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Ann Thorac Surg 2007;83:72-76
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Impact of Heparin-Induced Thrombocytopenia on Outcome in Patients with Ventricular Assist Device Support: Single-Institution Experience in 358 Consecutive Patients

^a Department of Anesthesia, Deutsches Herzzentrum Berlin, Germany
^b Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Germany
^c Institute of Transfusion Medicine, Charité, Berlin, Germany
^d Baylor College of Medicine, Houston, Texas

Accepted for publication May 18, 2006.

^_* Address correspondence to Dr Koster, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany (Email: koster{at}dhzb.de).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: Cardiac surgical patients are at an approximate 1% to 2% risk of experiencing heparin-induced thrombocytopenia (HIT), a severe immune-mediated disease that is associated with thromboembolic events. We assessed the occurrence of this disease and its influence on clinical outcome in patients after implantation of a ventricular assist device (VAD).

METHODS: This retrospective analysis assessed data from our adult patient VAD program between the years 2000 and 2005. Patients were divided into three groups: those without confirmed HIT (_nonHIT), those in whom the diagnosis of HIT was made before VAD implantation (HIT_pre), and those who experienced HIT after VAD implantation (HIT_post). End points assessed were procedural success, as defined by discharge from hospital or transplantation or recovery of the failing heart, as opposed to death before procedural success was achieved.

RESULTS: The data of 358 consecutive patients were analyzed. There were 330 _nonHIT patients (91.6%), 15 HIT_pre patients (4.5%), and 13 HIT_post patients (3.9%). Procedural success was observed in 50% of _nonHIT patients, 67% of HIT_pre patients, and 31% of HIT_post patients.

CONCLUSIONS: Heparin-induced thrombocytopenia is a frequent complication in VAD patients and is associated with detrimental outcome when occurring after implantation. Preoperative diagnosis of HIT and the implementation of alternative anticoagulation procedures appears to be associated with better results. Early detection of HIT antibodies before or shortly after VAD implantation and immediate implementation of an alternative anticoagulation regimen may be a strategy to improve outcome.

	Introduction

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Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated disease that is frequently associated with thromboembolic complications and, particularly if diagnosed after cardiac surgery, with detrimental clinical outcome [1, 2]. In patients with HIT, antibodies directed against the complex of heparin and (predominately) platelet-factor 4 are generated. These antigen–antibody complexes and immunglobulin G bind to the platelet Fc receptor, causing platelet activation. Besides release of platelet-factor 4, activated platelets release microparticles providing a surface for the activation of thrombin. As thrombin itself is among the strongest activators of platelets, a powerful self-boosted prothrombotic cascade is initiated, which may finally result in consumption of platelets with subsequent thrombocytopenia, thromboembolism, and fatal outcome [1]. Although early and late onset of HIT during heparin anticoagulation has been described, HIT usually develops between days 5 and 10 of heparin therapy, particularly when unfractionated heparins are used [1].

The medical history of patients on ventricular assist device (VAD) support often reveals repeated episodes of prolonged heparin anticoagulation before surgery and after VAD implantation. Therefore, it is conceivable that this patient population is at an increased risk to experience HIT. The current investigation was conducted to assess the incidence of HIT and its implications for clinical outcome in patients on VADs.

	Patients and Methods

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The study was conducted after approval by the ethics committee. Written informed consent to publish relevant clinical data was obtained from patients before implantation of the VAD.

The source for the analysis was the database of VAD patients at the Deutsches Herzzentrum Berlin [3]. Included in this retrospective analysis were all adult patients who underwent VAD implantation between January 2000 and October 2005.

Patients were divided into three groups: patients without confirmed HIT (_nonHIT), patients in whom the diagnosis of HIT was made before VAD implantation (HIT_pre), and patients who had HIT after VAD implantation (HIT_post).

Criteria for the Diagnosis of Heparin-Induced Thrombocytopenia
The HIT assessment protocol was initiated in January 2000 at our institution (Table 1). In all patients platelet count was measured twice a day. Initial testing for HIT antibodies was performed with the particle gel immune assay (DiaMed AG, Cressier sur Morat, Switzerland), a test that reveals reliable results within 20 minutes and, similar to the enzyme-linked immune sorbent assay methods, detects antibodies against heparin–platelet-factor 4 complexes. The trigger for performance of the assay preoperatively was a platelet count of less than 150,000/µL or a decrease of more than 50% from the baseline value. After implantation of the VAD, HIT testing was performed when postoperative platelet counts remained less than 100,000/µL on postoperative day 2 or decreased by more than 50%. Tests were evaluated as positive when direct determination of heparin–platelet-factor 4 antibodies gave a 3* or 4* strong positive result [4]. If the result was questionable a heparin-induced platelet aggregation assay (HIPAA) was performed. An HIPAA was also performed in patients evaluated as HIT positive with the particle gel immune assay if the platelet count did not increase within 2 days after the change to alternative anticoagulation, which as standard was performed with intravenous infusion of lepirudin (Refludan, Pharmion Germany). An HIPAA was evaluated as HIT positive when three of four channels showed a clearly positive reaction. An HIPAA was also performed in patients who had a negative result in the particle gel immune assay but who were clinically strongly suspected for HIT to rule out HIT owing to less typical antigens than platelet factor 4, such as interleukin 6 or neutrophil-activating peptide. The HIPAA was performed by an experienced laboratory and as described previously [5].

Anticoagulation in Patients With Heparin-Induced Thrombocytopenia
Preoperative and postoperative anticoagulation
In patients diagnosed with HIT before surgery, preoperative anticoagulation was performed with intravenous administration of lepirudin to a target activated partial thromboplastin time value of 40 to 60 seconds.

In patients diagnosed with HIT after the implantation of the VAD, anticoagulation was performed with lepirudin (target activated partial thromboplastin time, 40 to 80 seconds) as long as intravenous anticoagulation was necessary. Additionally, coumadine, aspirin, dipyridamole, and clopidogrel were given depending on the results of thrombelastography and platelet aggregometry, as described before [6].

Intraoperative anticoagulation
In 6 patients who were diagnosed with HIT before biventricular assist device implantation, anticoagulation during cardiopulmonary bypass was performed with unfractionated heparin and the short-acting platelet glycoprotein IIb/IIIa inhibitor tirofiban (Aggrastat, Merck Sharpe & Dhome, Haar, Germany) as described before [7]. In these patients, who predominantly underwent emergency surgery, tirofiban was used as it does not cause vasodilatation. Because of the impaired renal function of these patients, enhanced elimination of the high tirofiban levels with modified ultrafiltration was performed after cardiopulmonary bypass. In 9 HIT patients with coexisting severe pulmonary hypertension scheduled for left VAD implantation, anticoagulation during cardiopulmonary bypass was performed with heparin and the short-acting prostaglandin iloprost (Ilomedin, Schering, Berlin, Germany) to inhibit HIT-induced platelet activation and to reduce pulmonary artery resistance [8]. In these patients the infusion was slowly increased to 15 ng · kg^–1 · min^–1 before heparinization and was continued at this dose until arrival in the intensive care unit. Then the infusion rate was decreased to 0.5 to 2 ng · kg^–1 · min^–1, dependent on pulmonary artery pressures, until the patients were weaned from mechanical ventilation.

In all patients intravenous anticoagulation with lepirudin was started (activated partial thromboplastin time, 40 to 60 seconds) immediately after transfer to the intensive care unit, and no signs of increased postoperative hemorrhage were observed.

End Points
The two end points assessed were procedural success and death before achievement of procedural success. The VAD implantation was considered to be successful when one or more of the following occurred: discharge from hospital, transplantation, or weaning from mechanical support after recovery of the failing heart.

Statistical Analysis
Data are presented as mean values ± standard deviation. Data analysis was performed with Pearson’s chi-square test. A probability value of less than 0.05 was determined as significant. For the calculations the Statistical Package for Social Science (SPSS) 10.0. for Windows (SPSS Inc, Chicago, IL) was used.

	Results

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Data of 358 patients were analyzed (Table 2). Details of the diagnosis of HIT are outlined in Table 2. In brief, in 11 of the 15 HIT_pre patients diagnosis of HIT was made at our institution in the preoperative period. In 4 patients the diagnosis of HIT was made preoperatively in external hospitals. Ten of the 15 HIT_pre patients were diagnosed as having HIT antibodies at the time of surgery. In the 13 HIT_post patients, platelet counts recovered to values of greater than 100,000/µL postoperatively in 11 patients and decreased typically between days 5 and 11 of heparin therapy. In the remaining 2 patients the postoperative platelet count remained less than values of 50.000/µL. However, in these 2 patients anticoagulation with unfractionated heparin had already been initiated 3 and 6 days before surgery (Table 2).

In all groups the incidence of implantations under emergency conditions as a result of postcardiotomy heart failure or severe catecholamine refractory low cardiac output with beginning multiorgan failure was comparable. The overall percentage of emergency procedures, approximately 40%, was high.

Postoperative diagnosis of HIT was associated with an almost significant decrease of procedural success rate (31%) in comparison with that of HIT_pre patients (67%). A trend toward improved success rate was observed when HIT_pre patients were compared with the _nonHIT patients (50%). Of the _nonHIT patients, 50% died before success was achieved compared with 33% of HIT_pre patients and 69% of HIT_post patients (Table 3).

	Comment

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Our data show that HIT is a frequent complication in patients on mechanical circulatory support, and, if diagnosed after VAD implantation, it is associated with detrimental clinical outcome.

Schenk and coworkers [9] observed HIT in 8 of 40 (20%) patients after implantation of a VAD compared with an incidence of 8.4% in our patients. Notably, in our investigation, among the female patients 20% experienced HIT. These figures are significantly higher than the reported incidence of 1% to 2% of clinically manifested HIT in patients after cardiac surgery [1, 2]. In some of the implanted devices, such as the Berlin Heart Excor and Incor and the MicroMed DeBakey LVAD, heparin coating by the Carmeda process (Carmeda, Lund, Sweden) is used in an attempt to reduce the thrombogenicity of the nonendothelial inner surface. In a previous investigation we demonstrated that heparin coating of the VAD does not enhance generation of HIT antibodies and therefore can be ruled out as an underlying mechanism for the increased incidence of HIT [10]. As HIT usually occurs after 5 to 10 days of heparin therapy, it is conceivable that the repeated episodes of prolonged heparin therapy before and after implantation of the VAD are responsible for the increased incidence.

In the 8 patients diagnosed with HIT, Schenk and associates [9] reported five major thromboembolic events (62%), which in 3 patients directly caused death and in 2 patients seriously complicated the clinical course. In our patients, there was a significant increase in the incidence of major thromboembolic events in patients diagnosed with HIT after VAD implantation compared with the other two groups, although in comparison with the data published by Schenk and colleagues [9], the overall incidence of major thromboembolic events was low. The clinical outcome, however, was detrimental when HIT developed after the procedure. In these patients only 30% achieved procedural success, whereas the remaining patients died relatively early after implantation of the device. The observation that postoperative development of HIT was associated with detrimental outcomes corresponds to previous observations showing that surgical trauma apparently results in a more frequent and stronger HIT reaction than nonsurgical scenarios [11]. The fact that not major thromboembolic complications but multiorgan failure was the predominant cause of death is in line with the results of the study published by Walls and colleagues [2] in 1990, which still represents the only large clinical investigation assessing incidence and clinical outcomes of HIT patients after cardiac surgery.

In contrast, there was a notable trend toward a higher procedural success rate in the patients diagnosed with HIT before the procedure than in the non-HIT patients. A recent meta-analysis revealed a significant improvement of outcome when bivalent direct thrombin inhibitors were used as a replacement for unfractionated heparin during percutaneous intervention [12]. Our data suggest that the prolonged use of a direct thrombin inhibitor may be an interesting alternative to heparins for long-term anticoagulation in VAD patients.

There are limitations of this investigation that clearly have to be outlined: apart from its retrospective character and, for an outcome analysis, relatively small numbers of patients in the HIT subgroups, the main limitation is the large variation of the clinical conditions of the patients in whom VADs were implanted. Although in most cases implantation took place under planned conditions as a bridge to heart transplantation or as destination therapy in elderly patients not scheduled for transplantation, because of the character of our institution as a supraregional cardiac surgery emergency center, there was a relatively high percentage of patients receiving the mechanical support under emergency conditions with beginning or apparent multiorgan failure. This clearly has major impact on clinical outcomes and provides an explanation for the comparatively high mortality rate even in the non-HIT patients.

The diagnosis of HIT is based on a synoptic evaluation of clinical assessments and laboratory assays, which, however, present major differences in sensitivity and specificity. Therefore the diagnosis of HIT can always be questioned, particularly when patient populations are assessed that often have thrombocytopenia as a result of other medications or because of beginning organ failure. However, most patients showed a characteristic sudden decrease of the platelet count during days 5 to 14 of heparin therapy. Moreover, the first-line assay used in our investigation was demonstrated in a recent study to have specificity and sensitivity comparable to those of the gold standard of the functional HIPAA [12]. Nevertheless, samples were later reassessed with the functional assay to confirm diagnosis. Therefore, we believe that in the current investigation the diagnosis of HIT had a strong clinical and serologic fundament.

This is the largest investigation assessing the incidence and implications of HIT in patients on VAD support. Based on this set of data, we conclude that HIT is a relatively frequent complication in VAD patients, particularly in female patients. The development of HIT after implantation of a VAD is associated with negative outcome. Our data provide convincing evidence that diagnosis before the procedure and implementation of alternative anticoagulation protocols considerably improve results. The usual "trigger" for assessment of HIT is a sudden decrease of the platelet count or, particularly postoperatively, persistent thrombocytopenia. However, thrombocytopenia already signals consumption of platelets, possibly in micro or macro thromboembolic events. Reliable, quick, and inexpensive tests for direct measurement of HIT antibodies are available [4]. We believe that our data strongly support the suggestion of screening patients before and after implantation of a VAD during episodes of heparinization. If HIT antibodies are detected, alternative anticoagulation strategies should be preemptively used before a decrease of the platelet count or HIT-associated complications occur. Further controlled and adequately powered multicenter studies will show to what extent the implementation of such a protocol can improve outcome.13

	Acknowledgments

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We thank Anne Gale, Editor in the Life Sciences, for editorial assistance. The study was supported by the Deutsches Herzzentrum Berlin, Germany.

	References

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1. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in cardiac surgery Ann Thorac Surg 2003;76:2121-2131.[Abstract/Free Full Text]
2. Walls JT, Curtis JJ, Silver D, Boley TM. Heparin-induced thrombocytopenia in patients who undergo open heart surgery Surgery 1990;108:686-693.[Medline]
3. Huebler S, Potapov EV, Loebe M, et al. Development of a database of patients supported by ventricular assist devices ASAIO J 2003;49:340-344.[Medline]
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6. Koster A, Loebe M, Hansen R, et al. Alterations in coagulation after implantation of a pulsatile Novacor LVAD and the axial flow MicroMed Debakey LVAD Ann Thorac Surg 2000;70:533-537.[Abstract/Free Full Text]
7. Koster A, Meyer O, Fischer T, et al. One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia J Thorac Cardiovasc Surg 2001;122:1254-1255.[Free Full Text]
8. Antoniou T, Kapetanakis EI, Theodoraki K, et al. Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of ilprost Heart Surg Forum 2002;5:354-357.[Medline]
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