alternatives such as argatroban, lep-ondary to anticoagulation with a DTI.8-11 irudin, epoprostenol, or tirofiban. The ACT was used to In cardiothoracic surgery, hypothermia may be induced monitor the degree of anticoagulation, as ecarin clottingduring a procedure to decrease metabolic rate and oxygen time is no longer available at our institution. The patient’sconsumption.12 When cooling the patient for therapeutic baseline ACT (ACT Plus, Medtronic, Minneapolis, MN)hypothermia, hemostatic function, including the clotting was 141 seconds. A dosing protocol was started that wascascade and platelet activity, may not operate normally, similar to those in previous studies using bivalirudin dos-limiting or decreasing the need for anticoagulation during ing in patients undergoing on-pump bypass surgery.3,4 A bi-this period.13 In addition, the elimination of bivalirudin valirudin loading dose of 0.5 mg/kg was given intra-may be decreased, creating a longer duration of action.14 venously, with a subsequent ACT of 257 seconds. An ad- We report the decreased dose requirement of bivalirudin ditional 0.5 mg/kg (total loading dose 1 mg/kg) was thenduring hypothermic CPB for repair of an aortic arch given, with a subsequent ACT of 358 seconds. The patientaneurysm in a patient with a heparin allergy, as well as the then received intermittent infusions of 1.25-2.5 mg/kg/huse of a relatively low dose of rFVIIa to expedite hemosta- during CPB (~5 hours). The infusion rates were adjustedsis and potentially reverse bivalirudin’s effect to manage with pharmacist assistance per measured ACTs (Figure 1).postoperative bleeding. In an attempt to counterbalance anticoagulation, aminocaproic acid 10 g was infused prior to incision and continued at 1 g/h until the end of the operation.Case Report Goal ACT levels were not well defined prior to surgery. A 48-year-old male with chronic type B aortic dissec- The team wished to maintain ACTs longer than 400 sec-tion presented to our facility with chest pain ranking of onds to achieve sufficient anticoagulation. Measured ACTs7/10 from a visual analog pain scale and an elevated blood throughout the surgery ranged from 219 to 999 secondspressure of 194/121 mm Hg. At presentation, the patient (maximum reportable value).weighed 92 kg and serum creatinine was 1.23 mg/dL. The Cooling was accomplished over a 55-minute period, andpatient had a history significant for aortic dissection status the temperature was lowered to 22.5 ˚C. Bivalirudin waspost-repair in 2005, hypertension, coronary artery disease stopped when the cooling process was initiated. At this timepost–myocardial infarction, renal insufficiency, anxiety, the ACT was 461 seconds. DHCA lasted approximately 30and posttraumatic stress disorder. To our knowledge, the minutes. The patient was subsequently warmed over 90patient did not have a genetic predisposition that would in- minutes and weaned from CPB without difficulty. Bi-crease his risk for aortic dissection. The patient was not valirudin 2.5 mg/kg/h was given for 15 minutes during thetreated with preoperative anticoagulants and had no history warming period when the ACT was 488 seconds, out ofof aspirin use within 7 days of the surgery. A computed to- concern for potential clot formation in the bypass circuitmography scan revealed that the aortic aneurysm was en- with recovery of hemostasis. The subsequent measuredlarging into a widely fenestrated type B aortic dissection ACT was 507 seconds and the infusion was decreased toextending from the distal aortic arch into the descending 1.25 mg/kg/h for 30 minutes, with a resulting ACT of 504aorta at the level of the thorax and abdomen. seconds. At this time bivalirudin was withheld; however, On hospital day 2, the patient provided consent for tho- diffuse coagulopathy persisted, with clinically significantracotomy and resection of the aortic aneurysm under deep oozing and lack of thrombus formation. The next measuredhypothermic circulatory arrest (DHCA). Just prior to ACT was 611 seconds; 15 minutes later it was 999 secondssurgery, the patient stated that he was allergic to both hep- (maximum reportable value). After bivalirudin had beenarin and warfarin, but was unable to describe the reaction. stopped for approximately 90 minutes, the patient’s ACTe47 I The Annals of Pharmacotherapy I 2011 September, Volume 45
  3. 3. Bivalirudin and rFVIIa During Hypothermic Cardiopulmonary Bypasswas 219 seconds, suggesting elimination of the drug effect. accurate history or perform a skin test, given the patient’sThe total bivalirudin dose infused throughout the procedure concomitant use of a β-blocker and acute condition at thewas approximately 440 mg (4.75 mg/kg). time of the consultation. Since these DVTs were distal and During the procedure, blood removed from the patient the patient was asymptomatic, pharmacologic anticoagula-was saved in citrated bags for readministration. Calcium tion was not initiated; however, on postsurgical day 8, fon-was administered to reverse the effects of the citrate during daparinux 2.5 mg subcutaneously daily was initiated as athe procedure and after transfusion. A thromboelastogram precaution to prevent thrombus extension. From a coagula-was done to assess the source of coagulopathy. Results tion standpoint, the patient’s course was uneventful and heshowed a clotting time of 365 seconds, amplitude of 335 was discharged on hospital day 23 with no acute issues. Heseconds, and angle degree of 45.1. The maximal amplitude did not experience thrombosis-related issues per the outpa-was 32.4 mm and lysis 30 minutes after maximal ampli- tient follow-up notes.tude was 0%. The low maximal amplitude suggested alack of platelet effect. Discussion To promote hemostasis, blood products, including a to-tal of 12 units cryoprecipitate, 6 units of fresh frozen plas- Use of alternative agents to heparin for anticoagulationma, 9 units of platelets, and 13 units of packed red blood during cardiac surgery remains controversial; no othercells (PRBCs), were administered. One hundred five min- agent has established an equivalent role. Compared to oth-utes after CPB, with no evidence of thrombus formation, a er parenteral anticoagulants, bivalirudin is an attractive al-single 0.5-mg dose (~5 µg/kg) of rFVIIa was given intra- ternative agent in situations where heparin is not indicated.venously secondary to persistent oozing observed within Because of bivalirudin’s short half-life, coagulation param-the surgical field, including the needle holes. Within 4 min- eters should return to baseline within 1-2 hours of stoppingutes of administration, clotting was visualized in the surgi- the infusion. In comparison to heparin, benefits of bi-cal field. The patient continued to receive blood products, valirudin include inhibition of both unbound and fibrin-and after 15 minutes, an additional 0.5-mg dose of rFVIIa bound thrombin, no requirement for the cofactor an-was administered. Approximately 90 minutes later, an ad- tithrombin, and low immunological potential. One limita-ditional 1 mg of rFVIIa was given to provide some addi- tion to bivalirudin therapy during cardiac surgery andtional hemostasis to assist in completing closure of the sur- perfusion is that it undergoes proteolytic cleavage bygical sites. This appeared to control the bleeding. Chest thrombin, leading to subtherapeutic concentrations of bi-tubes were placed and the chest closure was completed. valirudin in stagnant blood, with clotting observed in theThe patient was transferred to the intensive care unit. On extracirculatory surgical field. Other adjuncts, such as cit-postsurgical day 6, a duplex scan showed bilateral calf rate, must be used for pooled blood or when using cell-deep vein thromboses (DVTs). An allergy consultation was saver devices to overcome this limitation.requested to determine the nature of the previous allergic Studies have evaluated the efficacy and safety of bi-reaction; however, the consultants were unable to obtain an valirudin in patients during CPB surgery.2-4 In a pilot studyFigure 1. Timeline of activated clotting times (ACTs; L) and bivalirudin infusion during deep hypothermic circulatory arrest (DHCA) induction, which in-cludes the cooling and rewarming period. CPB = cardiopulmonary The Annals of Pharmacotherapy I 2011 September, Volume 45 I e47
  4. 4. EL Nagle et al.of bivalirudin for CPB, Koster and colleagues reported that Excessive anticoagulation with DTIs is a serious and po-a bivalirudin bolus dose of 1.5 mg/kg, infusion of 2.5 tentially life-threatening complication associated with theirmg/kg/h, 50 mg in the pump prime, and additional boluses use during CPB. The EVOLUTION-ON and CHOOSE-ONof 0.25 mg/kg were adequate to achieve an ecarin clotting trials demonstrated significant bleeding rates and frequenttime above 400 seconds, with successful surgical out- requirement for blood transfusions in the studied popula-comes.3 Other studies used a lower dose protocol, initiating tions, similar to those in our patient.3,4 When faced withwith a 1-mg/kg bolus, 50 mg to the pump prime, infusion this degree of blood loss and potential for associated ad-of 2.5 mg/kg/h, stopping 15 minutes prior to going off verse outcomes, there is confusion regarding the best waypump.4 Intraoperative boluses of 0.1-0.5 mg/kg were given to reverse or neutralize bivalirudin to supplement hemosta-as needed, which achieved similar ecarin clotting time and sis. One drug gaining some use in the management ofACT results as the higher dose protocol. The need for ad- acute bleeding during cardiac surgery is rFVIIa.8ditional bolus doses may depend on the duration of rFVIIa promotes hemostasis and clot formation by com-surgery. plexing with tissue factor, resulting in subsequent activa- In the EVOLUTION-ON (Evaluation of Patients Dur- tion of factor X. The activation of clotting factor X resultsing Coronary Artery Bypass Graft Operation: Linking Uti- in the conversion of prothrombin to active thrombin, withlization of Bivalirudin to Improved Outcomes and New consequent fibrin formation. rFVIIa is FDA-approved forAnticoagulant Strategies) study, bivalirudin was compared bleeding episodes in patients with hemophilia and factorto unfractionated heparin in patients without HIT requiring VII deficiency, but not to control operative bleeding in pa-bypass graft surgery.4 No significant difference in acute tients who do not have hemophilia.17 Although dose-relat-procedural success, defined as absence of death, Q-wave ed outcomes are limited in this setting, a dose of 70-90myocardial infarction, stroke, or repeat coronary revascu- µg/kg given every 2 hours until hemostasis occurs haslarization, was observed between heparin and bivalirudin been used.16 rFVIIa is not without complications; its usefor patients undergoing CPB. Approximately 57% of pa- has been associated with an increased incidence of throm-tients on bivalirudin compared to approximately 52% of boembolic complications.18 The use of lower bolus dosespatients in the heparin group required a PRBC transfusion. titrated to effect by visualization of clot formation in theThe CHOOSE-ON (CABG HIT/TS On- and Off-Pump field and suture holes, as was done in our case, has beenSafety and Efficacy: On Pump) study, which enrolled pa- explored to reduce potential complications.19tients requiring bypass graft surgery with suspected or con- There have been 3 case reports to date that specificallyfirmed HIT, found that a majority of patients receiving bi- reported on the use of rFVIIa in patients undergoing anti-valirudin (94%) achieved procedural success, but 84% of coagulation with bivalirudin.9-11 In one case, a patient withpatients also required a PRBC transfusion by day 7 or hos- HIT undergoing CPB for a cardiac transplant received bi-pital discharge.3 valirudin.9 The patient received an initial bivalirudin bolus We used a dosing protocol similar to those in the of 1.5 mg/kg followed by a continuous infusion of 2.5EVOLUTION-ON and CHOOSE-ON studies. Unlike in mg/kg/h. Upon completion of the surgery and before chestour case, DHCA was not used in either of these studies. In closure, the patient received 4 units of PRBC, 6 units ofour case, the bivalirudin infusion was withheld when the fresh frozen plasma, and 5 units of platelet concentrate,patient was put into DHCA secondary to anticipated loss with no clot observed in the field. To facilitate removal ofof the clotting cascade function and potential slowing of bivalirudin, modified ultrafiltration was performed. Bleed-drug elimination. We observed an increase in the ACT ing continued at more than 1.5 L/h, despite additional(from 575 to 999 seconds) during this time, necessitating blood products (4 units PRBCs, 4 units fresh frozen plas-continued withholding of the bivalirudin infusion until a ma, 12 units of platelets, 20 units cryoprecipitate). Sincedecline in ACT toward the goal range was noted. This chest closure was not possible due to refractory hemor-could be the result of use of DHCA, which could cause rhage, rFVIIa 90 µg/kg was administered intravenously; achanges in blood stasis and enzymatic activity. A study of clot was then visualized and chest closure commenced.the effect of DHCA on bivalirudin and ACT also found a Hemodialysis was then used in an effort to remove morecorrelation between decreasing temperature and increasing bivalirudin. Upon the patient’s arrival to the intensive careACT, which the authors attributed to decreased proteolysis unit, chest tubes drained 200 mL of blood over 20 minutesof bivalirudin.15 An in vitro study also found that hypother- and an additional dose of rFVIIa 90 µg/kg was adminis-mia has an independent inhibition on coagulation factors tered. This patient experienced an uneventful recoveryand platelet function, potentially having an independent ef- with no thrombotic complications.fect on the measured ACT.13 Another study observed in- A second case involved a patient with preexisting HITcreased mean prothrombin and partial thromboplastin who underwent intracorporeal left ventricular assist devicetimes and proposed that the enzymatic reactions of the co- placement with bivalirudin anticoagulation and experi-agulation cascade are strongly inhibited by hypothermia.16 enced severe bleeding after the bypass.10 The patient re-e47 I The Annals of Pharmacotherapy I 2011 September, Volume 45
  5. 5. Bivalirudin and rFVIIa During Hypothermic Cardiopulmonary Bypassceived an intravenous bivalirudin bolus of 50 mg (0.63 In a recent systematic review of off-label rFVIIa use, themg/kg) followed by a continuous infusion of 2 mg/kg/h, use of lower-dose rFVIIa (mean dose 18 µg/kg) in cardiacwith an additional 50 mg added to the CPB priming solu- surgery was associated with a lower rate of thromboembol-tion. The patient received significant transfusion of blood ic events relative to higher doses of 40-100 µg/kg.21 Notproducts, which included 15 units of PRBCs, 10 units of only is the relatively low dose of rFVIIa preferred in thisfresh frozen plasma, 6 units of plasmapheresis platelets, 12 setting for safety reasons, but it also has significant eco-units of cryoprecipitate, and eventually a single 90-µg/kg nomic benefits. The timing of administration of the rFVIIadose of rFVIIa. Shortly after receiving rFVIIa, the patient and visualized clot formation reflected an effective dose inexperienced a new left atrial thrombus detected by a trans- our case.esophageal echocardiogram. Our patient did develop distal DVTs, a potential compli- In a third report, we described a patient with HIT, in ad- cation of rFVIIa administration.18 This patient had addi-dition to impaired cardiac (ejection fraction 10%), hepatic tional risk factors for venous thromboembolism, including(total bilirubin 5.2 mg/dL), and renal function (serum crea- recent surgery, immobility, and a significant smoking his-tinine 1.9 mg/dL), as well as critical aortic stenosis requir- tory.22 Initially, pharmacologic DVT prophylaxis was noting aortic valve replacement (bovine) and removal of utilized due to the patient’s allergies to heparin and war-biventricular thrombi.11 During surgery, the bypass circuit farin and concern for postoperative bleeding. Subcuta-was primed with 50 mg of bivalirudin and an intravenous neous fondaparinux is a viable option, which was initiatedbolus of 89 mg was given, followed by an infusion of 2.5 upon detection of distal The first ACT obtained 5 minutes after the bolus The mechanism of reversal of anticoagulation of bi-was 999 seconds, and remained at that value during and af- valirudin with rFVIIa has not been established, and thereter stopping the bivalirudin infusion. Administration of are few data to support or negate its use. Unlike othermultiple units of fresh frozen plasma 4 hours after stopping DTIs, bivalirudin has an intracellular elimination processthe bivalirudin in preparation for closure dropped the ACT largely independent of the liver or kidney.2,23 Potential ex-to 233 seconds, which rebounded to 500 seconds (45 min- planations include reversal of coagulopathy via the extrin-utes later) and subsequently 999 seconds (1 hour later). sic pathway rather than a direct neutralization of bi-Approximately 7 hours into the procedure, the ACT re- valirudin. Another theory is that thrombin cleaves bi-mained at 999 seconds, and continued bleeding in the sur- valirudin near the amino-terminal end in the active site.24gical field delayed closure. Intravenous rFVIIa 1.2 mg (13 Administration of rFVIIa in the presence of adequateµg/kg) was administered, resulting in a rapid drop in the platelets can initially cause a burst in thrombin, potentiallyACT to 200 seconds, with notable reduction in bleeding. creating additional enzymatic degradation of the drug toAn additional 1.2 mg of rFVIIa was given followed by expedite the removal of its effects.25successful closure and discharge from the hospital. We observed an excessive response to bivalirudin in the In our patient, consistent with others’ observations, dif- setting of deep hypothermia, which we propose is due tofuse coagulopathy was observed after stopping the bi-valirudin and removing the patient from CPB. The patient the decreased activity of the proteolytic enzymes resultingreceived multiple blood products to supplement hemosta- in a prolonged anticoagulant effect; therefore, the infusionsis, including platelets initially due to the thromboelas- may need to be lowered or stopped prior to DHCA. Fur-togram result and observations of reduced platelet function thermore, we suggest that the use of relatively low-dosein hypothermia.13 As previously mentioned, the patient rFVIIa (0.5-1 mg, repeated as necessary) may be an effec-also received continuous aminocaproic acid, which is com- tive supplemental strategy to reestablish hemostasis fol-mon practice during cardiothoracic surgery to reduce ex- lowing anticoagulation with bivalirudin when standard ad-cessive bleeding and transfusion requirements.20 Despite juncts have not been successful, although this is not with-these measures to promote hemostasis, bleeding continued out thromboembolic risk. The lower dose of rFVIIa mayto occur in the field, creating difficulty in surgical closure. potentially reduce the risk of thromboembolic events, espe-Since there was concern for prolonged-closure complica- cially when there is a hesitancy to initiate thromboprophy-tions such as infection or atrial fibrillation, the decision laxis postoperatively. Prospective studies and more thor-was made to administer rFVIIa to jump-start the coagula- ough mechanistic data are needed to determine the impacttion cascade to minimize time to closure. A dose of rFVIIa of hypothermia on bivalirudin and the appropriate, safe,0.5 mg was given intravenously based on the institution’s and effective dose of rFVIIa to reverse the coagulopathyguidelines and anecdotal experience. The relatively low that may persist.dose of rFVIIa is advantageous given the rapid onset of ef-fect within minutes, allowing for the ability to titrate any Erin L Nagle PharmD, PGY-1 Pharmacy Resident, University of California, Davis Medical Center, Sacramento, CAnecessary additional doses to effect while potentially mini- Laura V Tsu PharmD BCPS, PGY-2 Cardiology Pharmacy Resi-mizing associated risk of thromboembolic events. dent, University of California, Davis Medical The Annals of Pharmacotherapy I 2011 September, Volume 45 I e47
  6. 6. EL Nagle et al.William E Dager PharmD BCPS (AQ Cardiology) FCSHP FCCP 11. Dager WE, Young N. Reversal of bivalirudin with recombinant activatedFCCM FASHP, Pharmacist Specialist, University of California, Davis factor VII during cardiac surgery (abstract). Thromb ThrombolysisMedical Center 2011;31:393.Correspondence: Dr. Dager, 12. Alsoufi B, Caldarone C, Abouassaly C. Hypothermia, circulatory arrestReprints/Online Access: and cardiopulmonary bypass 2007. 902596-overview (accessed 2010 Nov 24).Conflict of interest: Authors reported none 13. Shimokawa M, Kitaguichi K, Kawaguchi M, Sakamoto T, Kakimoto M, Furuya H. The influence of induced hypothermia for hemostatic functionReferences on temperature-adjusted measurements in rabbits. Anesth Analg 2003;96:1209-13. DOI 10.1213/01.ANE.0000050767.86196.AF 1. Gravlee GP, Davis RF, Stammers AH, Ungerleider RM. Cardiopul- 14. Dirkmann D, Hanke AA, Horlinger K, et al. Hypothermia and acidosis monary bypass: principles and practice. 3rd ed. Philadelphia: Lippincott synergistically impair coagulation in human whole blood. Anesth Analg Williams and Wilkins, 2008. 2008;106:1627-32. DOI 10.1213/ane.0b013e31817340ad 2. Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 15. Leissner KB, Ketchedjian A, Crowley R, et al. Deep hypothermic circu- 2008;99:830-9. DOI 10.1160/TH07-10-0644 latory arrest and bivalirudin use in a patient with heparin-induced thrombo- 3. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary cytopenia and antiphospholipid syndrome. J Card Surg 2007;22:78-82. bypass in patients with previous or acute heparin-induced thrombocy- DOI 10.11111/j.1540-8191.2007.00351 topenia and heparin antibodies: results of the CHOOSE-ON trial. Ann 16. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cas- Thorac Surg 2007;83:572-7. DOI 10.1016/j.athoracsur.2006.09.038 cade. Crit Care Med 1992;10:1402-5. 4. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to 17. Package insert. NovoSeven, Coagulation Factor VIIa (recombinant). heparin with protamine reversal in patients undergoing cardiac surgery Princeton, NJ: Novo Nordisk Pharmaceuticals, Sept. 1999. with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac 18. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboem- Cardiovasc Surg 2006;131:533-9. DOI 10.1016/j.jtcvs2005.09.057 bolic adverse events after use of recombinant human coagulation factor 5. Riess FC, Dobritzsch B, Kormann J. Lepirudin for cardiopulmonary by- VIIa. JAMA 2006;295:293-8. DOI 10.1001/jama.295.3.293 pass surgery in a patient with terminal renal insufficiency and acute hep- 19. Flynn JD, Hatton KW. Pharmacotherapy assessment program, 7th ed. arin-induced thrombocytopenia. Thorac Cardiovasc Surg 2006;54:140-2. Perioperative management of antithrombotic therapy. American College DOI 10.1055/s-2005-872806 of Clinical Pharmacy, 2010. 6. 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Recombinant factor VIIa to manage clinical practice guidelines (8th edition). Chest 2008;133(6 suppl):381S- major bleeding from newer parenteral anticoagulants. Ann Pharmacother 453S. DOI 10.1378/chest.08-0656 2010;44:718-26. DOI 10.1345/aph.1M447 23. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacoki- 9. Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin netics and pharmacodynamics: effect of renal function, dose and gender. inhibition after cardiopulmonary bypass in a patient with heparin-in- Clin Pharmacol Ther 2002:71:433-9. DOI 10.1067/mcp.2002.124522 duced thrombocytopenia. Anesth Analg 2004;98:1635-9. 24. Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. DOI 10.1213/01.ANE.0000114072.71353.D5 Ann Pharmacother 2002;36:1028- 41.10. Apostolidou I, Sweeney MF, Missov E, Joyce LD, John R, Prielipp RC. 25. Kessler CM. Urgent reversal of warfarin with prothrombin complex con- Acute left atrial thrombus after recombinant factor VIIa administration centrate: where are the evidence-based data? J Thromb Haemost 2006;4: during left ventricular assist device implantation in a patient with hep- 963-6. arin-induced thrombocytopenia. Anesth Analg 2008;106:404-8. DOI 10.1213/ane.0b013e31815edb52e47 I The Annals of Pharmacotherapy I 2011 September, Volume 45