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Ann Thorac Surg 1999;68:137-142
© 1999 The Society of Thoracic Surgeons

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Original Articles

Increased incidence of antiphospholipid antibodies in left ventricular assist system recipients

^a Center for Reproduction and Transplantation Immunology, Methodist Hospital, Indianapolis, Indiana, USA

Address reprint requests to Dr McIntyre, Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, 1701 N Senate Blvd, Indianapolis, IN 46202
e-mail: jmcintyre{at}clarian.com

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Antiphospholipid antibodies are associated with thrombosis. Because thromboembolic complications are often observed in recipients of a left ventricular assist system, we questioned if antiphospholipid antibodies were present in these patients. We report results from 10 patients who received a Novacor left ventricular assist system.

Methods. Serum samples were collected before left ventricular assist system placement and weekly thereafter until discharge after cardiac transplantation. Samples were tested for IgG, IgA, and IgM antiphosphatidylserine, anticardiolipin, and antiphosphatidylethanolamine using an enzyme-linked immunosorbent assay.

Results. Development of phospholipid-binding plasma protein–dependent antiphospholipid antibodies was observed in 9 of the 10 patients. Before placement of the assist system, 3 patients had IgG antiphospholipid antibodies, and 9 were positive after placement. None had IgA antiphospholipid antibodies before placement, whereas 5 seroconverted for IgA after placement. One patient had IgM antiphospholipid antibodies before placement, and 1 additional patient became positive after placement. In patients with a preexisting antibody, increased titers and additional specificities developed subsequent to placement.

Conclusions. All but 1 patient showed development of phospholipid-binding plasma protein–dependent antiphospholipid antibodies after left ventricular assist system placement.

	Introduction

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Data show that 3,900 patients were registered for cardiac transplantation in the United States for 1997 [1]; however, ten to 20 times that number are in need of cardiac transplantation [2]. In 1997, only 1,920 cardiac transplantations were performed in this country [3]. Because the demand for donor hearts greatly exceeds supply, 10% to 40% of patients die while waiting for a donor heart [1]. In an attempt to minimize this mortality, the left ventricular assist system (LVAS) is being used increasingly as a bridge to cardiac transplantation. Although patients who are bridged have outcomes after transplantation equivalent to those who are not [2], use of the LVAS engenders complications. When these complications are understood and managed, the LVAS may be a more permanent solution to the donor shortage. Major complications associated with LVAS placement are infection, bleeding, and thrombosis [2, 4].

Thrombosis was described in patients with systemic lupus erythmatosus more than 30 years ago despite the fact that many were found to have an inhibitor of in vitro phospholipid (PL)–dependent clotting assays [5]. The observation that patients with and without systemic lupus erythematosus who had this "lupus anticoagulant" also were falsely positive for the serologic test for syphilis, which used the PL cardiolipin, led to the realization that the anticoagulant was an antiphospholipid antibody (aPA) [5]. Since that time, specific tests for aPAs have been developed and aPA screening of patients with thromboembolic (TE) complications has become more routine. The association of aPAs with TE complications such as recurrent venous and arterial thrombosis, thrombocytopenia, and recurrent spontaneous abortion has become so strong, it has defined the antiphospholipid syndrome [6].

Antiphospholipid antibodies are a complex group of antibodies with certain aPAs recognizing PLs and others recognizing complexes of PLs and PL-binding plasma proteins. Although the pathogenic mechanisms of aPAs are not entirely understood, many hypotheses have developed since the discovery that several proteins involved in coagulation and anticoagulation bind PLs [6]. Antiphospholipid antibodies have been observed in nonautoimmune patients who experience TE complications such as stroke [7] and cardiac complications [8, 9]. These antibodies also have been noted in recipients of renal, cardiac, and hepatic allografts who subsequently experience TE complications [10–12]. Because aPAs have been shown to be associated with an increased risk of TE complications after cardiovascular surgical procedures [13], we questioned if aPAs were present in LVAS recipients.

	Material and methods

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Patient population
Serum samples were collected from patients hospitalized because of cardiac complications who received a Novacor LVAS while awaiting cardiac transplantation. Samples were collected before placement and at least weekly thereafter until discharge after cardiac transplantation. From 1992 to 1997, 10 of 12 patients who received an LVAS underwent transplantation. The 2 patients who died while being supported by the device were not included in this study. One of them was supported by the LVAS for 21 days before dying of renal failure, and the other died of anoxia after 19 days of LVAS support. The other 10 patients are alive. All of the patients were men, and the median age for the 10 who underwent transplantation was 48 years (range, 32 to 54 years). The indications for LVAS placement were cardiomyopathy in 4 patients, ischemic heart disease in 4 patients, and a combination of these in 1 patient. The remaining patient had endocardial fibroelastosis.

All patients received intravenous heparin sodium in the immediate postsurgical period. Five patients continued to receive heparin for the duration of LVAS support, and 5 were switched to a regimen of Coumadin (crystalline warfarin sodium). The 5 patients treated with heparin only received heparin 95.5% of the LVAS support time, and the 5 patients treated with heparin followed by Coumadin received these medications 30% and 63% of the time, respectively. Table 1 lists heparin or heparin-coumadin treatment along with antiplatelet therapy.

Serum samples from the 10 LVAS recipients were tested for aPAs by enzyme-linked immunosorbent assay as previously described [11]. Briefly, flat-bottom microtiter plates (ICN; Horsham, PA) were coated with 30 µL of a 50 µg/mL solution of CL, PS, or PE (Sigma; St. Louis, MO) diluted in methanol and chloroform (3:1) and then were dried under nitrogen. Nonspecific binding (NSB) plates were prepared by coating with methanol and chloroform only (3:1) and drying under nitrogen. The plates were washed three times with Tris [tris (hydroxymethyl) aminomethane]–buffered NaCl (0.02 mol/L Tris, 0.15 mol/L NaCl, pH 7.3), blocked with 100 µL of 10% bovine serum albumin (Sigma) per well for 1 hour at room temperature, and then washed three times with Tris-buffered NaCl. All samples were diluted separately (1:100) in 1% bovine serum albumin for the detection of PL-binding plasma protein–independent aPAs and in either 10% adult bovine serum or 10% adult bovine plasma for the detection of PL-binding plasma protein–dependent aPAs. The adult bovine serum is a source of plasma proteins, such as ß₂-glycoprotein I [14] and prothrombin [15], for anionic PLs. The adult bovine plasma is a source of plasma proteins, such as kininogens and the kininogen-binding proteins factor XI and prekallikrein [16] for zwitterionic PLs. To PL-coated and control plates was added in triplicate 50 µL per well of the diluted samples. Samples diluted in 1% bovine serum albumin were added to all plates, samples diluted in 10% adult bovine serum were added to the CL, PS, and NSB plates, and samples diluted in 10% adult bovine plasma were added to the PE and NSB plates.

Positive and negative aPA control samples in 10% adult bovine serum were added to the CL, PS, and NSB plates, and control samples in 10% adult bovine plasma were added to the PE and NSB plates. After 1-hour incubation at room temperature, the plates were washed three times with Tris-buffered NaCl before the addition of 50 µL per well of alkaline phosphatase conjugated affinity purified antibodies to human IgG, IgA, or IgM (Sigma) diluted 1:1,000 in 1% bovine serum albumin. After 1 hour at room temperature, the plates were washed three times in Tris-buffered NaCl, and then 50 µL of substrate consisting of paranitrophenyl phosphate tablets (Sigma) dissolved in diethanolamine buffer (10% wt/vol, 5 mmol/L MgCl₂, pH 9.8) was added to each well. The plates were incubated at 37°C in the dark.

Positive control optical density (OD)₄₁₀ values were monitored and reactions were stopped for each PL-isotype combination when the corresponding positive control reached the cutoff OD₄₁₀ value (ie, 1.0). Continuing the reaction until the cutoff OD₄₁₀ value is achieved allows for normalization of values and comparison of samples tested on different days, thus avoiding daily testing variances. The reaction was stopped with 75 µL per well of 3 mol/L NaOH, and the OD of each well was read at 410 nm. Patient NSB plate OD₄₁₀ values were subtracted from PL plate OD₄₁₀ values when the NSB values were equal to or greater than 0.100.

Patient results are reported as multiples of the mean (MoM) of OD₄₁₀ enzyme-linked immunosorbent assay values obtained from the 252 normal controls [17]. Results were defined as positive for aPAs if they were greater than the MoM, which include 95% of the normal controls [11]. Significance was determined with Fisher’s exact test and the t test with an of 0.05.

	Results

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The median time of LVAS support was 67.5 days (range, 11 to 101 days). Three patients had neurologic events, either cerebral vascular accidents confirmed by imaging (n = 2) or transient ischemic attacks as determined by clinical impressions (n = 1). Nine patients experienced bleeding that required multiple transfusions and large volumes of blood as well as surgical intervention. Five patients had development of bacterial infections requiring antibiotic therapy. Organisms identified included Staphylococcus aureus (n = 3), Pseudomonas (n = 1), Corynebacterium (n = 1), Klebsiella pneumoniae (n = 1), and Candida albicans (n = 1); infections of the blood, pulmonary system, urinary system, and LVAS pocket and driveline were noted. In 1 patient hepatic dysfunction developed as determined by an increase in bilirubin greater than three times the value before placement. One patient experienced cardiac dysfunction, which was evidenced by arrhythmia. Two patients had respiratory dysfunction requiring prolonged ventilatory support or reintubation. Pulmonary, hepatic, and cardiovascular complications were not associated with thrombosis.

The aPA assays used in this investigation can detect aPA reactivity both in the absence and in the presence of PL-binding plasma proteins, the latter supplied in the patient sera diluent buffer. Figures 1 and 2 are representative of IgG and IgA aPAs observed, respectively. Only the increase in PL-binding plasma protein–dependent aPAs was significant when the number of aPAs before and after placement was compared (5 versus 28; p = 0.0003). The number of patients positive for PL-binding plasma protein–dependent aPAs was significantly increased from 4 of 10 before placement to 9 of 10 after placement (p = 0.029). In particular, the increase in the number of IgG aPA–positive patients from 3 of 10 to 9 of 10 was significant (p = 0.010). The increase in the number of IgA aPA–positive patients from 0 to 5 of 10 also was significant (p = 0.016).

View larger version (16K): [in this window] [in a new window]   Fig 1. IgG antiphosphatidylethanolamine (anti-PE) from a representative recipient of left ventricular assist system (LVAS). Bovine serum albumin (BSA) was used for detection of phospholipid (PL)–binding plasma protein–independent anti-PE and adult bovine plasma (ABP), is for detection of PL-binding plasma protein–dependent anti-PE. The broken line indicates the positive/negative cutoff. Day of LVAS placement and day of cardiac transplantation (Heart) are noted. (OD = optical density.)

View larger version (16K): [in this window] [in a new window]   Fig 2. IgA antiphosphatidylethanolamine (anti-PE) from a representative recipient of left ventricular assist system (LVAS). Bovine serum albumin (BSA) was used for detection of phospholipid (PL)-binding plasma protein-independent anti-PE and adult bovine plasma (ABP), is for detection of PL-binding plasma protein–dependent anti-PE. The broken line indicates the positive/negative cutoff. Day of LVAS placement and day of cardiac transplantation (Heart) are noted. (OD = optical density.)

The number of PL-binding plasma protein–dependent aPA–positive patients who received heparin followed by Coumadin compared with those who received heparin only was not different (5 of 5 versus 4 of 5; p = 0.500). The total number of aPAs developed was different (16 versus 7; p = 0.047), but the titer (8.8 ± 2.7 versus 12.4 ± 11.3; p = 0.114) was not different. Individual aPA numbers and titers were not different except that the number of IgG anti-PE was increased in the heparin-Coumadin group compared with the heparin-only group (4 of 5 versus 0 of 5; p = 0.024).

The number of PL-binding plasma protein–dependent aPA–positive patients with infection compared with the number without infection was not greater (5 of 5 versus 4 of 5; p = 0.500). The total number of aPAs developed was not greater in patients with infection compared with those without (14 versus 9; p = 0.153), nor was the titer greater (11.3 ± 7.9 versus 7.8 ± 2.8; p = 0.108). The aPA numbers and titers for individual specificities were not greater in the group with infection than in the group without infection.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Although 4 of the 10 patients were positive for PL-binding plasma protein–dependent aPAs before placement, all 4 patients were positive for only one aPA specificity. The increase to 9 positive patients after placement is significant (p = 0.029), and all 9 patients were positive for two or more aPA specificities with an average of three different antibodies per patient. The comparison of frequencies before and after LVAS placement is important because it represents a comparison between LVAS recipients and cardiac patients without the LVAS. The presence of aPAs before placement perhaps was due to the cardiac complications that made transplantation and thus LVAS support necessary in these patients [8, 9].

The presence of aPAs before LVAS placement and the increase in number and titer subsequent to LVAS placement may be of consequence in these patients, as aPAs are associated with TE risk after cardiovascular operations and transplantation [10–13]. Recipients of an LVAS have increased activation of coagulation immediately after the placement procedure compared with patients who undergo coronary artery bypass grafting [18]. Markers of platelet activation and thrombin generation remain elevated for at least 50 days after placement [19]. Although hemostasis appears to be maintained in some LVAS recipients even without the use of anticoagulation, increased activation of coagulation in LVAS recipients suggests there is potential for TE complications [20].

This underlying complication may be exacerbated by the development of PL-binding plasma protein dependent aPAs, which leads to thrombosis, perhaps because thrombin generation is further increased in aPA–positive patients [21]. Because the reported aPAs are dependent on PL-binding plasma proteins that are involved in coagulation and anticoagulation, aPAs could alter normal pathways. For example, ß₂-glycoprotein I functions as an anticoagulant by inhibiting platelet activation and contact activation of the coagulation cascade [5, 14]. When bound to platelets, high molecular weight kininogen (HMWK) also inhibits platelet activation by thrombin [6, 16]. Thus binding of aPAs could prevent ß₂-glycoprotein I and HMWK from inhibiting activation of platelets and coagulation. Furthermore, aPAs could bind thrombomodulin, thereby inhibiting protein C activation by the thrombin-thrombomodulin complex [22], and aPAs could prevent inactivation of coagulation factor Va by protein C [21].

In our patient population, TE events were observed in 3 LVAS recipients, which is consistent with other reports [2, 4]. There were no differences in the specificity, number, or titer of aPAs in these 3 patients compared with the 7 patients without TE events. However, differences in anticoagulant therapy were noted. The 3 patients with TE complications were from the group of 5 patients switched from heparin to Coumadin shortly after LVAS placement. Thus, 60% of these aPA-positive patients experienced TE complications. The remaining 4 aPA-positive patients and the aPA-negative patient remained on a regimen of heparin for the duration of LVAS support and experienced no TE complications. Although the frequency of TE complications in the heparin-Coumadin group is not significantly higher than the frequency in the heparin-only group (3 of 5 versus 0 of 5; p = 0.083), this observation is clinically significant and may reach significance with larger patient numbers. Interestingly, the total number of aPAs developed, IgG anti-PE specifically, was higher in the heparin-Coumadin group than in the heparin-only group. The combination of increased number of PL-binding aPAs and the absence of heparin after the development of these aPAs may lead to TE complications.

The decision to use intravenous heparin therapy was made without the influence of the possible effects of heparin on aPAs; in retrospect, however, the therapy may be beneficial for several reasons. First, heparin may protect aPA–positive LVAS patients from thrombosis by inhibiting thrombin generation [23], which is increased after microvascular injury in patients with aPAs [21]. Second, a complex of CL and ß₂-glycoprotein I has been shown to inhibit binding of certain anti-heparin antibodies to heparin [24]; thus, aPA cross-reactivity with heparin may inhibit aPA binding. Third, heparin may benefit aPA–positive LVAS recipients by direct blocking of the antibody [25].

The use of heparin therapy raises concern over the development of anti-heparin antibodies and the associated TE complications as well as the risk for bleeding over time. Patients treated with heparin in our program did not experience the thrombocytopenia often associated with anti-heparin antibodies. For all 10 patients, thrombocytopenia was observed only in the immediate postsurgical period, and as mentioned, TE complications were not observed in patients treated with heparin alone. Patients treated with heparin for the duration of LVAS support also did not experience bleeding requiring reoperation more often than patients who were switched from heparin to Coumadin in our experience. The use of intravenous heparin therapy appears to have been beneficial for our aPA–positive LVAS recipients. The benefit of heparin, however, must be weighed against the possible heparin-induced complications for each patient population.

In addition to the aPAs reported in patients with TE complications, aPAs have been reported in patients with infection [5, 6]. In our patient population, infections were noted in 5 LVAS recipients. To rule out the possibility that the infections were the cause of aPA development, the number and the titer of aPAs developed during LVAS support in patients with infection were compared with the number and the titer in patients without infection. There were no differences in the specificity, the number, or the titer of aPAs in the 5 patients with infection compared with the 5 who were infection free during LVAS support. This suggests that infection was not responsible for the development of aPAs in the patients. This is not unreasonable, as the reported aPAs recognize complexes of PLs and PL-binding plasma proteins. Although there can be exceptions [26], aPAs detected in patients with infections mainly recognize PL in the absence of PL-binding plasma proteins [5, 6, 27] and unlike aPAs, which require PL-binding plasma proteins, are reported to be nonpathogenic, although recent data may suggest otherwise [28].

In conclusion, significant increases in frequency and titer of PL-binding plasma protein–dependent aPAs were noted in Novacor LVAS recipients after placement compared with before placement. The aPAs observed in LVAS recipients are indistinguishable from those seen in other patient populations who experience aPA–associated TE complications. The LVAS may not be directly responsible, but the development of these pathogenic aPAs occurs after its placement. Prospective laboratory investigation indicated that the topical bovine thrombin component of fibrin glue used during placement stimulates the development of aPAs [29, 30]. The presence of aPAs in patients after LVAS placement may have implications for TE complications, as LVAS recipients may be predisposed as a result of increased activation of coagulation. The incidence of thromboembolism appeared to be increased in LVAS recipients with PL-binding plasma protein–dependent aPAs who did not remain on a regimen of heparin therapy. This suggests that heparin may either neutralize or diminish the TE complications attributed to aPAs.

	Acknowledgments

 
This study was supported in part by grants from the Showalter Foundation and Baxter Novacor, Inc.

We acknowledge the staff of the Cardiac Transplant Program for clinical data collection.

	References

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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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fastenau, D. R. Articles by McIntyre, J. A. Search for Related Content PubMed PubMed Citation Articles by Fastenau, D. R. Articles by McIntyre, J. A.