HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Warkentin, T. E. Articles by Koster, A. Search for Related Content PubMed PubMed Citation Articles by Warkentin, T. E. Articles by Koster, A. Related Collections Mechanical Circulatory Assistance

---

Reviews

Heparin-Induced Thrombocytopenia in Patients with Ventricular Assist Devices: Are New Prevention Strategies Required?

^a Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
^b Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany
^c Department of Anesthesia, Deutsches Herzzentrum, Berlin, Germany

^_* Address correspondence to Dr Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, 237 Barton St E, Rm 1-180A, Hamilton, Ontario, L8L2X2, Canada (Email: twarken{at}mcmaster.ca).

Dr Warkentin discloses that he has a financial relationship with GTI Inc, GlaxoSmithKline, The Medicines Company, Organon Inc (part of Schering-Plough), and Sanofi-Aventis; Dr Greinacher with Organon Inc; and Dr Koster with The Medicines Company, Mitsubichi Pharma, and Organon Inc.

 

	Abstract

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antiplatelet factor 4/heparin antibodies. However, clinical HIT (thrombocytopenia or thrombosis, or both) develops in only a minority of patients who form antibodies. It is difficult to distinguish HIT from non-HIT thrombocytopenia in patients after ventricular assist device (VAD) implantation. Further, the risks of heparin-induced immunization and clinical HIT approach 65% and 10%, respectively, in this patient population, with a particularly high risk of cerebrovascular ischemia/infarction. Given the apparent high risk of HIT and its complications, and the diagnostic challenges, we suggest that the VAD patient population be evaluated using alternative, nonheparin agents for routine postimplantation anticoagulation.

Ventricular assist devices (VADs) are mechanical pumps intended to assist partially or completely the function of a failing heart. These devices can provide short-term support, such as after myocardial infarction or cardiac operations, or longer-term support in patients with chronic cardiac failure. Although VADs were primarily intended as a bridge to transplant, they also can be used as destination therapy. Some VADs preferentially assist the right ventricle or left ventricle, or even both, with device selection depending on such factors as the type of heart disease and the degree of pulmonary arterial resistance.

VADs expose blood to artificial surfaces, with areas of high shear stress predisposing to thrombosis due to combined activation of platelets and the clotting cascade. Thus, VAD usage requires anticoagulation therapy, generally in therapeutic doses. Unfractionated heparin (UFH) is most commonly used, for reasons of low cost, short half-life, rapid neutralization (with protamine), and well-established monitoring by activated clotting time or activated partial thromboplastin time (APTT). Despite anticoagulation, stroke remains the most common thrombotic event. Bleeding complications are also frequent. Other complications include infection and mechanical (device) failure.

Thrombocytopenia occurs frequently after VAD insertion. Although the absolute numbers of patients with thrombocytopenia depend on the device used and the definition of thrombocytopenia, nearly all patients experience a substantial decrease in the platelet count for several reasons. First, large platelet count falls universally accompany cardiac operations. Second, patients can have circulatory failure, and accompanying multiorgan system dysfunction, often with prominent thrombocytopenia and coagulopathy. Third, infection can result in thrombocytopenia. Fourth, heparin—particularly UFH—can cause immune-mediated thrombocytopenia, a condition named heparin-induced thrombocytopenia (HIT). Thus, the issue often arises whether the thrombocytopenia is caused by one of the aforementioned factors, or whether HIT has developed, a diagnosis that requires a change in the anticoagulant regimen.

The conceptual framework of HIT is that of a clinicopathologic syndrome in which (1) one or more clinical events (most often, thrombocytopenia with or without thrombosis) occur in a temporal relation to an immunizing heparin exposure, and in which (2) the presence of pathologic heparin-dependent platelet-activating antibodies that recognize complexes of platelet factor 4 (PF4)/heparin are detectable [1]. In most clinical settings, HIT can be readily distinguished from non-HIT disorders because the temporal relationship to the preceding heparin is evident, a competing non-HIT diagnosis is not prominent, and tests for HIT antibodies give unequivocally strongly positive results in both functional (platelet activation) or in antigen assays (PF4-dependent immunoassays).

However, this straightforward conceptual framework is problematic in the setting of VAD usage for several reasons. First, as already highlighted, thrombocytopenia occurs universally after cardiac procedures but can persist in VAD patients because of ongoing circulatory failure. Second, thrombocytopenia is not necessarily severe in patients with HIT, as 15% to 20% of patients have platelet count nadirs that exceed 100 x 10⁹/L. Third, thrombotic complications—an important sign of HIT [2, 3]—are not uncommon in the VAD patient population, particularly thrombotic strokes [4]. Fourth, anti-PF4/heparin antibodies—some with platelet-activating properties—are commonly observed in patients after cardiac operations who do not evince any other features of HIT [5–7]. Thus, it is no simple matter to distinguish HIT from non-HIT thrombocytopenia or thrombosis in this patient population.

The iceberg model (Fig 1) describes the interrelationship between formation of PF4/heparin-reactive antibodies and the risk that HIT will develop [8]. The model infers that only a subset of heparin-induced antibodies is pathogenic. After cardiac operations, patients (outside of VAD use) have high frequencies of anti-PF4/heparin antibodies (up to 50% to 75%) detected by commercial enzyme immunoassays (EIAs) [5–7]. These immunoassays detect not only the immunoglobulin (Ig) G class of platelet-activating antibodies but also (nonpathogenic) IgA and IgM antibodies. Interpretation of EIA results is improved by considering antibody reactivity levels; a weakly positive EIA result (0.40 to 1.00 U of optical density [OD]) makes a diagnosis of HIT very unlikely (risk 5%) [9].

View larger version (18K): [in this window] [in a new window]   Fig 1. Iceberg model of heparin-induced thrombocytopenia (HIT): applicability to ventricular assist device (VAD) patients. Upper panel, generic iceberg. The model illustrates that there is a greater sensitivity for detecting clinically irrelevant anti-platelet factor 4 (PF4)/heparin antibodies, as follows: (EIA-IgGAM) (commercial enzyme immunoassays that detect any of the three immunoglobulin (Ig) classes, IgG, IgA, or IgM) > particle gel immunoassay (PaGIA) > EIA-IgG > platelet-activation assay (HIPA or SRA). The tip of the iceberg is represented by clinical HIT, comprising isolated HIT (HIT) and HIT with associated thrombosis (HIT-T). The dashed bracket for PaGIA indicates that some antibodies detectable by the EIA-IgG give a false-negative result in the PaGIA. Genetic Testing Institute (GTI) and Stago indicate two different manufacturers of the EIA-IgGAM. Ortho and cardiac denotes orthopedic and cardiac surgery patients, respectively. Lower panel, four differing clinical situations, indicating that VAD patients have a particularly high frequency of both antibody formation and clinical HIT. (LMWH = low-molecular weight heparin; UFH = unfractionated heparin.)

As will be discussed, VAD patients are characterized by a high frequency of anti-PF4/heparin antibody formation as well as by a very high frequency of clinical HIT itself (Fig 1; lower panel).

	Superimposition of HIT With Non-HIT Thrombocytopenia

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Because thrombocytopenia is common in VAD patients, HIT can coincide with coexisting thrombocytopenia. Indeed, in a study of HIT complicating critically ill patients after cardiac operations, HIT produced superimposition of HIT-related thrombocytopenia on prevailing thrombocytopenia secondary to critical illness [10]. In contrast, a critically ill patient with early postoperative thrombocytopenia that persists beyond a week without further platelet count fall or development of thrombosis could simply have coincidental formation of clinically irrelevant antibodies [11].

	Risk Factors

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
The four established risk factors for HIT are duration of heparin therapy, type of heparin (UFH > low-molecular-weight heparin [LMWH] > fondaparinux), type of patient (postsurgical > medical > obstetric/pediatric), and patient sex (females > males) [2, 8, 12, 13]. A stoichiometrically optimal ratio of PF4 to heparin is required for immunization, and in most clinical situations, plasma heparin concentrations are higher than those required for optimal immunization risk [14]. As a consequence, settings of substantial PF4 release and associated with relatively low concentrations of heparin, such as postsurgical thromboprophylaxis, maximize immunization risk.

Cardiac operations are associated with the highest rates of anti-PF4/heparin antibody formation, presumably reflecting marked PF4 release/availability and variable UFH concentrations ranging from very high (during cardiopulmonary bypass [CPB]) to low (after protamine), thereby enhancing likelihood that stoichiometrically optimal PF4/UFH ratios are achieved at some point. Levels of PF4 and UFH probably continue to vary in the early postoperative period, providing more opportunities to achieve immunizing PF4/UFH ratios. Inflammation associated with the operation is also a risk factor stimulating the anti-PF4/heparin immune response [15].

In VAD patients, ongoing release of PF4 from activated platelets, together with prolonged exposure to a therapeutic dose of UFH to prevent circuit thrombosis, means that if PF4/heparin-reactive antibodies are formed, they can bind to many PF4/heparin complexes. This creates a situation with a high breakthrough risk of clinical HIT; thus, the risk is relatively high that clinical HIT will develop in the VAD patient (Fig 1).

	Anecdotal Reports of HIT Complicating VADs

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Adult Literature
The literature on HIT complicating VAD use in adults includes several case reports [16, 17, 18, 19, 20, 21] and one small series [22] comprising 8 reported patients. Minimal—if any—information on HIT antibody test results is provided, and so some cases might not represent "true" HIT.

Pediatric Literature
HIT is uncommon in children, and especially rare in neonates and infants [23]. Two reports of young children—a neonate [24] and a 13-month-old [25]—claimed HIT as the explanation for VAD-associated thrombocytopenia but did not report platelet-activating antibody status. Of note, the neonate presented with circuit thrombosis during argatroban anticoagulation and severe bleeding occurred in the infant during lepirudin use, drawing attention to problems resulting from the use of alternative anticoagulants in children due to a diagnosis of HIT, whether real or not.

	Epidemiology of PF4-Dependent Antibody Formation in VAD Patients: Initial Studies

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Systematic studies of anti-PF4/heparin antibody formation in the setting of VAD use began when Koster and colleagues [26] in Berlin reported 55 patients who received either UFH-coated or uncoated devices. The initial study was extended by an additional 45 patients, and their combined 100 VAD patient experience was reported in 2000 [27]. Blood obtained at (preoperative) baseline and at three postoperative time points was assessed for anti-PF4/heparin antibodies by commercial EIA.

Overall, PF4-dependent antibodies were detected at the preoperative baseline in about half of the patients, presumably reflecting preoperative UFH use. Postoperative antibody formation, and subsequent waning of antibody levels, was not influenced by whether or not the VADs were UFH-coated. Interestingly, thrombotic events (stroke, mesenteric infarction, pulmonary embolism, peripheral embolism) occurred in 22 of 63 EIA+ patients (35%) vs none of the EIA– patients (p < 0.0001), with no difference between UFH-coated and noncoated devices. In contrast, the frequency of recurrent pump thrombosis was not affected by antibody status.

	Epidemiology of HIT in VAD patients—HIT Incidence and Serosurveillance Studies

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Two different groups of investigators in Germany, from Berlin [28] and Bad Oeynhausen [29, 30], and a third group in the United States from Durham, North Carolina [31], evaluated the frequency of HIT in VAD patients. Only the German groups included a functional test for platelet-activating antibodies.

Berlin
Koster and colleagues [28] examined HIT incidence using a protocol commenced in January 2000 in which thrombocytopenia during the preoperative or postoperative period led to serologic investigations for HIT by the rapid assay, PaGIA. These workers retained PaGIA+ sera and thus could study later whether platelet-activating antibodies (by HIPA test) were present. All but 1 patient regarded by the investigators as having HIT were HIPA+.

In the preoperative period, 15 of 358 VAD patients (4.2%) were diagnosed with HIT, and ischemic stroke developed in 2 of these 15 patients (13%). Subsequent anticoagulation during VAD implantation was performed using UFH plus an antiplatelet agent, with 9 receiving iloprost and 6 receiving tirofiban, depending on pulmonary hypertension status (iloprost is a potent vasodilator). Procedural success did not differ between HIT and non-HIT patients.

This complication developed in the postoperative period in 13 of the remaining 343 patients (3.8%) without HIT at the time of VAD implantation. Of these 13 patients, ischemic strokes developed in 2 (15%), and only 4 (31%) survived, with multiorgan failure the predominant cause of death.

Bad Oeynhausen
Schenk and colleagues [29, 30] evaluated HIT frequency and associated antibody status in 115 VAD patients during a 2-year period. Testing for HIT was prompted by "otherwise unexplained thrombocytopenia and/or the occurrence of thromboembolism." In addition, plasma routinely collected on postoperative days 5 to 7 and stored at –80°C, was used to test for PF4-dependent antibodies by commercial EIA and the PaGIA. Samples testing positive were then evaluated for individual immunoglobulin (Ig) classes (IgG, IgA, IgM), as well as for platelet-activating properties by HIPA.

Of 113 VAD patients evaluated, 74 (65%) tested positive by EIA or PaGIA, or both. Of these antibody-positive patients, EIA-IgG and HIPA assay results were used to define three groups as follows: 12 were HIPA+/IgG+, 28 were HIPA–/IgG+, and 34 were HIPA–/IgG–. The first group was judged to have HIT, indicating that this diagnosis occurred in 12 of 113 VAD patients (10%).

Figure 2 compares the end point of freedom from thromboembolic events during mechanical support for these three patient groups. A significantly greater risk of thromboembolic events was seen in the HIPA+/IgG+ group. These findings support observations in non-VAD populations that only platelet-activating antibodies are associated with an increased risk of thromboembolic events [32]. Interestingly, no significant differences in platelet counts were found among these three patient groups, although a tendency for platelet counts to rebound to higher levels by 2 weeks after VAD implantation was seen in the HIPA+/IgG+ subgroup.

View larger version (14K): [in this window] [in a new window]   Fig 2. Freedom from thromboembolic events during mechanical circulatory support. HIPA+/IgG+, indicates positive (or indeterminate) heparin-induced platelet activation (HIPA) test plus positive enzyme immunoassay (EIA)-immunoglobulin (Ig) G; HIPA–/EIA+, indicates that the HIPA test was negative, and at least one of the three EIAs that detect IgG, IgA, or IgM antibodies was positive; HIT– = indicates negative testing in all assays. (Reprinted with permission from Schenk S et al [29].)

Duke University
Schroder and colleagues [31] reported their experience with HIT complicating VAD use as a bridge to transplantation in 92 consecutive patients evaluated during a 6-year period. Patients in whom "clinically significant thrombocytopenia developed after heparin exposure" were tested using a commercial EIA, with any positive result (>0.40 OD U) considered to indicate HIT.

Of 30 patients who underwent serologic investigation, 24 tested EIA+; thus, 24 of the 92 VAD patients (26%) met the study criteria for HIT. Although the EIA+ patients had a mean ODU value of 1.46, only 13 of the 24 EIA+ patients (54%) had values that exceeded 1.00 ODU, suggesting that many of the antibodies were unlikely to have been platelet-activating. Thus, the high frequency of HIT reported (26%) likely is an overestimate.

In keeping with a high frequency of overdiagnosis, no increase in thromboembolic events was seen in HIT patients: 4 of 24 HIT (17%) vs 16 of 68 non-HIT controls (24%). No thrombotic events were evident in the 7 HIT patients who died while on VAD support. Moreover, survival to transplantation was similar irrespective of HIT status: 17 of 24 (71%) vs 58 of 68 (85%; p = 0.14).

Although management of EIA+ patients included heparin avoidance, UFH anticoagulation was performed at the time of heart transplantation irrespective of EIA test status. Overall, 12 of 17 EIA+ patients who survived to transplantation had significant decrease in EIA OD values (Fig 3), an observation consistent with reported transience of PF4-dependent antibodies [33]. Although significantly lower platelet counts were observed in the early period after transplantation among the HIT patients (Fig 4A), survival after transplantation (Fig 4B) and thromboembolic-free survival (Fig 4C) did not differ from controls.

View larger version (22K): [in this window] [in a new window]   Fig 3. Antiplatelet factor 4 (PF4)/heparin antibody levels from the time of diagnosis of heparin-induced thrombocytopenia (HIT) to heart transplantation. The absolute change in antibody levels from diagnosis to transplantation is represented for each of 17 ventricular assist device (VAD) patients who tested positive for anti-PF4/heparin antibodies. The average decline in antibody levels is represented by the heavy line. The dashed line represents 0.40 optical density units (upper limit of normal for the enzyme immunoassay [EIA]). (Reprinted with permission from Schroder JN et al [31].)

View larger version (22K): [in this window] [in a new window]   Fig 4. (A) Percentage change in platelet counts after transplantation. Comparison of the percentage change in mean daily platelet counts from 1 day before transplant (preTx) to 1 month after transplant (postTx). Ventricular assist device (VAD) patients positive for heparin-induced thrombocytopenia (HIT+; squares) had significantly greater decreases in platelet counts on postoperative day (POD) 1 through 4 compared with controls (triangles). Data are presented with the standard deviation. (B) Kaplan-Meier analysis of survival after transplantation in patients positive for HIT (HIT+, solid line) vs controls (dashed line). (C) Kaplan-Meier analysis of thromboembolic-free survival after transplantation in patients positive for HIT (HIT+) [solid line] vs controls (dashed line). (Reprinted with permission from Schroder JN et al [31].)

	Thrombotic Events in VAD Patients With HIT

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

	Systematic Studies of HIT in VAD Patients: Main Findings

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Several key points emerge from the aforementioned studies. First, it is difficult to distinguish HIT from non-HIT thrombocytopenia using only PF4-dependent immunoassays. Second, notwithstanding the potential for overdiagnosis, the frequency of true HIT nonetheless appears to be high in the period after VAD implantation (Fig 1). Although HIT frequencies up to 5% have been reported in other postsurgical patient populations [34, 35], the Bad Oeynhausen VAD study found HIT was twice as frequent (10%) [29, 30]. Third, the VAD studies that used a platelet activation assay to define clinical HIT found a strong association between HIT and thromboembolism. Fourth, thrombotic stroke is especially common in VAD patients when HIT develops.

	Alternative Nonheparin Anticoagulants for HIT

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Anticoagulant management of patients after VAD implantation with a possible diagnosis of HIT is challenging because risks of thrombotic and hemorrhagic complications must be carefully balanced. This is especially difficult in the immediate postoperative period, when impaired hemostasis and alterations in organ function (influencing anticoagulant elimination) are common. A variety of alternative anticoagulants to UFH have been introduced in recent years, and their safety and efficacy profiles have been established in a variety of clinical settings. However, they have undergone limited assessment in VAD patients.

There are five nonheparin anticoagulants with a rational basis for treatment of HIT and for which evidence exists regarding efficacy [36]. These comprise three direct thrombin inhibitors (DTIs)—hirudin, argatroban, bivalirudin—and two indirect antithrombin-mediated factor Xa inhibitors—danaparoid and fondaparinux.

Unlike indirect inhibitors of thrombin, DTIs also inhibit clot-bound thrombin that accumulates on artificial surfaces. DTIs also differ from UFH in other important respects: whereas UFH elimination is largely organ-independent, hirudin is excreted renally, and argatroban undergoes hepatobiliary elimination. Accordingly, renal or hepatic dysfunction, or both—and the potential for DTI accumulation—is common in VAD patients. Bivalirudin is a hirudin analogue (hirulog) with only a minor renal and no hepatic excretory component; however, its predominant route of elimination is enzymic degradation, which predisposes to loss of anticoagulant effect in stagnant blood and could be an issue within parts of the VAD and within the impaired left ventricle.

A disadvantage of DTIs is that their anticoagulant level is usually judged by global clotting assays, such as the APTT. These only infer the level of anticoagulation, however, and may not correlate well with plasma DTI levels in patients with coagulopathy. Although assays exist to determine drug levels directly, these are not widely available. Also, short DTI half-lives could result in rapid loss of anticoagulant effect—with resulting risk of rebound thrombosis—if they are stopped abruptly.

Danaparoid (a mixture of anticoagulant glycosaminoglycans) differs from fondaparinux, the synthetic factor Xa inhibitor, by additionally inhibiting thrombin by both antithrombin and heparin cofactor II. Clot-bound thrombin is not inhibited. Use of danaparoid and fondaparinux for treatment and prevention of VAD-associated thrombosis remains largely unexplored.

	Preoperative and Postoperative Anticoagulation: Shorter-Acting Agents

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Rapid achievement of therapeutic dose anticoagulation, such as for treatment of acute HIT, generally requires use of an intravenous agent. Argatroban and lepirudin are DTIS that are approved for treatment of acute HIT, whereas bivalirudin is an off-label option in selected patients with multiorgan failure. All three are administered intravenously.

Lepirudin has a plasma half-life of 80 minutes. Drug accumulation and bleeding risk increase considerably in patients with renal impairment [37]. Even in the absence of renal dysfunction, current guidelines recommend initial dosing of approximately one-half that recommended by the manufacturer (0.05 to 0.10 mg/kg/h vs 0.15 mg/kg/h) [36]. Given the high frequency of renal impairment after VAD implantation, lepirudin is not an ideal option.

Argatroban has a plasma half-life of 40 to 50 minutes. This anticoagulant was used in 28 non-HIT patients after VAD implantation [38] in whom thrombotic and bleeding complications appeared comparable with standard UFH therapy. Unfortunately, no information regarding argatroban dosing was given. However, in patients after cardiac operations as well as those with multiorgan dysfunction, initial dosing should be reduced from 2 mcg/kg/min (per package insert) to much lower levels of about 0.5 mcg/kg/min [36, 39, 40]. Protocols exist for argatroban dosing in the setting of renal replacement therapy [41].

Although both lepirudin and argatroban can be monitored by the APTT, this assay loses linearity in the range of 60 seconds or more, and therefore monitoring by ecarin clotting time [42] or direct determination of drug levels is advised.

Bivalirudin is a further option. Its plasma half-life of 25 to 30 minutes is the shortest, and its route of elimination predominantly enzymic (cleavage by thrombin), thus its elimination is largely independent of special organ function [43]. This unique pharmacology renders bivalirudin an interesting option for anticoagulation of HIT patients during cardiac procedures and particularly in patients with renal and hepatic failure. The suggested starting dose is 0.25 mg/kg/h and should be titrated to target APTT values [44].

	Preoperative and Postoperative Anticoagulation: Long-Acting Agents

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Danaparoid and fondaparinux have relatively long half-lives of 25 and 17 hours for antifactor Xa effect, respectively. They also can be administered subcutaneously, and so (unlike DTIs) have greater potential for intermediate-term or long-term anticoagulation after VAD implantation, such as in postoperative patients who are leaving the intensive care unit and beginning to mobilize. Anticoagulant monitoring of danaparoid is performed using plasma antifactor Xa levels. For therapeutic dose anticoagulation, approximately 4800 U/24 h (about 200 U/h) are usually given, initially intravenously. In most settings, intravenous boluses are also given at treatment onset to achieve therapeutic levels quickly [36]. The initial maintenance infusion rate should be reduced by about 25% in severe renal impairment to about 150 U/h, with more frequent anticoagulant monitoring. Danaparoid is not currently available in the United States.

Fondaparinux, a pentasaccharide, is another alternative; however, few data exist for treatment of HIT, and no data are available for use in VAD patients. Further caution is warranted in renal dysfunction, because drug levels can accumulate, and little experience with anti-Xa monitoring exists. The dose of fondaparinux ranges from 2.5 to 7.5 mg/d, depending on whether antithrombotic prophylaxis or therapy is desired.

LMWH is not a therapeutic option in HIT [36].

	Anticoagulation During VAD Implantation

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Strategies for anticoagulation of HIT patients during cardiac procedures are outlined elsewhere [36, 44, 45]. However, because VAD implantation is usually associated with complex operations with increased risk for hemorrhage, we discuss anticoagulation strategies focusing on enhancing safety.

Antibody Status at Time of Operation
HIT antibodies usually become undetectable within several weeks after an episode of HIT [33]. In case of heparin reexposure, the generation of new antibodies—if they recur at all—takes at least 4 or 5 days. Therefore, in patients with a recent history of HIT, but with negative (or weakly-positive) antibodies, anticoagulation during VAD implantation can be safely performed with UFH. This strategy was successfully used in patients in whom HIT developed after VAD implantation and were bridged to heart transplantation using UFH as anticoagulant during CPB [31]. Successful outcomes using intraoperative UFH anticoagulation were also observed in EIA+ patients in whom platelet-activating antibodies were not detectable [46].

Patients with Platelet-Activating Antibodies at Time of Operation
An alternative anticoagulant approach should be used in patients who have detectable platelet-activating antibodies at the time of VAD implantation. Possible strategies include UFH administration together with an inhibitor of platelet activation/aggregation such as iloprost, epoprostenol, or tirofiban, or the use of a nonheparin agent. Current experience and theoretic considerations favor bivalirudin over other alternative agents.

Bivalirudin
Primarily for reasons of short half-life and elimination kinetics being largely independent of special organ function, bivalirudin is the only nonheparin agent that has been studied systematically in prospective trials of HIT and non-HIT patients in the setting of intraoperative anticoagulation for on-pump cardiac operations [47, 48]. Owing to its enzymic clearance, special considerations for surgical and perfusion practice, particularly the avoidance of stagnant blood flow within the CPB system, are crucial [44, 45, 47, 48]. This applies particularly for VAD implantation, because any stoppage of blood flow within the device or cannulas is associated with risk of local thrombus formation. Therefore, if in the extracorporeal devices the cannulas are implanted and circulation not immediately started, air should be removed with saline and the cannula clamped. In rotary blood pumps, blood flow may be best provided by slight loading of the beating ventricle after the implantation of the apical cannula so that the blood can be ejected through the outflow tract when the aortic connection is performed and aspirated by cardiotomy suction.

UFH plus antiplatelet therapy
The main advantage of combining UFH with a potent inhibitor of platelet activation/aggregation is that standard UFH dosing, monitoring, and protamine reversal are maintained, whereas the concomitant short-acting antiplatelet therapy attenuates HIT antibody-induced platelet activation. One option is a prostacyclin analogue such as iloprost or epoprostenol, which also decreases pulmonary artery resistance [49]. Interpatient variations in platelet inhibition and severe dose-dependent hypotension are drawbacks.

Another option is to inhibit platelet aggregation with the use of tirofiban, a short-acting platelet glycoprotein inhibitor [45]. However, tirofiban is predominantly eliminated by the kidneys, so renal failure increases bleeding risk as well as platelet transfusion refractoriness due to persistent tirofiban concentrations. Therefore, this strategy seems too risky for patients with preexisting renal failure. If renal failure occurs after VAD insertion, then tirofiban elimination can be enhanced using modified ultrafiltration [50].

	Is it Time to Use an Alternative Anticoagulant for Routine After VAD Anticoagulation?

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Given that thrombocytopenia or thrombosis, or both, are common in VAD patients for both HIT and non-HIT reasons, it is difficult to diagnose HIT on clinical grounds alone. Further, the available laboratory tests are better at ruling out, rather than ruling in, the diagnosis of HIT, and results are not usually available in real time. Both undertreatment in case of real HIT and overtreatment in case of clinically insignificant antibodies can cause severe complications.

Although UFH will remain the preferred intraoperative anticoagulant for use during VAD implantation in most patients, avoiding UFH postoperatively should largely negate the issue of HIT. Several current alternative anticoagulants appear suitable for this approach. For early postoperative anticoagulation, a DTI—with its relatively short half-life (selected with due consideration for coexisting renal or liver impairment)—would be appropriate. For example, Samuels and coworkers [38] used argatroban in 20 patients after VAD implantation and observed reduced bleeding complications compared with heparin (5% vs 20%), thus demonstrating an adequate safety profile of argatroban in this situation. In patients with simultaneously impaired renal and liver function, bivalirudin offers an even shorter half-life and elimination essentially independent of renal and liver function. More frequent use of these drugs would also promote implementation of more specific assays, such as the ecarin clotting time, or direct quantitation of drug levels. Transition to an agent with a longer half-life (danaparoid, fondaparinux), with the option for subcutaneous administration, could occur subsequently when the patient's clinical situation has stabilized.

With this approach, even if significant levels of platelet-activating, PF4-dependent antibodies were formed due to preoperative or intraoperative UFH use, these would be unlikely to cause clinical consequences of HIT. Such a strategy would not only greatly reduce the risk of HIT and its complications but also potentially improve thrombotic and bleeding outcomes after VAD implantation. We call for cardiac surgeons and anesthesiologists, critical care physicians, and hematologists to develop alternative anticoagulant protocols and to test their efficacy and safety in this challenging patient population.

	Acknowledgments

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 
Several cited studies [2, 6, 7, 9, 13-15, 32-34] were funded by the Heart and Stroke Foundation of Ontario; and by the German Federal Ministry for Education and Research (CAN04/00613,36 and NBL3 program, reference 01-ZZ040314,31,47); Landesförderungsprogramm EFRE.10.38.

	References

Top Abstract Introduction Superimposition of HIT With... Risk Factors Anecdotal Reports of HIT... Epidemiology of PF4-Dependent... Epidemiology of HIT in... Thrombotic Events in VAD... Systematic Studies of HIT... Alternative Nonheparin... Preoperative and Postoperative... Preoperative and Postoperative... Anticoagulation During VAD... Is it Time to... Acknowledgments References

 

1. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus Thromb Haemost 1998;79:1-7.[Medline]
2. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin N Engl J Med 1995;332:1330-1335.[Medline]
3. Warkentin TE. Think of HIT when thrombosis follows heparin Chest 2006;130:631-632.[Free Full Text]
4. Gonzalez-Stawinski GV, Cook DJ, Smedira NG, et al. Attrition from heart transplant waiting list for patients on ventricular assist devices is not affected by desensitization strategies Transplant Proc 2007;39:1571-1572.[Medline]
5. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery Circulation 1997;95:1242-1246.[Abstract/Free Full Text]
6. Warkentin TE, Sheppard JI, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia Blood 2000;96:1703-1708.[Abstract/Free Full Text]
7. Warkentin TE, Sheppard JI. No significant improvement in diagnostic specificity of an anti-PF4/polyanion immunoassay with use of high heparin confirmatory procedure J Thromb Haemost 2006;4:281-282.[Medline]
8. Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopeniaIn: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th ed.. New York, NY: Informa Healthcare USA; 2007. pp. 67-116.
9. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays J Thromb Haemost 2008;6:1304-1312.[Medline]
10. Selleng S, Selleng K, Wollert HG, et al. Heparin-induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass J Thromb Haemost 2008;6:428-435.[Medline]
11. Warkentin TE, Crowther MA. When is HIT really HIT? Ann Thorac Surg 2007;83:21-23.[Free Full Text]
12. Warkentin TE, Eikelboom JW. Who is (still) getting HIT? Chest 2007;131:1620-1622.[Free Full Text]
13. Warkentin TE, Sheppard JI, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia Blood 2006;108:2937-2941.[Abstract/Free Full Text]
14. Greinacher A, Alban S, Omer-Adam MA, Weitschies W, Warkentin TE. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings Thromb Res 2008;122:211-220.[Medline]
15. Paparella D, Scrascia G, Galeone A, et al. Formation of anti-platelet factor 4/heparin antibodies after cardiac surgery: influence of perioperative platelet activation, the inflammatory response, and histocompatibility leukocyte antigen status J Thorac Cardiovasc Surg 2008;136:1456-1463.[Abstract/Free Full Text]
16. Tandler R, Weyand M, Schmid C, Gradaus R, Schmidt C, Scheld HH. Long-term anticoagulation with recombinant hirudin in a patient on left ventricular assist device support ASAIO J 2000;46:792-794.[Medline]
17. Christiansen S, Jahn UR, Meyer J, Scheld HH, Van Aken H, Hammel D. Successful cardiac transplantation after Novacor implantation in a HIT II-patient using heparin J Cardiovasc Surg 2001;42:769-771.[Medline]
18. Schenk S, Arusoglu L, Morshuis M, et al. Triple bridge-to-transplant in a case of giant cell myocarditis complicated by human leukocyte antigen sensitization and heparin-induced thrombocytopenia type II Ann Thorac Surg 2006;81:1107-1109.[Abstract/Free Full Text]
19. Koster A, Weng Y, Böttcher W, Gromann T, Kuppe H, Hetzer R. Successful use of bivalirudin as anticoagulant for ECMO in a patient with acute HIT Ann Thorac Surg 2007;83:1865-1867.[Abstract/Free Full Text]
20. Schmid C, Tjan TDT, Welp H, Klotz S, Scheld HH. Implantation of a right heart assist device without a heart-lung machine in a patient with an acontractile right ventricle and HIT type II Thorac Cardiovasc Surg 2007;55:395-400.[Medline]
21. Lutz JT, Exner HJ, Schannewitzky A, Fehske W, Görlinger K. Patient mit heparininduzierter Thrombozytopenie Typ II und implantiertem links-ventrikulärem Assistdevice Anaesthesist 2008;57:49-52.[Medline]
22. Christiansen S, Jahn UR, Meyer J, et al. Anticoagulative management of patients requiring left ventricular assist device implantation and suffering from heparin-induced thrombocytopenia type II Ann Thorac Surg 2000;69:774-777.[Abstract/Free Full Text]
23. Klenner AF, Greinacher A. Heparin-induced thrombocytopenia in childrenIn: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th ed.. New York, NY: Informa Healthcare USA; 2007. pp. 503-517.
24. Mejak B, Giacomuzzi C, Heller E, et al. Argatroban usage for anticoagulation for ECMO on a post-cardiac patient with heparin-induced thrombocytopenia J Extra Corpor Technol 2004;36:178-181.[Medline]
25. Eghtesady P, Nelson D, Schwartz SM, et al. Heparin-induced thrombocytopenia complicating support by the Berlin Heart ASAIO J 2005;51:820-825.[Medline]
26. Koster A, Sänger S, Hansen R, et al. Prevalence and persistence of heparin/platelet factor 4 antibodies in patients with heparin coated and noncoated ventricular assist devices ASAIO J 2000;46:319-322.[Medline]
27. Koster A, Loebe M, Sodian R, et al. Heparin antibodies and thromboembolism in heparin-coated and noncoated ventricular assist devices J Thorac Cardiovasc Surg 2001;121:331-335.[Medline]
28. 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]
29. 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]
30. Schenk S, El-Banayosy A, Morshuis M, et al. IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support J Thromb Haemost 2007;5:235-241.[Medline]
31. Schroder JN, Daneshmand MA, Villamizar NR, et al. Heparin-induced thrombocytopenia in left ventricular assist device bridge-to-transplant patients Ann Thorac Surg 2007;84:841-846.[Abstract/Free Full Text]
32. Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007;82:1037-1043.[Medline]
33. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia N Engl J Med 2001;344:1286-1292.[Medline]
34. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients Arch Intern Med 2003;163:2518-2524.[Abstract/Free Full Text]
35. Greinacher A, Eichler P, Lietz T, Warkentin TE. Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lower the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia Blood 2005;106:2921-2922.[Free Full Text]
36. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia. American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest 2008;133(suppl):340S-380S.[Abstract/Free Full Text]
37. Lubenow N, Eichler P, Lietz T, Greinacher A, HIT Investigators Group Lepirudin in patients with heparin-induced thrombocytopenia—results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3 J Thromb Haemost 2005;3:2428-2436.[Medline]
38. Samuels LE, Kohout J, Casanova-Ghosh E, et al. Argatroban as a primary or secondary postoperative anticoagulant in patients implanted with ventricular assist devices Ann Thorac Surg 2008;85:1651-1655.[Abstract/Free Full Text]
39. Koster A, Buz S, Hetzer R, Kuppe H, Breddin K, Harder S. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiovascular surgery with cardiopulmonary bypass: first results from the ARG-E03 trial J Thorac Cardiovasc Surg 2006;132:699-700.[Free Full Text]
40. Hoffman WD, Czyz Y, McCollum DA, Hursting MJ. Reduced argatroban doses after coronary artery bypass graft surgery Ann Pharmacother 2008;42:309-316.[Abstract/Free Full Text]
41. Koster A, Hentschel T, Groman T, et al. Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery J Thorac Cardiovasc Surg 2007;133:1376-1377.[Free Full Text]
42. Harder S, Graff J, Klinkhardt U, et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and ecarin clotting time Thromb Haemost 2004;91:1137-1145.[Medline]
43. Bartholomew JR. Bivalirudin for the treatment of heparin-induced thrombocytopeniaIn: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th ed.. New York, NY: Informa Healthcare USA; 2007. pp. 409-439.
44. Koster A, Pötzsch B, Madlener K. Management of intraoperative anticoagulation in patients with heparin-induced thrombocytopenia undergoing cardiovascular surgeryIn: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th ed.. New York, NY: Informa Healthcare USA; 2007. pp. 487-502.
45. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery Ann Thorac Surg 2003;76:2121-2131.[Abstract/Free Full Text]
46. Selleng S, Haneya A, Hirt S, Selleng K, Schmid C, Greinacher A. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation Blood 2008;112:4024-4027.[Abstract/Free Full Text]
47. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial Ann Thorac Surg 2007;83:575-577.
48. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study J Thorac Cardiovasc Surg 2006;131:533-539.[Abstract/Free Full Text]
49. Aouifi A, Blanc P, Piriou V, et al. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia Ann Thorac Surg 2001;71:678-683.[Abstract/Free Full Text]
50. Koster A, Chew D, Merkle F, et al. Extracorporeal elimination of large concentrations of tirofiban by zero-balanced ultrafiltration during cardiopulmonary bypass: an in vitro investigation Anesth Analg 2004;99:989-992.[Abstract/Free Full Text]

This article has been cited by other articles:

				S. E. A. Felix, J. R. Martina, J. H. Kirkels, C. Klopping, H. Nathoe, E. Sukkel, N. Hulstein, F. Z. Ramjankhan, P. A. F. M. Doevendans, J. R. Lahpor, et al. Continuous-flow left ventricular assist device support in patients with advanced heart failure: points of interest for the daily management Eur J Heart Fail, February 3, 2012; (2012) hfs012v1. [Abstract] [Full Text] [PDF]

				G. L. Torres, J. L. Taylor, and N. D'Attellis A Painful HIT J Intensive Care Med, October 1, 2011; 26(5): 335 - 340. [PDF]

				A. Wahba Strategies in heparin-induced thrombocytopenia MMCTS, January 1, 2011; 2011(0126): mmcts.2010.004481 - mmcts.2010.004481. [Abstract] [Full Text] [PDF]

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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Warkentin, T. E. Articles by Koster, A. Search for Related Content PubMed PubMed Citation Articles by Warkentin, T. E. Articles by Koster, A. Related Collections Mechanical Circulatory Assistance