ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Talia B. Spanier
Mehmet C. Oz
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Williams, M. R.
Right arrow Articles by Oz, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Williams, M. R.
Right arrow Articles by Oz, M. C.

Ann Thorac Surg 2000;70:873-877
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

A randomized trial of antithrombin concentrate for treatment of heparin resistance

Mathew R. Williams, MDa, Alyssa B. D’Ambra, BAa, James R. Beck, CCPa, Talia B. Spanier, MDa, David L.S. Morales, MDa, David N. Helman, MDa, Mehmet C. Oz, MDa

a Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA

Address reprint requests to Dr Williams, Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, 17–401, 630 W 168th St, New York, NY 10032
e-mail: mw365{at}columbia.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Heparin resistance is an important clinical problem traditionally treated with additional heparin or fresh frozen plasma. We undertook a randomized clinical trial to determine if treatment with antithrombin (AT) concentrate is effective for treating this condition.

Methods. Patients requiring cardiopulmonary bypass who were considered to be heparin resistant (activated clotting time < 480 seconds after > 450 IU/kg heparin) were randomized to receive either 1000 U AT or additional heparin.

Results. AT concentrate was effective in 42 of 44 patients (96%) for immediately obtaining a therapeutic activated clotting time. This compared favorably to 28 of 41 patients (68%) treated with additional heparin (p = 0.001). All patients who failed heparin therapy were successfully treated with AT. The patients receiving AT required less time to obtain an adequate ACT but there was no difference in clinical outcomes among the groups. Study patients had deficient AT activity at baseline (56% ± 25%), which improved in those given AT concentrate (75% ± 31% versus 50% ± 23%, p < 0.0005).

Conclusions. Heparin resistance is frequently associated with AT deficiency. Treating this deficiency with AT concentrate is more effective and faster for obtaining adequate anticoagulation than using additional heparin.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Heparin resistance is an increasingly recognized clinical problem characterized by an inadequate response to high doses of heparin that makes initiation or continuance of cardiopulmonary bypass unsafe [1]. Heparin resistance has various but similar definitions, and for the purpose of this study is defined as an inadequate response after receiving greater than 450 U/kg of heparin. Antithrombin (AT) deficiency is argued to be a primary cause of this condition because the mechanism of action of heparin is through interaction with this molecule. Conventional treatment of heparin resistance includes administering fresh frozen plasma (FFP) as a source of AT, or administering increasingly higher doses of heparin to bind all available AT. FFP can transmit viral infections and its use can result in intraoperative delays while waiting for the product to become available. Additional heparin may prove ineffective if AT is severely deficient and can cause increased bleeding and heparin rebound.

Antithrombin concentrate is purified from heat-treated plasma that is part of the pasteurization process and has not been associated with viral transmission. We investigated the efficacy of AT concentrate in obtaining adequate anticoagulation for heparin-resistant patients requiring cardiopulmonary bypass. To do so, we designed a randomized trial comparing use of AT concentrate versus use of additional heparin in this population.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Protocol
All adult patients undergoing a procedure requiring cardiopulmonary bypass from May 1997 to April 1999 were eligible for enrollment. Only patients who were heparin resistant were enrolled in the study. Heparin resistance was defined as an activated clotting time (ACT) less than 480 seconds (or < 600 seconds if using aprotinin) after administering 450 U/kg of heparin. All patients received an initial loading dose of 300 U/kg of heparin, followed by a dose of 150 U/kg. If the clinical scenario required patients to receive cardiopulmonary bypass despite inadequate anticoagulation, they were still eligible for study enrollment (eg, hemodynamic instability). Patients who developed heparin resistance while on cardiopulmonary bypass despite having a prior adequate ACT were not eligible for enrollment. Patients determined to be heparin resistant were randomized to one of two groups. Group one received 1000 U (2 vials) of AT concentrate (Thrombate III, Bayer Pharmaceuticals, West Haven, CT). If the ACT was subtherapeutic after AT administration patients were crossed into the second group and received additional heparin. Conversely, group two received additional doses of heparin until an adequate ACT was obtained. If a total heparin dose of 800 U/kg without an adequate ACT was reached, patients were crossed over into the AT group. All patients received supplemental heparin for the remainder of the cardiopulmonary bypass run as necessary to maintain adequate anticoagulation. Blood samples were obtained at the time of randomization, 30 minutes after entering the study, and at the termination of bypass. These samples were assayed for AT activity levels, thrombin-antithrombin (TAT), and the prothrombin fragment (F1 + 2). To determine if a time advantage existed for one of the treatments, we quantitated the number of cycles involving dosing or redosing the appropriate agent, waiting for equilibration and then running an ACT. The total number of cycles was quantitated starting from study enrollment to obtaining a therapeutic ACT. This calculation is more reliable than actual time between measurements in assessing the time consequences of each treatment. Each dosing cycle represents a minimum of 12 minutes, as it includes administering the appropriate agent, waiting for equilibration, and waiting at least 8 minutes before a therapeutic ACT is returned. Additionally, preoperative demographics were obtained that included preoperative heparin therapy; this was defined as at least 24 hours of intravenous heparin that was not discontinued earlier than 24 hours before surgery. Patients were followed-up for 24 hours after surgery to obtain clinical parameters of bleeding complications, including chest tube output, transfusion requirements, hematocrit, and platelet count. The use of human subjects was approved by the Institutional Review Board of the College of Physicians and Surgeons and the Presbyterian Hospital.

Blood analysis
We performed ACTs using celite tubes and the Hemochron system (International Technodyne, Edison, NJ). TAT and F1 + 2 levels were determined by commercially available enzyme-linked immunosorbent assay (ELISA) kits (Behring Diagnostics GmbH, Marburg, Germany). AT activity levels were determined using an STA Hemostasis Testing System (Diagnostica Stago, Asnieres, France). All protamine doses were determined using a Hepcon system (Medtronic, Minneapolis, MN).

Statistics
Statistical relevance was determined using Student’s t test or Fischer’s exact test where appropriate using either Microsoft Excel (Microsoft Corporation, Redmond, WA) or InStat (GraphPad Software, San Diego, CA) for the Macintosh (Apple Computer, Cupertino, CA). A p value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Population
As seen in Table 1 both groups represented similar populations, without any baseline differences. Table 2 lists the types of procedures performed in each group. In the time period of the study there were 2270 cases on adults requiring cardiopulmonary bypass and 85 (3.7%) of them were found to be heparin resistant.


View this table:
[in this window]
[in a new window]
  		Table 1. Study Population Characteristics

 

View this table:
[in this window]
[in a new window]
  		Table 2. Operative Procedure

 
Intraoperative
The intraoperative data are listed in Table 3. The bypass and cross-clamp times were similar. There was a significantly higher total amount of heparin utilized in the additional heparin group. This group also had a higher postprotamine ACT despite similar protamine doses. Of the 44 patients in the AT group, 2 (5%) did not obtain an adequate ACT after receiving AT and both successfully crossed to the heparin group. Thirteen of the 41 heparin patients (32%) did not develop an adequate ACT after receiving 800 U/kg of heparin. All of these patients crossed over successfully to the AT group. This represented significantly more failures in the heparin group (p = 0.001). On average, the AT group had significantly fewer dosing cycles than the heparin group before an adequate ACT was obtained (1.09 versus 1.95, p < 0.001) and, perhaps more importantly, had a smaller range (1 to 2 versus 1 to 4).


View this table:
[in this window]
[in a new window]
  		Table 3. Introperative Data

 
Postoperative
There was no difference in any of the parameters related to bleeding after surgery among the two groups (Table 4). There were no deaths in either group within the 24-hour follow-up of the study. There were no adverse events that could be directly related to either administration of AT or additional heparin in any patient.


View this table:
[in this window]
[in a new window]
  		Table 4. Blood Loss and Transfusions

 
Blood analysis
Analysis of TAT and F1 + 2 data were complicated by the large number of patients started on bypass before adequate anticoagulation was obtained and the high cross-over rate between the groups. Analysis of those patients who obtained an adequate ACT before initiating bypass and without cross-over revealed no difference between the two groups at any time point with regards to TAT or F1 + 2.

Analysis of AT activity revealed that 77% of the 61 patients measured were AT deficient at baseline (normal range, 70% to 120%). Patients receiving AT (including cross-over patients) demonstrated a significantly higher AT level at the 30-minute and terminating bypass time points, compared to those who did not (Fig 1).



View larger version (17K):
[in this window]
[in a new window]
  		Fig 1. Antithrombin (AT) activity at baseline, 30 minutes after commencing cardiopulmonary bypass (CPB), and at termination of CPB. Both groups had similarly deficient AT activity at baseline but there was a significant rise in activity in the AT concentrate group at the two later time points (p = 0.007 and p = 0.009). (AT = antithrombin; CPB = cardiopulmonary bypass; * denotes statistical significance.)

 
Analysis of patients obtaining therapeutic ACT before bypass
Although the number of patients (n = 35) in this study who had cardiopulmonary bypass initiated before obtaining a fully adequate ACT may impact our results, the short period of time on cardiopulmonary bypass before an adequate ACT and the absence of any patient with an ACT less than 300 seconds make this unlikely. Nonetheless, a subanalysis of the population enrolled before initiating bypass was undertaken to determine if a difference existed. The results are summarized in Table 5. In short, the differences between the two groups in this population were similar to the analysis of the entire cohort. More dosing cycles were also required in the heparin group in this subanalysis.


View this table:
[in this window]
[in a new window]
  		Table 5. Patients Enrolled Before Initiation of CPB

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Anecdotally, the occurrence of heparin resistance appears to be increasing. Current management of heparin resistance includes administering additional heparin, changing from porcine to beef heparin, and transfusing FFP. Heparin resistance is usually explained by decreased AT levels [2–4]. AT is a serine protease inhibitor that acts as a relatively weak anticoagulant on its own; however, when bound to heparin a conformational change occurs that results in a 300-fold increase in affinity for the clotting factors it inhibits, primarily factor Xa but also thrombin, factor IXA, and factor XIa [5].

Antithrombin deficiency as a congenital disorder occurs in only 1 of 3,000 people; however, several additional factors may also lead to acquired AT deficiency including decreased synthesis from liver failure or malnutrition, increased loss of AT from nephrotic syndrome, consumption, or iatrogenic causes [6]. In the cardiac surgery setting the most relevant and common iatrogenic cause is heparin therapy. Administration of heparin will decrease the circulating half-life of AT [7] and is likely the explanation for the higher incidence of heparin resistance in patients previously treated with heparin [8–12]. Other possible culprits include nitroglycerin and oral estrogen [6, 13].

The beneficial effect of FFP in treating heparin resistance is likely explained by its AT content and has prompted use of purified AT concentrate in patients with heparin resistance who required cardiopulmonary bypass [3, 4]. AT has also been used in bypass patients as a method to control and preserve the hemostatic system during bypass outside of the setting of heparin resistance, although this has not been performed on a large scale and strong evidence does not exist regarding its effectiveness [2, 14].

The most significant finding with this study is the high failure rate in the heparin group (32%) compared to the AT group (5%). In all of the heparin failures, administering AT concentrate successfully elevated the ACT to a therapeutic range. Previously at our institution these patients would have received FFP as treatment. The use of FFP, though not studied in this trial, has several disadvantages. First, at our institution, a minimum of 20 minutes is required before the product is available in the room. The AT concentrate is available immediately. Second, FFP carries a risk of viral transmission and allergic reactions. In terms of the AT concentrate, there have been no reports that have confirmed transmission of any virus in clinical studies or during postmarketing surveillance. However, as with any plasma-derived product, one should still maintain caution, as transmission of viral or other pathogenic molecules remains a possibility. Finally, FFP represents a substantial volume load that can be dangerous, especially in patients with congestive heart failure. AT concentrate is only 20 mL.

In this study we have demonstrated advantages of using AT concentrate versus additional heparin in treating heparin resistance. Acquired AT deficiency is a common occurrence among patients with heparin resistance, and a correlation exists between preoperative heparin therapy and the development of heparin resistance. Because the design of this study only evaluated patients with heparin resistance, we are uncertain what percentage of our patients are normally taking preoperative heparin therapy, but we suspect that the 74% receiving this therapy in the study cohort is higher than that of the general population.

The effectiveness of AT was clearly demonstrated by the increased AT activity levels in our patients, accompanied by a resulting appropriate rise in the ACT. This also illustrates that perhaps we are treating a relative heparin insensitivity, as evidenced by a poor ACT response rather than a true heparin resistance. Because these patients are generally AT deficient, they have an altered heparin response curve, which can be restored to normal by repleting their AT.

We were unable to demonstrate an advantage in terms of thrombotic markers, as evidenced by no difference in TAT or F1 + 2 generation; however, these results were skewed by patients entering the trial after cardiopulmonary bypass was initiated and a high cross-over rate between the two groups. In our study we were unable to demonstrate a clinical advantage between any of the groups though follow-up was only for 24 hours. At the doses of AT we used it is unlikely to effect a positive benefit on the hemostatic system outside of its reversal of heparin resistance.

The advantages of a rapid ACT elevation after AT administration must not be overlooked. Potential thrombotic consequences associated with inadequate anticoagulation during cardiopulmonary bypass are avoided, particularly in unstable clinical scenarios mandating emergency cardiopulmonary bypass. Furthermore, additional heparin does not address the underlying problem in AT-deficient patients. Finally, by lowering the total heparin dose one can avoid the theoretical complications of heparin rebound as, over time, heparin becomes unbound from other circulating proteins [15]. This is suggested by a higher postprotamine ACT in the heparin group.

Finally, there is potentially a cost benefit of using AT in appropriately selected patients. Although AT concentrate costs approximately $860/1000 U compared to $144 for 2 units of fresh frozen plasma, the time saved may result in a shorter operating room time. The patients who received additional heparin required almost twice as many dosing cycles as those in the AT group, representing a minimum of 12 minutes of operating room time. In the patients who normally would have required FFP, an additional 20-minute wait was avoided. Thus, in a patient who had one additional dose of heparin and then required FFP followed by a repeat ACT, a minimum wait time of 40 minutes exists. The hospital cost of $1200 for the operating room does not reflect the time lost by the anesthesiologists, perfusionists, nurses, and surgeons. Obviously, this cost is a theoretical advantage and the AT concentrate does represent a real and not insignificant cost to the hospital.

Our dose of 1000 U of AT was derived from past experience and by examining the literature. Most patients responded sufficiently to this dose with a rise in AT activity, even though the rise was not to a normal value. This implies that only small amounts of AT need to be supplemented to achieve this effect. This contrasts to the high doses that are required in other clinical scenarios, including disseminated intravascular coagulation and maintenance of the hemostatic system during bypass. Supplementation of 500 U of AT may have been sufficient in our study, thus reducing the cost of the intervention, though this was not determined.

In conclusion, this study demonstrates that acquired AT deficiency is likely the primary cause of heparin resistance in patients requiring cardiopulmonary bypass. This condition can be managed effectively, safely, and efficiently by administering AT concentrate. It is faster than using only additional heparin and may avoid the use of FFP. No postoperative benefit was identified although an intraoperative time advantage exists. We recommend use of AT concentrate in any heparin-resistant patient and have made it our standard of care.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This research was funded by a grant from Bayer Pharmaceuticals-Biologics Division. Doctor Matthew R. Williams is supported by National Institutes of Health Training Grant T32-HL07343.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Staples M.H., Dunton R.F., Karlson K.J., Leonardi H.K., Berger R.L. Heparin resistance after preoperative heparin therapy or intraaortic balloon pumping. Ann Thorac Surg 1994;57:1211-1216.[Abstract]
  2. Despotis G.J., Levine V., Joist J.H., Joiner-Maier D., Spitznagel E. Antithrombin III during cardiac surgery. Anesth Analg 1997;85:498-506.[Abstract]
  3. Van Norman G.A., Gernsheimer T., Chandler W.L., Cochran R.P., Spiess B.D. Indicators of fibrinolysis during cardiopulmonary bypass after exogenous antithrombin-III administration for acquired antithrombin III deficiency. J Cardiothorac Vasc Anesth 1997;11:760-763.[Medline]
  4. Irani M.S. Antithrombin concentrates in heparin-resistant cardiopulmonary bypass patients. Clin Appl Thrombosis/Hemostasis 1996;2:103-106.
  5. Jin L., Abrahams J.P., Skinner R., Petitou M., Pike R.N., Carrell R.W. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci 1997;94:14683-14688.[Abstract/Free Full Text]
  6. Bucur S.Z., Levy J.H., Despotis G.J., Spiess B.D., Hillyer C.D. Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion 1998;38:481-498.[Medline]
  7. DeSwart C.A.M., Nijmeyer B., Andersson L.O., Holmer E., Sixma J.J., Bouma B.N. Elimination of intravenously administered radiolabeled antithrombin III and heparin in humans. Thromb Haemostas 1984;52:66-70.[Medline]
  8. Cloyd G.M., D’Ambra M.N., Akins C.W. Diminished anticoagulant response to heparin in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 1987;94:535-538.[Abstract]
  9. Esposito R.A., Culliford A.T., Colvin S.B., Thomas S.J., Lackner H., Spencer F.C. Heparin resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;85:346-353.[Medline]
  10. Lidon R.M., Theroux P., Robitalille D. Antithrombin-III. Plasma activity during and after prolonged use of heparin in unstable angina. Thrombosis Res 1993;72:23-32.[Medline]
  11. Marciniak E., Gockerman J.P. Heparin-induced decrease in circulation antithrombin-III. Lancet 1977;2:581-584.[Medline]
  12. Dietrich W., Spannagl M., Schramm W., Vogt W., Barankay A., Richter J.A. The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;102:505-514.[Abstract]
  13. Becker R.C., Corrao J.M., Bovill E.G., et al. Intravenous nitroglycerin-induced heparin resistance. Am Heart J 1990;119:1254-1261.[Medline]
  14. Hashimoto K., Yamagishi M., Sasaki T., Nakano M., Kurosawa H. Heparin and antithrombin III levels during cardiopulmonary bypass. Ann Thorac Surg 1994;58:799-805.[Abstract]
  15. Teoh K.H.T., Young E., Bradley C.A., Hirsh J. Heparin binding proteins. Circulation 1993;88:420-425.
Accepted for publication March 21, 2000.




This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
B. D. Spiess
Treating heparin resistance with antithrombin or fresh frozen plasma.
Ann. Thorac. Surg., June 1, 2008; 85(6): 2153 - 2160.
[Abstract] [Full Text] [PDF]

Home page
 Canadian J. AnesthesiaHome page
S. Bar-Yosef, H. B. Cozart, B. Phillips-Bute, J. P. Mathew, and H. P. Grocott
Preoperative low molecular weight heparin reduces heparin responsiveness during cardiac surgery: [L'heparine de bas poids moleculaire en preoperatoire reduit la reponse a l'heparine pendant la chirurgie cardiaque]
Can J Anesth, February 1, 2007; 54(2): 107 - 113.
[Abstract] [Full Text] [PDF]

Home page
 Canadian J. AnesthesiaHome page
A. Vincentelli, B. Jude, and S. Belisle
Antithrombotic therapy in cardiac surgery: [Traitement antithrombotique en chirurgie cardiaque].
Can J Anesth, June 1, 2006; 53(6_suppl): S89 - S102.
[Abstract] [Full Text] [PDF]

Home page
 Journal of Pharmacy PracticeHome page
A. K. Wittkowsky
Anticoagulation in Hypercoagulable Conditions: Special Considerations in the Treatment and Prevention of Venous Thromboembolism
Journal of Pharmacy Practice, October 1, 2004; 17(5): 308 - 316.
[Abstract] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
J. H. Lemmer Jr and G. J. Despotis
Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery
J. Thorac. Cardiovasc. Surg., February 1, 2002; 123(2): 213 - 217.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Talia B. Spanier
Mehmet C. Oz
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Williams, M. R.
Right arrow Articles by Oz, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Williams, M. R.
Right arrow Articles by Oz, M. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS