Eur J Cardiothorac Surg 2000;17:760-762
© 2000 Elsevier Science NL
Undergoing cardiopulmonary bypass using enoxaparin only during a cardiac transplantation procedure
Edvin Priftia,
Massimo Bonacchia,
Marzia Leaccheb,
Fabio Miraldia
a Istituto di Chirurgia Toracica, Cardiovascolare e Technologie Biomediche, Università degli Studi di Siena, Siena, Italy
b Istituto di Chirurgia del Cuore e dei Grossi Vasi, Università degli Studi di Roma, "La Sapienza", Rome, Italy
Corresponding author. Istituto di Chirurgia del Cuore e dei Grossi Vasi, Policlinico Umberto I, Universita degli Studi di Roma ‘La Sapienza’, Viale del Policlinico, 155, 00161, Rome, Italy. Tel.: +-39-6-499-72693; fax: +39-6-499-72410
e-mail: edvinprifti{at}hotmail.com
 |
Abstract
|
|---|
The use of enoxaparin as a replacement drug to standard heparin, for anticoagulation during extracorporeal circulation, in patients with heparin-induced thrombocytopenia, is still very limited. Enoxaparin significantly reduces thrombin formation and activity during cardiopulmonary bypass. The prolonged circulating rate, slow elimination rate and non-total reversion of enoxaparin by protamine can induce important postoperative bleeding. We are describing the first case of cardiac transplantation where enoxaparin was used as a replacement drug to standard heparin.
Key Words: Enoxaparin • Cardiac transplantation • Heparin-induced thrombocytopenia
|
1. Introduction
|
|---|
Enoxaparin, is a low molecular weight heparin (LMWH), already demonstrated to be a safe and effective alternative to standard heparin in unstable coronary artery disease, but its use for undergoing CPB is still very limited [1–3]. Some authors do not indicate the use of enoxaparin because of significant blood loss [1] or because of possible cross-reactivity in cases with heparin-induced thrombocytopenia (HIT) [3]. The biodistribution and pharmacocinetics of standard heparin and enoxaparin are almost similar, except the anti Xa plasma half-life that is three times longer for enoxaparin [4]. Enoxaparin has a prolonged circulating time and the rate of plasma clearance is slower compared with heparin [5]. We are describing the first case of cardiac transplantation (CT) where enoxaparin was used as a replacement drug to standard heparin.
|
2. Case report
|
|---|
A 40-year-old man with an 8-year history of idiopathic dilated cardiomyopathia, 5-year history of diabetes, was admitted for acute heart failure. The right heart catheterism, demonstrated a CI of 1.4 l/min per m2, CO 2.6 l/min, wedge pressure of 25 mmHg, PAP (51–25 mmHg) and pulmonary resistance of 3.8 Wood units. He was accepted at CT waiting list. The transthoracic echocardiography revealed a LVEDD of 70 mm, LVEF of 18%, and presence of a thrombotic mass at the left atrium that treated with heparin. After 4 h the patient presented cutaneous allergic reactions (cutaneous eritema), hypotension, thrombocytopenia (65x103 platelets/µl). Clinical score according Greinacher [6] resulted to be 6, demonstrating a probable HIT II. It was initiated treatment with warfarine (for 3 months) immediately after withdrawal of heparin. Patient was found to tolerate enoxaparin without cross-sensitivity. The subcutaneous and intravenously (i.v.) tests for enoxaparin allergy resulted negative.
Six months later the patient underwent CT. A total dose of 25 000 UI of enoxaparin (Clexane; Rhone–Poulenic Rorer) was administered i.v.. The activated clotting time (ACT) was 182 s. It were adjuncted two other doses of 10 000 UI each of enoxaparin. The ACT before cannulation resulted to be 479 s. CT was performed according the bicaval technique. The clamping time was 74 min. At the end of CPB 500 mg of protamine were given and contemporary the remaining blood in the CPB circuit was retransfused. The ACT resulted 172 s at time of decannulation. During hemosthasis the patient manifested important blood loss and significant hypotension. Eight units of fresh-frozen plasma (FFP) and 3 units of packed red blood cells (PRBC) were administered intraoperatively. In the first 3 h a blood loss of 1000 ml occurred. The ACT resulted 248 s. Other 200 mg of protamine were given. The Hct was 19%, Hgb 6.6 mg/dl and 54x103 platelets/µl. It was given 6 units of FFP, 4 PRBC units and 10 platelets units. The patient underwent a surgical revision for significant blood loss, which did not reveal any surgical cause. In the following 5 h a blood loss of 1500 ml occurred. PT was 25%, aPTT 62 s and Antithrombine III 56%. Antithrombine III (2000 UI), tranexamic acid (1.5 g), were administered. The patient underwent a second surgical revision without revealing any surgical cause. The patient was sent in the ICU with an inotropic support of 8 µg/kg per min of dopamine, 0.015 µg/kg per min of norepinephrine. CO was 5.4 l/min. Hct after the second surgical revision was 22%, Hgb 8 mg/dl, 88x103 platelets/µl. The total blood loss in the following 10 h was 1200 ml (other 4 PRBC and 8 FFP were administered) and after 7 h stopped totally. The imunosupression therapy consisted in Neoral 4 mg/kg, Azathyoprin 2 mg/kg and Prednisone 0.2 mg/kg. 8 months after CT procedure the patient was alive.
|
3. Discussion
|
|---|
HIT is a rare occurrence represented in two types: HIT I is characterized by a transitory reduction in platelets count; HIT II is characterized by a significant thrombocytopenia, cutaneous allergic manifestations, thrombosis. The patient's clinical manifestations indicated a probable HIT II, but we were not able to demonstrate in vitro, the heparin-dependent anti-platelets antibodies. In these cases, standard heparin has to be contraindicated because of the severe allergic reactions after CPB. Other alternatives as r-hirudin and heparinoids have been investigated, but none of them reduced the generation or activity of thrombin. In contrast, enoxaparin reduces significantly thrombin formation [7] and activity during CPB but does not suppress complement activation [8]. Other studies demonstrated that prostaglandins were most effective when they were administered as a supplement to heparin [9]. Partial neutralization of enoxaparin by protamine reduces the postoperative bleeding compared with no reversion of r-hirudin, which is associated with prolonged bleeding after CPB [10]. It is demonstrated that enoxaparin led to increased 
-TNF and interleukin-ß inducing vasodilatation and endothelial cells dysfunction. Our patient was able to tolerate enoxaparin i.v. without cross-sensitivity. This was unexpected because enoxaparin is derived from unfractionated porcine heparin.
The prolonged circulating time, non-total reversion by protamine, which can reverse only 60% of the circulating LMWHs, and slower elimination of enoxaparin, increase the risk for postoperative bleeding. Other studies demonstrated that enoxaparin (100 UI/kg) causes a near-complete abolishment of platelet-dependent cyclic flow reductions, increment significantly the anti-Xa levels, anti-IIa levels, increase aPTT and template bleeding time significantly higher than heparin [7]. The impaired hepatic function found preoperatively (Table 1), due to end-stage heart failure, associated with an altered coagulative status was an adjunctive risk factor for significant bleeding. 4 h after protamine the ACT returned on its normal values even that bleeding continued during the first 24 postoperative hours. Other studies [3,6–7] demonstrated normal ACT values only 3 h after protamine, however, bleeding time was still prolonged during the first 24 h. Direct inhibition of platelet function by enoxaparin or activation of platelets by enoxaparin–protamine complexes that are slowly cleared, may interfere with platelet function and prolonged bleeding times. It seems that ACT alone, can not provide a precised monitoring of the anticoagulation effects of enoxaparin.
|
4. Conclusion
|
|---|
The enoxaparin therapy permits to undergo CPB. Partial neutralization of enoxaparin by protamine compared with no reversion of other alternative drugs makes enoxaparin the drug of choice in patients with HIT undergoing cardiac operations that can tolerate LMWHs without cross-reactivity.
|
References
|
|---|
-
Robitaille D., Leclerc J.R., Laberge R., Sahab P., Atkinson S., Cartier R. Cardiopulmonary bypass with a low molecular weight heparin fraction (enoxaparin) in a patient with a history of heparin-associated thrombocytopenia. J Thorac Cardiovasc Surg 1992;103:597-599.[Medline]
-
Ganjoo A.K., Harloff M.G., Johnoson W.D. Cardiopulmonary bypass for heparin-induced thrombocytopenia: management with a heparin-bonded circuit and enoxaparin. J Thorac Cardiovasc Surg 1996;112:1390-1392.[Free Full Text]
-
Peters F.P.J. Treatment of heparin induced thrombocytopenia. J Thorac Cardiovasc Surg Sep 1997;114(3):517-518.
-
Laforest M.D., Colas-Linhart N., Guiraud-Vitaux F., Bok B., Bara L., Samama M., Marin J., Imbault F., Uzan A. Pharmacocinetics and biodistribution of technetium 99m labelled standard heparin and a low molecular weight heparin (enoxaparin) after intravenous injection in normal volunteers. Br J Haematol 1991;77(2):201-208.[Medline]
-
Brieger D., Dawes J. Production method affects the pharmacocinetics and ex vivo biological properties of low molecular weight heparins. Thromb Haemost 1997;77(2):317-322.[Medline]
-
Greinacher A., Amiral J., Dummel V., Vissac A., Kiefel V., Mueller-Heckhardt C. Laboratory diagnosis of heparin-associated thrombocypenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion 1994;34:381-385.[Medline]
-
Leadley R.J., Jr, Kasiewski C.J., Bostwick J.S., Bentley R., Dunwiddie C.T., Perrone M.H. Inhibition of repetitive thrombus formation in the stenosed canine coronary artery by enoxaparin, but not by unfractionated heparin. Arterioscler Thromb Vasc Biol 1998;18(6):908-914.[Abstract/Free Full Text]
-
Gikakis N., Rao A.K., Miyamoto Sh., Gorman J.H., Khan M.M.H., Anderson H.L., Hack C.E., Sun L., Niewiarowski S., Colman R.W., Edmunds L.H. Enoxaparin suppresses thrombin formation and activity during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 1998;116:1043-1051.[Abstract/Free Full Text]
-
Kozek-Langenecher S.A. Anticoagulation with prostaglandins during extracorporeal circulation. Wien Klin Wachenschr 1999;111(4):129-140.
-
Kwapisz M.M., Schindler E., Muller M., Akinturk H. Prolonged bleeding after cardiopulmonary bypass with recombinant hirudin in heart transplantation. Eur J Cardio-thorac Surg 1999;16(2):256-257.
Received November 10, 1999;
received in revised form February 14, 2000;
accepted February 22, 2000.
This article has been cited by other articles:
|
|
|
|
 
L. Mildh, P. Tynkkynen, I. Mattila, and P. Rautiainen
Initial experience of enoxaparine as anticoagulant during mechanical circulatory support in children
Interactive CardioVascular and Thoracic Surgery,
August 1, 2006;
5(4):
499 - 501.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J DeBois, J. Liu, L. Y Lee, L. N Girardi, C. Mack, A. Tortolani, K. H Krieger, and O W. Isom
Diagnosis and treatment of heparin-induced thrombocytopenia
Perfusion,
January 1, 2003;
18(1):
47 - 53.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. K.S. Nair, L. S. Zisman, E. Lader, A. Dimova, and C. C. Canver
Heart transplant for anomalous origin of left coronary artery from pulmonary artery
Ann. Thorac. Surg.,
January 1, 2003;
75(1):
282 - 284.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
1. Introduction
