Ann Thorac Surg 2005;79:334-336
© 2005 The Society of Thoracic Surgeons
Case report
Delayed Thrombin Generation With Hirudin Anticoagulation During Prolonged Cardiopulmonary Bypass
Fraser D. Rubens, MD, MSa,*,
Gilbert Lavaleeb,
Marc A. Ruel, MD, MPHa,
Thierry Mesana, MD, PhDa,
Michael Bourke, MDc
a Division of Cardiac Surgery, Ottawa, Ontario, Canada
b Division of Perfusion, Ottawa, Ontario, Canada
c Division of Cardiac Anaesthesia, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Accepted for publication August 12, 2003.
* Address reprint requests to Dr Rubens, Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada
frubens{at}ottawaheart.ca
 |
Abstract
|
|---|
Patients with heparin-induced thrombocytopenia requiring urgent cardiac surgery present a unique challenge that must be addressed by the use of nonheparin alternatives for anticoagulation during cardiopulmonary bypass. Although isolated cases have been presented involving the use of antithrombin III independent thrombin inhibitor hirudin in this situation, its ability to completely inhibit thrombin activity has not been demonstrated. In this report we describe the efficacy of this drug in inhibiting thrombin during a case requiring prolonged cardiopulmonary bypass.
|
Introduction
|
|---|
The management of patients with heparin-induced thrombocytopenia acutely requiring cardiopulmonary bypass (CPB) present a therapeutic dilemma for the surgical team because alternative means of anticoagulation must be sought. Most recently, successful approaches involving the use of antithrombin III independent thrombin inhibitors, such as argatroban [1] and hirudin [2, 3] during CPB have been described in the cardiac surgical literature. Despite the clinical success of these cases, there has been no data supporting the efficacy of these drugs in terms of thrombin inhibition during CPB, which is clearly the most important goal of anticoagulation. In this report we characterize the effect of hirudin anticoagulation on thrombin activity in a patient with heparin-induced thrombocytopenia undergoing prolonged CPB with deep hypothermic circulatory arrest.
A 65-year-old woman presented with a 2-month history of progressive shortness of breath. She had been diagnosed as having an acute pulmonary embolus 2 months prior, and despite warfarin therapy, a pulmonary angiogram demonstrated persistent, complete occlusion of the left pulmonary artery with findings consistent with chronic thromboembolic pulmonary hypertension. Low molecular weight heparin was resumed due to suspected warfarin failure, but the patient developed acute thrombocytopenia (platelet count 65,000/µL) with suspected heparin-induced thrombocytopenia, and the patient was placed on danaparoid in the intensive care unit. Due to severe right heart failure and persistent maximal oxygen requirements by mask, the patient was referred for consideration of urgent pulmonary thromboendarterectomy.
In this situation, it was elected to utilize recombinant hirudin (lepirudin) as the chosen anticoagulant for cardiopulmonary bypass for the following reasons: (1) we previously published the feasibility of the use of this anticoagulant for pulmonary thromboendarterectomy [3]; (2) there is extensive experience in the world literature in the use of this anticoagulant for routine CPB with demonstrated safety [4]; (3) there is nonavailability in Canada of prostacyclin [5]; (4) there is lack of ability for online measurement of anticoagulation with the heparinoid danaparoid and the defibrinogenating agent acrod; and (5) short half-life of hirudin as compared with danaparoid
A written informed consent to use hirudin bypass was also obtained from the patient before surgery. Her preoperative renal function was normal. Danaparoid therapy was discontinued 18 hours preoperatively and no anticoagulation was used in the interim. Citrate was used for flushing all monitoring lines.
An initial bolus of 24 mg (0.4 mg/kg) of lepirudin (Refludan, Berlex Canada) was given followed by infusion of lepirudin (0.2 mg/kg/h) before CPB. An additional 6.5 mg of lepirudin was included in the pump prime. Two extra boluses of 6 mg were administered during CPB when a pattern of dropping ecarin clotting time was recognized. Cardiopulmonary bypass was conducted using a roller pump and a hollow fiber membrane oxygenator with an open venous reservoir (SMARxT, COBE Cardiovascular Inc, Arvada, CO). The pump was primed with Ringer's lactate. The technical aspects of CPB management and pulmonary thromboendarterectomy have been well described by Jamieson and associates [6]. The total CPB time was 222 minutes, which included a cross-clamp time of 102 minutes and a period of total circulatory arrest of 13 minutes. All cardiotomy blood was processed by filtration (30 µm) and centrifugal washing (BRAT, COBE Cardiovascular Inc) before reinfusion.
After successful discontinuation of CPB, the lepirudin infusion was discontinued. A blood sample taken at the end of the lepirudin infusion demonstrated the following coagulation values: INR 1.6, aPTT 83, TT 60+, fibrinogen 2.3, platelet count 113,000/µL. Based on best clinical judgment and the anticipated dilutional coagulopathy, while waiting for the lepirudin to reverse, the patient was given cryoprecipitate, fresh frozen plasma, and platelets. When hemostasis was achieved, the sternum was closed and the patient was transferred to the recovery room in stable condition. The total time from the termination of the lepirudin infusion to transfer to the intensive care unit was approximately 2.5 hours. The total amount of bleeding in the ensuing 12 hours after chest closure was 220 mL. The following day the patient was reanticoagulated with danaparoid and warfarin. The remainder of the postoperative course was unremarkable.
A determination of hirudin, prothrombin fragment, and thrombin-antithrombin III levels were made. Blood samples were taken into tubes with citrate (3.8%) on ice at intervals before, during, and after CPB. At each sampling, 10 mL of whole blood was collected after discarding the initial 2 mL of blood. Portions of the samples were centrifuged to produce platelet-poor plasma. Whole blood samples were used for the determination of the ecarin clotting time with of a modification of the ACT II device (Medtronic Inc, Minneapolis, MN) as described by Koster and colleagues [7] and a final ecarin concentration in the cuvette of 5 IU/mL. A standard curve was prepared with the patient's nonhirudinized blood before CPB to determine a target hirudin (lepirudin) level between 3.5 and 4 mg/mL [7]. Prothrombin fragment and thrombin-antithrombin III levels were quantified in samples of platelet-poor plasma using the sandwich enzyme-linked immunosorbent assay technique (Dade Behring Enzygnost Micro Tests [Dade Behring, Marburg, Germany]). Measured hirudin (lepirudin) levels, as well as the levels of thrombin-antithrombin III and prothrombin fragment, are demonstrated in Figure 1. Accelerated thrombin generation became more obvious after a period of approximately 1 hour despite apparent therapeutic levels of hirudin [7]. Although thrombin-antithrombin III levels did not exceed baseline, the levels of prothrombin fragment increased sixfold by the time the cross clamp was removed. A further increase was blocked by the administration of an additional bolus of lepirudin.
View larger version (77K):
[in this window]
[in a new window]
|
Fig 1. Effect of recombinant hirudin (lepirudin) on measured hirudin levels, as well as thrombin generation and activity during a case of prolonged cardiopulmonary bypass (CPB). Diamonds = hirudin (µg/mL); squares = TAT (µg/L); triangles = F1.2 (nmol/L). (TAT = thrombin antithrombin III; F1.2 = prothrombin fragment 1.2.)
|
|
|
Comment
|
|---|
Hirudin has been advocated as a safe and facile means for anticoagulation during CPB in patients in whom heparin is contraindicated [2]. This drug, derived from the European medicinal leech (Hirudo medicinalis) is a highly specific inhibitor of thrombin with little or no activity against other proteins in the coagulation cascade such as activated factors X and XII [8]. Hirudin's anticoagulant effect is primarily related to inhibition of thrombin-mediated factor V activation, the latter necessary for the formation of the prothombinase complex and the amplification of the coagulation cascade [9]. Some degree of thrombin generation should still occur [8, 10], however rapid binding to circulating hirudin should prevent further amplification of the coagulation cascade by the thrombin itself [11]. Should the system become overwhelmed, there is the potential that hirudin levels may be inadequate to prevent this process, particularly during long CPB runs.
The clinical significance of the demonstrated degree of thrombin generation during prolonged CPB is difficult to determine as the plasma levels were much lower than those seen after the discontinuation of the infusion after CPB when clot formation was expected. The subsequently detected rises in these values (time point 16 on Fig 1) occurred after the administration of the fresh frozen plasma (FFP) and cryoprecipitate, which likely replenished plasma levels of coagulation factors including ATIII. Cessation of the lepirudin infusion after CPB resulted in a more vigorous increase in prothrombin fragment, which paralleled visible clot formation.
In summary, this case presents the first demonstration of the effect of hirudin on thrombin generation during prolonged CPB. Although the detected levels of prothrombin fragment and thrombin-antithrombin III were relatively low, it does suggest that some degree of coagulation was ongoing, particularly after 1 hour of CPB exposure. Therefore, augmentation of the hirudin concentration (> 4 mg/mL) should be considered after this point and further testing should be directed to ascertain if this increased anticoagulation intensity successfully limits the rise in thrombin generation.
|
Acknowledgments
|
|---|
We would like to thank Dr Feng Wang for his assistance.
|
References
|
|---|
- Furukawa K, Ohteki H, Hirahara K, Narita Y, Koga S. The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations. J Thorac Cardiovasc Surg. 2001;122:1255–1256[Free Full Text]
- Koster A, Kuppe H, Hetzer R, Sodian R, Crystal GJ, Mertzlufft F. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology. 1998;89:777–780[Medline]
- Rubens FD, Sabloff M, Wells PS, Bourke M. Use of recombinant-hirudin in pulmonary thromboendarterectomy. Ann Thorac Surg. 2000;69:1942–1943[Abstract/Free Full Text]
- Koster A, Hansen R, Kuppe H, Hetzer R, Crystal GJ, Mertzlufft F. Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth. 2000;14:243–248[Medline]
- Kappa JR, Fisher CA, Todd B, et al. Intraoperative management of patients with heparin-induced thrombocytopenia. Ann Thorac Surg. 1990;49:714–722[Abstract]
- Jamieson SW, Auger WR, Fedullo PF, et al. Experience and results of 150 pulmonary thromboendarterectomy operations over a 29 month period. J Thorac Cardiovasc Surg. 1993;106:116–127[Abstract]
- Koster A, Loebe M, Hansen R, et al. A quick assay for monitoring recombinant hirudin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: adaptation of the ecarin clotting time to the ACT II device. J Thorac Cardiovasc Surg. 2000;119:1278–1283[Abstract/Free Full Text]
- Markwardt F. Hirudin and derivatives as anticoagulant agents. Thromb Haemostas. 1991;66:141–152[Medline]
- Fenton JW, Villanueva GB, Ofosu FA, Maraganore JM. Thrombin inhibition by hirudin: how hirudin inhibits thrombin. Haemostasis. 1991;21:27–31
- Zoldhelyi P, Bichler J, Owen WG, et al. Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation. 1994;90:2671–2678[Abstract/Free Full Text]
- Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochem. 1986;25:4622–4628[Medline]
This article has been cited by other articles:
|
|
|
|
 
D Belway, F D Rubens, B Henley, A Babaev, and T Mesana
Delayed thrombin generation is not associated with fibrinopeptide formation during prolonged cardiopulmonary bypass with hirudin anticoagulation
Perfusion,
September 1, 2006;
21(5):
259 - 262.
[Abstract]
[PDF]
|
|
|
Top
Abstract
Introduction
