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Ann Thorac Surg 2007;84:841-846
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Heparin-Induced Thrombocytopenia in Left Ventricular Assist Device Bridge-to-Transplant Patients

^a Department of Surgery, Division of Cardiothoracic Surgery, Duke University Medical Center, Durham, North Carolina
^b Department of Anesthesiology, Division of Cardiac Anesthesia, Duke University Medical Center, Durham, North Carolina
^c Department of Medicine, Division of Hematology, Duke University Medical Center, Durham, North Carolina
^d Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina

Accepted for publication March 19, 2007.

^_* Address correspondence to Dr Milano, Box 3043, Department of Surgery, Duke University Medical Center, Durham, NC 27703 (Email: milan002{at}mc.duke.edu).

Presented at the Fifty-third Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 8–11, 2006.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
Background: The presence of heparin-induced thrombocytopenia (HIT) increases the risk for thromboembolic events in ventricular assist device (VAD) patients undergoing transplantation. However, cardiopulmonary bypass with alternative anticoagulants is often complicated by bleeding. Owing to this concern, we compared outcomes of HIT-positive versus control bridge-to-transplantation VAD patients; both groups were reexposed to heparin for cardiopulmonary bypass during transplant.

Methods: From February 2000 to January 2006, data were reviewed on 92 consecutive adult patients who underwent VAD placement as a bridge to transplantation. Patients in whom thrombocytopenia developed after heparin exposure were tested for HIT with an enzyme-linked immunosorbent assay for antiheparin/platelet factor-4 (HPF4) antibody (GTI Diagnostics, Waukesha, Wisconsin). During VAD support, heparin was avoided in HIT-positive patients, but all patients were reexposed to heparin during transplantation. Comparisons between HIT-positive and control patients for survival and freedom from thromboembolic events were determined using the Kaplan-Meier method and log-rank test. Continuous and categorical variables were compared using the Wilcoxon rank-sum and Student t test.

Results: Twenty-four of the 92 patients (26.1%) were determined to be HIT positive by enzyme-linked immunosorbent assay. Survival to transplant was not different between the two groups. When compared with control patients, HIT-positive patients who were reexposed to heparin had a greater decrease in platelet counts immediately after transplant (postoperative days 1 to 4, p < 0.05). Despite this transient thrombocytopenia, there was no difference in posttransplant mortality or thromboembolism.

Conclusions: Heparin-induced thrombocytopenia–positive VAD patients did not experience increased thromboembolism or mortality after heparin reexposure. In light of the risks of using heparin alternatives, heparin reexposure is a safe management strategy for HIT-positive VAD patients.

	Introduction

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Heparin-induced thrombocytopenia (HIT) represents a syndrome in which heparin exposure triggers a humoral immune response, resulting in platelet activation/aggregation, and hypercoagulability (increased thrombin generation), with the potential to cause thrombocytopenia and thrombosis. This syndrome is caused by platelet-activating antibodies that bind to the complex of platelet factor 4 (PF4) and heparin (HPF4) [1]. Clinical manifestations are highly variable, however, ranging from an asymptomatic thrombocytopenia to aggressive venous and arterial thrombosis. The cornerstones of treatment are heparin discontinuation and utilization of alternative anticoagulants such as direct thrombin inhibitors.

Applications of ventricular assist devices (VAD) are expanding and include bridge to ventricular recovery, bridge to transplantation, and destination therapy. Implantation and maintenance of patients on these devices often requires heparin anticoagulation therapy. A significant incidence of HIT during VAD support has been reported [2]. Heparin avoidance and substitution of alternative anticoagulants is feasible, but many of these patients require complex repeat cardiac surgical procedures including VAD removal, cardiac transplantation, or VAD replacement. These reoperations require cardiopulmonary bypass (CPB), conventionally with systemic heparinization, and are often complicated by coagulopathy and postoperative bleeding [3]. Reports have described the use of direct thrombin inhibitors for CPB and primary coronary revascularization surgery in patients with HIT [4]. However, utilization of heparin alternatives for complex, reoperative cardiac surgery with CPB (such as VAD removal and heart transplantation) has been limited owing to excessive bleeding, as these alternative agents are not reversible [5].

In this study, we examine a consecutive group of VAD patients who are bridged to transplantation at a single institution. A subset of the group are defined as having HIT, based on the development of thrombocytopenia after heparin exposure and elevated HPF4 antibody titers. These patients were managed with heparin avoidance during the VAD support period, but all were reexposed to heparin at the time of reoperation for cardiac transplantation. Overall survival, thrombotic events, and platelet counts are examined and compared between the two groups. The primary purpose of this study was to evaluate the safety of single heparin reexposure for transplant in HIT-positive VAD patients by reviewing our experience with this strategy.

	Patients and Methods

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Patient Selection
This study reviewed 92 consecutive patients who underwent VAD placement as bridge to transplantation at a single institution from February 2000 to January 2006. Preoperative risk factors for decreased survival after VAD implantation were collected on all patients and included urine output less than 30 cc/h, central venous pressure greater than 20 mm Hg, pre-VAD mechanical ventilation, intra-aortic balloon pump support, prothombin time greater than 16 s, and redo operation [6]. Postoperative outcomes after both the VAD procedure and the transplant procedure were also recorded and included platelet counts, thromboembolic events, and survival. Thromboembolic events were defined as ischemic cerebrovascular accident (CVA), pulmonary embolism, deep venous thrombosis (femoral, subclavian, or internal jugular), or acute arterial occlusion. These events were confirmed by brain or chest computed tomography, Doppler ultrasonography, or angiography, as appropriate. All data were reviewed after approval by the Institutional Review Board. The Institutional Review Board waived the need for consent in this retrospective study. No patients, families, or healthcare providers were contacted directly for this study. Furthermore, data were compiled, analyzed, and presented without patient identifiers.

HPF4 Antibody and Platelet Count Monitoring
Patients in whom clinically significant thrombocytopenia developed after heparin exposure were tested with an enzyme-linked immunosorbent assay (ELISA) for HPF4 antibodies (Genetic Testing Institute, Waukesha, Wisconsin). Other causes of thrombocytopenia, such as infection or adverse drug reactions were addressed before sending HPF4 assays. Patients were considered to be HPF4 positive if the HPF4 antibody ELISA was greater than 0.400 optical density (OD) units. The 92 study patients were divided into two groups: HIT positive (n = 24) and control (n = 68). The HIT-positive group was defined by clinically significant thrombocytopenia after heparin exposure, without other identifiable cause, and a positive HPF4 assay. In particular, neither thromboembolic complications nor a positive platelet function study were required for identification of HIT-positive patients. One of the 24 HIT-positive patients had a positive heparin-induced platelet aggregation study. The average platelet count for all HIT-positive patients at the time of diagnosis was 67, 220 ± 5,000/mL³. The average HPF4 count at the time of diagnosis was 1.46 ± 0.21 OD units. Notably, other centers may use HPF4 titer greater than 1.0 OD as defining a positive result. We did not use this upper limit because it reduces the sensitivity of the study. Nevertheless, 13 of the 24 HIT-positive patients had HPF4 antibody values greater than 1.0 OD.

Heparin-induced thrombocytopenia–positive patients were managed with heparin avoidance during the pretransplant, VAD support period. Many HIT-positive patients received treatment with direct thrombin inhibitors either as a primary therapy for HIT or as replacement anticoagulation for the VAD. Additionally, all HIT-positive patients were retested for HPF4 antibodies at varying intervals. In some cases, transplantation may have been delayed to allow for normalization of HPF4 titers. However, all patients (HIT positive and control) underwent CPB and transplantation using heparin. Platelet counts were monitored at least daily in all patients during the early posttransplantation period.

Statistical Analysis
Comparisons between HIT-positive and control patients for overall survival and freedom from thromboembolic events were determined using the Kaplan-Meier method and log-rank test. Continuous variables were compared using the Student t test and Wilcoxon rank-sum test when appropriate. Dichotomous variables were compared using the ² test, Fisher’s exact test, and row by column (R x C) contingency tables when indicated. A p value of 0.05 or less was considered statistically significant. All statistical analyses were performed using STATA Intercooled Version 9.0 software.

	Results

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
Of the 92 consecutive VAD patients studied, 24 (26%) were determined to be HIT positive; these patients experienced clinically significant thrombocytopenia after heparin exposure and were determined to be HPF4+ by ELISA. Because of clinical suspicion, 6 patients from the control group were tested for the presence of HPF4 antibodies, but were found to be negative. Demographic data are shown in Table 1. Age, sex, device types, incidence of acute myocardial infarction, and duration of VAD support were similar between the groups. The incidence of pre-VAD risk factors for adverse outcomes was not different between HIT-positive and control patients (Table 2).

View larger version (21K): [in this window] [in a new window]   Fig 1. Antiheparin/platelet factor-4 (HPF4) levels from the time of diagnosis to transplantation. The absolute change in HPF4 level from the time of diagnosis to transplantation is represented for each of the 17 ventricular assist device patients who were positive for heparin-induced thrombocytopenia. The average decline in HPF4 level is represented by the heavy line. The dashed line represents 0.4 optical density (OD) units, the upper limit of normal for the HPF4 enzyme-linked immunosorbent assay at our institution.

View larger version (17K): [in this window] [in a new window]   Fig 2. Percentage change in platelet counts after transplantation. Comparison of the percentage change in mean daily platelet counts from 1 day before transplantation (preTx) to 1 month after transplant (PostTx). Heparin-induced thrombocytopenia–positive ventricular assist device patients (squares) had significantly greater decreases in platelet counts postoperative day (POD) 1 through 4 compared with control (triangles).

View larger version (13K): [in this window] [in a new window]   Fig 3. Kaplan-Meier analysis of survival after transplantation. Patients positive for heparin-induced thrombocytopenia (HIT+ [solid line]) versus control (dashed line).

View larger version (15K): [in this window] [in a new window]   Fig 4. Kaplan-Meier analysis of thromboembolic-free survival after transplantation. Patients positive for heparin-induced thrombocytopenia (HIT+ [solid line]) versus control (dashed line).

	Comment

Top Abstract Introduction Patients and Methods Results Comment Discussion References

Single heparin reexposure for patients who carry a HIT diagnosis who require complex cardiac surgery with CPB has been previously described [9, 10]. As shown in this study, delaying the procedure and heparin reexposure, allows for reduction of the HPF4 titer, and thus may reduce the risks of the reexposure. Some of our patients received intraoperative plasmapheresis at the time of heparin reexposure to further remove antibody. Koster and colleagues [9, 10] also report successful heparin reexposure for HIT-positive patients requiring CPB and advocated simultaneous infusions of glycoprotein II_BIII_A inhibitors to prevent potential platelet aggregation. Some of our HIT-positive patients also received intraoperative prostaglandins, another treatment directed at prevention of platelet aggregation.

Several limitations of this report must be cited. This study is a retrospective analysis with a small number of patients, allowing for potential bias. The HIT positive group was defined by the presence of significant thrombocytopenia after a heparin exposure, in the absence of an alternative etiology, and by the presence of increased HPF4 antibody titers. This definition relied on clinical judgment and a high level of suspicion for HIT. It must be noted that only those with suspected HIT were tested for HPF4 antibodies. Thus, some "control" patients may have had significant HPF4 antibodies, but were not tested. Furthermore, the HPF4 ELISA is highly sensitive, but less specific; false positives may have been included or a less severe form of this condition may have been captured. Functional assays for heparin induced platelet activation and aggregation have also been described and are used to diagnose HIT. One such assay is the serotonin release assay in which the patient’s serum is examined for its ability to trigger platelet degranulation and serotonin release in the presence of heparin. Defining the HIT-positive subset with the serotonin release assay might have provided greater specificity or captured a more severe HIT subset. Unfortunately, the serotonin release assay is not readily available at our institution, and the HPF4 antibody titer remains the most common supplementary, diagnostic study to define the condition. It is unclear from this study if heparin reexposure would have been a safe strategy for a cohort defined by positive serotonin release assay.

Although all HIT-positive VAD patients had elevated HPF4 antibody titers, reexposure to heparin for transplantation occurred at variable intervals from the time of initial diagnosis. Therefore, HPF4 antibody titers of some HIT-positive VAD patients had returned to near normal levels at the time of heparin reexposure (see Fig 1). Furthermore, some HIT-positive VAD patients underwent serial HPF4 titers, and transplantation was purposefully delayed if titers remained high. The risk of heparin reexposure may be greater when HPF4 antibody titers are high; this study does not examine the risk of heparin reexposure early after the initial diagnosis when titers are high. Furthermore, as stated above, this group of HIT-positive VAD patients is heterogeneous in that alternative anticoagulants were utilized variably during parts of their clinical course. For example, some patients were maintained on direct thrombin inhibitors after the VAD implantation or transplantation.

Despite these limitations, this report provides valuable information regarding the management of HIT-positive VAD patients. Most of these patients can be maintained safely with direct thrombin inhibitors which should promote normalization of the platelet count and gradual reduction of HPF4 antibody titers. While heart transplantation and VAD removal have been described with heparin alternatives [5], the authors believe that this is a high-risk strategy for the following reasons. First, proper dosing and monitoring of heparin alternatives for CPB is poorly defined. The conventional activated clotting time measurement may not be sufficient for dosing direct thrombin inhibitors, such as bivalirudin [7]. Furthermore, metabolism of agents such as bivalarudin may be altered by hepatic and renal dysfunction commonly seen in heart failure patients [8]. Additionally, problematic bleeding can occur related to the inability to reverse these agents.

Our findings suggest that when patients return for VAD removal and transplantation, this can be conducted with a single heparin reexposure for CPB. While HIT-positive patients experience reduced posttransplant platelet counts, overall mortality and major thromboembolism are similar to the control group. Adjunctive treatments such as antiplatelet agents (aspirin, glycoprotein II_BIII_A inhibitors, or prostaglandin), preoperative or intraoperative plasmapheresis, or direct thrombin inhibitors during the postoperative period need to be investigated further, as these strategies may make heparin reexposure even safer [9, 10].

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
DR WILLIAM L. HOLMAN (Birmingham, AL): In this study, the mortality and incidence of thromboembolism for the HIT-positive and HIT-negative cardiac transplantation patients were similar, suggesting that heparin reexposure is still safe. Our group at UAB agrees that heparin reexposure is preferable to other anticoagulation regimens in this situation. This is partly due to the lack of well-validated protocols for alternative anticoagulants, and partly due to recent information regarding the HIT syndrome, which indeed suggests that this can be done safely.

Exposure to heparin for cardiac surgery causes an immune response in as many as 80% of patients if you measure everyone, even those who aren’t thrombocytopenic, but interestingly, HIT only occurs in 2% to 5% of these patients. These figures are based on the same ELISA used in the present study, which actually detects IgM, IgG, and IgA antiheparin antibodies. It is important to note that only a subgroup of the IgG antibodies actually can activate platelets, and these active antibodies are only detected by functional tests like the serotonin release assay.

Another important observation that was made in this paper is that antiheparin antibody titers become very low about 120 days after the last heparin exposure, suggesting that the safety of heparin redosing increases with the interval between exposures. Furthermore, there is no evidence of an anamnestic response to heparin with reexposure. Our approach is to serially test for antiheparin antibodies and to use plasmapheresis in HIT-positive patients. We are just starting to use the serotonin release assay as part of our decision making. I have the following questions for the Duke team.

First, will you use an assay that is significant for the IgG fraction of antiheparin antibodies or a functional assay like the serotonin release assay in your future decision-making? Second, did you define a level of antiheparin antibodies below which you considered it safe to reexpose patients to heparin, especially without pretransplant plasmapheresis? And finally, do you feel that there is a place for plasmapheresis in the routine management of the HIT-positive patients in this situation?

I would also like to acknowledge the contributions of Dr Marissa Marques in our group at UAB to our management of these patients, and I thank the Society for the opportunity of commenting on this paper.

DR SCHRODER: Thank you very much, Dr Holman. At this time we do only use an Ig ELISA as our test of choice. Your comments about the action of the subgroup of IgGs that activate platelets is correct, and the serotonin release assay is a more specific test for heparin-induced thrombocytopenia. Despite this, the serotonin release assay is not widely available, including at our own institution. I think if we did have this assay, we do not feel that it would significantly affect our management strategy for these patients. For instance, in a patient who is ELISA positive but serotonin release assay negative, we would still likely avoid repeated or long-term heparin administration to these patients, delay transplantation, and then still transplant with a single-dose heparin administration. For patients who are serotonin release assay positive, again, we would probably do the exact same thing. We would avoid heparin during VAD support, delay transplantation, and use adjunctive therapy such as plasmapheresis or platelet inhibitors.

Your question about do we have a specific level that we use to determine if it is safe, we do not. As the slide showed, the time from diagnosis to transplantation was widely variable, from 6 months to 2 weeks. Many of these patients went below our normal level, but there were patients whose HPF4 count went up. We of course would like to delay and see the HPF4 titer decrease, but that is not an absolute contraindication to transplantation.

And then your question about the role of plasmapheresis, many of these patients did receive plasmapheresis, some purely for their HIT positive status, others received it for a positive PRA. We do feel that this is a useful adjunctive strategy and may prove to be very important for these patients.

DR CLINTON E. BAISDEN (San Antonio, TX): I know it is risky business to assume anything, but I would assume that some of these patients got platelet transfusions after surgery, and as you showed, there was no real statistical difference between the platelet levels in the two groups. Was there any difference in platelet transfusions received by the patients in the two groups?

DR SCHRODER: Thank you very much for your question, Dr Baisden. If you correct for the units of fresh frozen platelets used during plasmapheresis, there was no difference in any type of blood products used.

	References

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 

1. Arepally GM, Ortel TL. Clinical practiceHeparin-induced thrombocytopenia. N Engl J Med 2006;24:809-817.
2. Schenk S, El-Banayosy A, Prohaska W, et al. Heparin-induced thrombocytopenia in patients receiving mechanical circulatory support J Thorac Cardiovasc Surg 2006;131:1373-1381.[Abstract/Free Full Text]
3. Goldstein DJ, Seldomridge JA, Chen JM, et al. Use of aprotinin in LVAD recipients reduces blood loss, blood use, and perioperative mortality Ann Thorac Surg 1995;59:1063-1067.[Abstract/Free Full Text]
4. Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study J Thorac Cardiovasc Surg 2006;131:686-692.[Abstract/Free Full Text]
5. Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor, and its reversal with modified ultrafiltration during heart transplantation in a patient with heparin-induced thrombocytopenia J Heart Lung Transplant 2005;24:222-225.[Medline]
6. Aaronson KD, Patel H, Pagani FD. Patient selection for left ventricular assist device therapy Ann Thorac Surg 2003;75(Suppl):29-35.
7. Cho L, Kottke-Marchant K, Lincoff AM, et al. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations Am J Cardiol 2003;91:1110-1113.[Medline]
8. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender Clin Pharmacol Therapeut 2002;71:433-439.[Medline]
9. Koster A, Meyer O, Fischer T, et al. One-year experience with platelet glycoprotein II_B/III_A antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II J Thorac Cardiovasc Surg 2001;122:1254-1255.[Free Full Text]
10. Koster A, Huebler S, Potapov E, et al. Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: single institution experience in 358 consecutive patients Ann Thorac Surg 2007;83:72-76.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mani A. Daneshmand Rebecca P. Petersen Andrew J. Lodge Carmelo A. Milano Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schroder, J. N. Articles by Milano, C. A. Search for Related Content PubMed PubMed Citation Articles by Schroder, J. N. Articles by Milano, C. A. Related Collections Transplantation - heart