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CARDIOVASCULAR ANESTHESIOLOGY

The Incidence and Implications of Anti-Heparin-Platelet Factor 4 Antibody Formation in a Pediatric Cardiac Surgical Population

Mary P. Mullen, MD, PhD^*, David L. Wessel, MD^*, Kristen C. Thomas, MS, RN^*, Kimberlee Gauvreau, ScD^*, Ellis J. Neufeld, MD, PhD^*, Francis X. McGowan, Jr, MD^*, and James A. DiNardo, MD^*

From the *Children's Hospital Boston and Harvard Medical School, Harvard School of Public Health, Boston, Massachusetts.

Address correspondence and reprint requests to James A. DiNardo, MD, Department of Anesthesia, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115. Address e-mail to james.dinardo{at}childrens.harvard.edu.

Abstract

BACKGROUND: The incidence and implications of anti-heparin-platelet factor 4 (PF4) antibody seroconversion in the pediatric cardiac surgical population remain largely unexplored. We sought to prospectively characterize the incidence of seroconversion in two populations: neonates undergoing primary cardiac surgery and children undergoing reoperative cardiac surgery with a history of unfractionated heparin (UFH) exposure.

METHODS: One hundred and thirty-five consecutive patients were studied: Neonatal = 60 neonates, first time cardiac surgery. Reoperative (ReOp) = 75 children, reoperative cardiac surgery. Preoperative and postoperative day (POD) 5 and 10 blood samples were used to determine the presence of PF4 immunoglobulin (Ig)G, IgA, and IgM antibodies with enzyme-linked immunosorbent assay.

RESULTS: No anti-heparin/PF4 antibodies were detected preoperatively in either group. On POD 5, antibodies were present in 1 of 60 (1.7%) Neonatal; and in 12 of 75 (16%) ReOp; P = 0.006. On POD 10, antibodies were present in 1 of 60 (1.7%) Neonatal; and in 39 of 75 (52%) ReOp; P < 0.001. Seroconversion in ReOp patients on POD 10 was significantly associated (P = 0.03) with previous UFH exposures. Heparin-induced thrombocytopenia (HIT) was not diagnosed in any Neonatal patients. One ReOp patient (1.3%) seroconverted and developed HIT without thrombosis or skin lesions.

CONCLUSIONS: HIT is a rare occurrence in pediatric cardiac surgical patients. The incidence of anti-heparin-PF4 antibody seroconversion in children undergoing reoperation is approximately 50% at 10 days postoperatively, a finding similar to that reported in adult cardiac surgical patients. Both age and previous UFH exposure correlate with this rate of seroconversion. In contrast, the rate of seroconversion in neonates undergoing first time surgery is substantially lower.

Although heparin-induced thrombocytopenia (HIT) and HIT associated with thrombosis or skin lesions (HITT) is reported in the pediatric population, prospective examination of the prevalence of heparin-associated antibodies or the incidence of these syndromes in children has been limited.1,2 Although postoperative thrombus formation in pediatric patients is an almost unavoidable consequence of prolonged hospitalization and central venous/arterial catheterization, it may also represent HITT. Patients with congenital heart disease face repeated exposures to IV and high dose unfractionated heparin (UFH) during catheterizations and surgical procedures, and therefore may be at increased risk of developing heparin-dependent platelet-reactive antibodies and HIT. Prompt recognition is necessary to avoid complications related to HITT, as alternative anticoagulation strategies such as direct thrombin inhibitors are available. Additional insights into immune mechanisms and pathophysiology of associated vascular thrombosis may derive from investigating this syndrome in patients of varying age groups, including those without prior UFH exposure and without the presence of superimposed atherosclerotic or other vascular diseases.

The purpose of this study was to characterize prospectively the prevalence of heparin-dependent platelet-reactive antibodies and the incidence of HIT and HITT in two pediatric populations undergoing repair of congenital heart lesions with cardiopulmonary bypass (CPB): neonates undergoing cardiac surgery for the first time and children undergoing reoperative cardiac surgery with known prior UFH exposure.

METHODS

The study protocol was reviewed and approved by the Committee on Human Investigations at Children's Hospital Boston. Informed, written consent was obtained from the parents of all subjects. One hundred and thirty-five consecutive patients were studied: Group Neonatal comprised 60 neonates undergoing first time cardiac surgery; group ReOp comprised 75 children undergoing reoperative cardiac surgery. Patients receiving anticoagulant medications other than UFH at the time of the study and those with a known history of hematological disorder were excluded. Operations performed on neonatal patients are summarized in Table 1 and those performed on ReOp patients are summarized in Table 2. Each patient's medical record was reviewed to determine the number of significant UFH exposures (cardiac catheterization or cardiac surgery using CPB) before the study period. In addition, the timing of the most recent exposure relative to commencing the study period was determined.

Porcine mucosal UFH was used for cardiac catheterization, CPB, and postoperative anticoagulation. Anticoagulation for cardiac catheterization was achieved with an initial dose of 100 U/kg to a maximum of 5000 U. Additional heparin was administered by bolus during CPB to maintain a celite-activated clotting time (ACT) >200 s (Hemochron, Edison, NJ). Anticoagulation for CPB was achieved with an initial dose of 200 U/kg for children weighing 30 kg or less and 300 U/kg for children weighing more than 30 kg. The CPB prime contained 2.5 U of UFH per milliliter of prime for children weighing 30 kg or less and 3.0 U/mL of prime for children weighing more than 30 kg. Additional heparin was administered by IV bolus during CPB to maintain an ACT >480 s. All ACT testing (Hemochron) was performed with a celite activator except when aprotinin was used in which case a kaolin activator was used. Following institutional preoperative and postoperative protocol, all patients with indwelling percutaneous central venous catheters received UFH infused through the catheter at a dose of 10 U · kg^–1 · h^–1 whereas direct intracardiac lines, umbilical catheters, and arterial catheters were infused with UFH at a dose of 2 U/h. Steroids (solumedrol 30 mg/kg, max. dose 2 g in the CPB prime) were used at the discretion of the attending surgeon and usage is summarized in Tables 1 and 2. Antifibrinolytics (aprotinin or tranexamic acid) were used at the discretion of the attending surgeon and anesthesiologist; usage is summarized in Tables 1 and 2. Aprotinin was administered as a 30,000 KIU/kg bolus to both the patient and the CPB prime, followed by a continuous patient infusion of 10,000 KIU · kg^–1 · h^–1. Tranexamic acid was administered as a 100 mg/kg initial loading dose to both the patient and the CPB prime followed by a continuous infusion of 10 mg · kg^–1 · h^–1.

Platelet counts were measured preoperatively and daily in the postoperative period as part of routine clinical care. Blood was drawn from each subject preoperatively and on postoperative day (POD) 5 and POD 10. These samples were used to determine the presence of anti-heparin-platelet factor 4 (PF4) immunoglobulin (Ig)G, IgA, and IgM antibodies with a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Asserachrom® HPIA kit, Diagnostica Stago, Parsippany, NJ) according to the manufacturer's instructions.3 Briefly, duplicate samples of plasma from each subject were allowed to incubate for 1 h at room temperature in a plastic microwell plate containing heparin-PF4 complexes. Plates were washed five times with a trisodium citrate buffer and goat serum, and then peroxidase conjugated goat antibodies to human IgG, IgA, and IgM were added to each well and incubated for 1 h at room temperature. After five washes, diluted ortho-phenylenediamine dihydrochloride and urea peroxide were added to each well to develop enzymatic activity. After 5 min, the color reaction was stopped with the addition of sulfuric acid and 10 min later optical density (OD) measured at 492 nm. As defined by the manufacturer, a positive test was an OD of 29% or more of the positive control. Each assay was run with negative and positive controls in duplicate.

HIT, a clinicopathologic syndrome, was defined as both a 50% reduction in platelet count from the postoperative peak and a positive assay for anti-heparin/PF4 antibodies occurring between POD 5 and 10 in patients exposed to high dose UFH during cardiac surgery.4 HITT was defined as HIT associated with thrombosis or skin lesions. An antibody screen was considered positive if the absorbance value was more than 0.5 OD units.

The proportions of subjects undergoing CPB surgery with anti-hep/PF4 antibodies detected on POD 5 and at POD 10 were compared for groups Neonatal and ReOp using Fisher's exact test. Differences in platelet counts were evaluated using the Wilcoxon's ranked sum test. On POD 5 and POD 10, patient characteristics were compared for subjects with and without antibodies using Fisher's exact test for categorical variables and the rank sum test for continuous variables; analyses were performed separately for neonates and patients undergoing reoperation. P values are two-tailed with a P value <0.05 considered significant.

RESULTS

No anti-heparin/PF4 antibodies were detected preoperatively in any patient in either group. On POD 5, anti-heparin/PF4 antibodies were present in 1 of 60 patients in group (1.7%, 95% confidence interval [0-9]) Neonatal; and in 12 of 75 (16%, [9-26]) ReOp; P = 0.006. On POD 10 anti-heparin/PF4 antibodies were present in 1 of 60 (1.7%, [0-9]) Neonatal patients; and in 39 of 75 (52%, [40-64]) ReOp patients; P < 0.001. The relationship of antibody seroconversion in ReOp patients on POD 5 and 10 to multiple variables is summarized in Tables 3 and 4. The proportion of ReOp patients with anti-heparin/PF4 antibodies on POD 10 was significantly associated (P = 0.008) with the total number of previous UFH exposures (both cardiac catheterization and previous cardiac surgery using CPB) and with exposures during either prior catheterization (P = 0.03) or surgery (P = 0.03) as illustrated in Figures 1 and 2. HIT was not diagnosed in any neonatal patient. One patient in the ReOp group (1.3%) developed thrombocytopenia and antibody seroconversion in association with UFH exposure (HIT) but did not manifest thrombosis or skin lesions (HITT).

View larger version (19K): [in this window] [in a new window]   Figure 1. Relationship of previous unfractionated heparin exposure based on previous cardiac surgical procedures to the likelihood of anti-heparin PF4 antibody seroconversion on postoperative day 10 in the 75 patients undergoing reoperation (ReOp).

View larger version (23K): [in this window] [in a new window]   Figure 2. Relationship of previous unfractionated heparin exposure based on previous cardiac catheterization procedures to the likelihood of anti-heparin PF4 antibody seroconversion on postoperative day 10 in the 75 patients undergoing reoperation (ReOp).

The seroconversion rate during the study interval among patients with known previous heparin exposure (previous cardiac catheterization or surgery) was analyzed based on whether the previous exposure was remote (cardiac catheterization or surgery in a previous hospital admission) or recent (cardiac catheterization in the same admission as the study interval surgery). Among the 75 patients undergoing reoperation, 22 had recent exposure (in addition to remote exposure), and 53 had remote exposure only. On POD 5, of the 53 patients with only remote exposure 4 (8%, [2-18]) had a positive assay whereas of the 22 patients with recent exposure 8 (36%, [17-59]) had a positive assay (P = 0.004). On POD 10, of the 53 patients with only remote exposure 30 (57%, [42-70]) had a positive assay whereas of the 22 patients with recent exposure 9 (41%, [21-64]) had a positive assay (P = NS). For patients with recent UFH exposure there was no significant difference in the rate of seroconversion at POD 5 versus POD 10. For the patients with remote UFH exposure, the rate of seroconversion on POD 10 (57%) was significantly greater (P < 0.001) than the rate on POD 5 (8%).

DISCUSSION

This prospective analysis suggests that HIT is a rare event in pediatric cardiac surgical patients. The incidence of anti-heparin-PF4 antibody seroconversion in older pediatric cardiac surgical patients, as determined by a commercially available ELISA, is approximately 50% at 10 days postoperatively, similar to that reported in adult cardiac surgical patients. Both age and previous UFH exposure correlate with this rate of seroconversion. In contrast, the rate of seroconversion in the neonatal population is substantially lower.

Two types of assays (antigenic and functional/ biologic) are currently used for detection of anti-heparin PF4 antibodies. Of the former, two ELISA that detect IgG, IgA, and IgM antibodies to PF4 are commercially available, use of an ELISA specific for IgG antibodies to PF4 has been used in some research laboratories.5 The most commonly used functional assay is the ¹⁴C-serotonin release assay (SRA). Washed donor platelets previously incubated with ¹⁴C-serotonin are mixed with subject plasma suspected to contain to anti-heparin PF4 antibodies. In vitro platelet activation is quantitated by measurement of released ¹⁴C-serotonin. This assay detects only titers of anti-heparin PF4 antibodies high enough to induce platelet aggregation, is technically demanding to perform, and requires specially designed equipment.

The ELISA used in this study has been shown to have a high sensitivity (approximately 80%) for detection of HIT in adults. It has been suggested that this ELISA could be negative in up to 20% of patients with HIT.6 This may be because antibodies to other antigens capable of causing HIT such as interleukin-8 and neutrophil activating peptide 2 (NAP-2) are not detected by an ELISA designed to detect antibodies to the heparin-PF4 complex.7,8 In addition, the ELISA used here does not detect free antibody. It has been demonstrated that, in some patients with HIT, clearing anti-heparin PF4 antibody complexes makes detection of antibodies possible only with a method designed to detect free antibodies.9 The high sensitivity of this assay may limit specificity for HIT to 60%-80% due to the detection of both subclinical seroconversion and nonpathogenic IgA and IgM antibodies to PF4.10 A better sensitivity-specificity tradeoff may be obtainable with use of an ELISA specific for IgG antibodies to PF4 or by using the SRA.10

Prospective studies in the adult cardiac surgical population have demonstrated that 27%-50% of patients develop anti-heparin PF4 antibodies detectable by ELISA after exposure to UFH during cardiac surgery.11 However, only 7%-40% of these patients develop antibody titers of IgG high enough to be capable of activating platelets in vitro.11 The observed frequency of HIT in adults after cardiac surgery is 1%-3%, suggesting that <10% of antibody positive patients develop thrombocytopenia, even when UFH is continued in the postoperative period.11 In a study of 111 adult patients undergoing cardiac surgery with CPB, heparin-dependent antibodies were detected before surgery in 5% of patients with SRA and 19% of patients with the same ELISA used in our study.12 By the fifth POD, there was a significant increase in patients positive for antibodies by both the SRA (13%) and ELISA (51%). Patients who had received heparin earlier in the same hospitalization were more likely to have a positive ELISA both before and after surgery. In two recent investigations, the incidence of a positive preoperative ELISA in adult cardiac surgical patients was found to be 13% and 5.4% respectively.13,14 A positive ELISA before surgery was an independent predictor for postoperative death or prolonged hospital in one study13 and for clinically significant multiorgan postoperative complications in the other.14

In our ReOp group, the incidence of antibody seroconversion (16% on POD 5 and 52% on POD 10) was similar to that seen in the adult population. Specifically, the rate of seroconversion on POD 10 (52%) in our ReOp group of patients was similar to that found on POD 5 in the adult study using the same ELISA.12 In contrast to that same study no patients in our study, including those previously exposed to UFH, had antibody seroconversion before surgery. Patients in the ReOp group were older, with a frequent incidence of documented previous UFH exposure. Both age and previous UFH exposure correlated with the rate of seroconversion.

The incidence of seroconversion (1.7% on both POD 5 and 10) in group Neonatal was substantially lower than group ReOp. In addition, there were no documented cases of HIT in this group. In a previous study, no episodes of HIT occurred in a cohort of 108 neonates receiving UFH infusions 5 days to maintain intravascular catheter patency.15 In addition, using the same ELISA used in our study, no episodes of seroconversion on days 1, 7, 14, 21, and 28 were detected.15 This cohort differs from ours in that our patients were exposed to high dose UFH in association with cardiac surgery and CPB. Given the larger UFH doses and the inflammatory response associated with surgery and CPB, one might expect greater potential for development of HIT in our neonatal population.

Whether this reduced incidence of seroconversion in neonates and infants when compared with older children is a result of age, lack of prior UFH exposure, or both is unresolved. Infants may have a reduced ability to produce the necessary quantity of IgG antibodies. Also, sufficient quantities of PF4 may not be present in this population. In the presence of therapeutic heparin concentrations, formation of the heparin PF4 complexes capable of binding antibodies and inducing subsequent platelet aggregation occurs only in the presence of high concentrations of PF4.3,16,17

Whether postoperative exposure to UFH was a risk factor for seroconversion or development of HIT could not be determined, as almost all of our patients were exposed to postoperative UFH infusions as part of routine clinical care. The role of postoperative UFH exposure in adult cardiac surgical patients in seroconversion and developing HIT remains unresolved.11

The true incidence of HIT in the pediatric population is unclear. There are an increasing number of reported cases, but the criteria defining HIT and HITT are inconsistent.1,2,18,19–23 A retrospective cohort study of 612 pediatric intensive care unit patients who received UFH therapy for more than 5 days demonstrated a 2.3% incidence of HITT and a 1.6% incidence of thrombosis without thrombocytopenia.24,25 Seventy-five percent of these patients had undergone cardiac surgery and most thromboses were catheter-related. Of the 14 patients with thrombosis and thrombocytopenia consistent with HITT, only 6 had seroconversion as determined by the ELISA used in our study. Of the 10 patients with thrombosis without thrombocytopenia, none had seroconversion as determined by the same ELISA, but all had higher antibody titers than a matched control group without thrombosis. These findings lead the authors to speculate the adult cutoff for OD used to define seroconversion with this ELISA may be too rigorous in infants and neonates and may lack sensitivity.24,25 However, the authors’ recommendation that a lower cutoff for the ELISA be used in neonates lacks corroboration.15

In addition, the authors suggest that HIT may have existed in their patients who manifested thrombosis without thrombocytopenia due to masking of thrombocytopenia by postoperative thrombocytosis. In adults, it has been reported that the combination of HIT and the presence of a central venous catheter interact to produce intravascular thrombosis.26 However, in neonates, the presence of an intravascular catheter is, in and of itself, a significant risk factor for developing thrombosis.27,28 Finally, these investigators performed the ELISA on blood samples collected 1-36 h after radiologic detection of thrombosis in their pediatric intensive care unit patients. The timing of these samples makes comparison with samples drawn at POD 5 and POD 10 in our study difficult. However, it is noteworthy that our ReOP patients who seroconverted had lower platelet counts on POD 10 than those who did not seroconvert.

One series reported 10 cases of HIT in neonates, infants, and young children after cardiac surgery.29 All 10 patients manifested thrombocytopenia and thrombotic sequelae as well as antibody seroconversion determined by a functional assay (heparin-dependant platelet aggregation in platelet-rich plasma). On the basis of this experience, the authors estimated the incidence of HIT in their pediatric cardiac surgical patients to be 1.3%, an incidence similar to that found in the adult cardiac surgical population. One of 75 (1.3%) of our ReOp patients developed thrombocytopenia and antibody seroconversion. Using strict criteria, our patients would be considered to have had HIT, but not HITT, given the absence of a thrombotic event or development of skin lesions.

Further studies are necessary to determine diagnostic criteria for HIT in infants and children. Specifically, the severity of thrombocytopenia necessary to make this diagnosis in pediatric cardiac surgical patients needs to be more clearly defined. The role of UFH in the genesis of catheter-related thrombosis, with and without thrombocytopenia, also requires clarification. Finally, it remains to be determined whether a functional platelet assay, such as the SRA or an ELISA specific for IgG antibodies, would provide a better sensitivity-specificity tradeoff for diagnosis of HIT in the pediatric population than the ELISA used in this study.

Footnotes

Accepted for publication March 5, 2008.

Supported by grant MO1-RR02172 from the National Center for Research Resources, NIH, to the Children's Hospital Boston General Clinical Research Center.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mullen, M. P. Articles by DiNardo, J. A. Search for Related Content PubMed PubMed Citation Articles by Mullen, M. P. Articles by DiNardo, J. A. Related Collections Cardiovascular Coagulation Pediatrics