Incidence of Heparin-Induced Thrombocytopenia and Therapeutic Strategies in Pediatric Cardiac Surgery

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Incidence of Heparin-Induced Thrombocytopenia and Therapeutic Strategies in Pediatric Cardiac Surgery Andreas Böning, MD, Torsten Morschheuser, MD, Udo Bläse, ECCP, Jens Scheewe, MD, Michael von der Brelie, MD, Ralf Grabitz, MD, PhD, and Jochen T. Cremer, MD, PhD Departments of Cardiovascular Surgery and Pediatric Cardiology, University Hospital Kiel, and Department of Cardiology, Albertinen-Hospital, Hamburg, Germany

Background. We identified the incidence of heparininduced thrombocytopenia and the antiheparin-platelet factor 4 (PF4) antibody in pediatric patients undergoing cardiac surgery and documented the differences in the anticoagulation management for the extracorporeal circulation. Methods. Between January 2001 and September 2003, 559 cardiac procedures with extracorporeal circulation in 415 patients with congenital heart defects were performed in our institution. Because the development of heparin-induced thrombocytopenia requires previous exposition to heparin, only the 144 patients undergoing a scheduled second procedure on extracorporeal circulation were screened preoperatively. Of these 144 patients, 41 underwent also a third procedure and were screened before each procedure for presence of antiheparin-PF4 antibodies and for clinical signs of heparin-induced thrombocytopenia. Results. The incidence of antiheparin-PF4 antibodies during the study period was 1.4% (2 of 144 patients).

Patients with clinically significant heparin-induced thrombocytopenia could not be identified. Outside the study protocol, 2 more patients with antiheparin-PF4 antibodies were found. In these 4 patients, surgery was performed using lepirudin (Schering, Berlin, Germany) instead of the usual heparin management for extracorporeal circulation. Three of these 4 patients had an uneventful procedure and postoperative course. In 1 patient after total cavopulmonary connection, a reoperation was necessary on the seventh postoperative day owing to partial thrombosis of the lateral tunnel. Conclusions. The incidence of heparin-induced thrombocytopenia and of antiheparin-PF4 antibodies in patients undergoing repeated cardiac surgery is low. In antiheparin-PF4 antibody positive patients, the complete avoidance of heparin can be achieved and may account for an uneventful perioperative course.

H

[8 –10]. Publications about the anticoagulation management of the ECC in pediatric cardiac surgery are even more rare [11]. We sought to identify the incidence of HIT II and antiheparin-PF4-antibody positivity in pediatric patients undergoing cardiac surgery and documented the differences in the intraoperative and postoperative anticoagulation management.

eparin-induced thrombocytopenia type II (HIT II) is an immune-mediated coagulation disorder resulting when preexisting antibodies against heparin are exposed to complexes of platelet factor 4 (PF4) and heparin [1, 2]. Platelet activation is then caused by complexes of heparin, PF4, and immunoglobulin G on the platelets’ surfaces, which leads to subsequent activation of coagulation and to a decrease in platelet counts in blood samples. In approximately 40% to 75% of HIT II patients, venous or even arterial thromboses develop [3, 4]. Heparin-induced thrombocytopenia type II is a rare (1% to 2.4%) but severe complication after adult cardiac surgery [4, 5] with the use of heparin for the anticoagulation management during extracorporeal circulation (ECC). Data regarding the frequency of HIT after pediatric cardiac surgery are not available. After the first publications about an alternative anticoagulation method in adult cardiac surgery [6, 7], there are few anecdotal reports about the treatment of HIT-positive children

Accepted for publication July 6, 2004. Address reprint requests to Dr Böning, Department of Cardiovascular Surgery, University Hospital, Arnold-Heller-Str 7, 24105 Kiel, Germany; e-mail: [email protected].

© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2005;79:62–5) © 2005 by The Society of Thoracic Surgeons

Patients and Methods Between January 2001 and September 2003, 559 cardiac procedures with ECC in 415 patients with congenital heart defects were performed in our institution. Because the development of HIT II requires previous contact with heparin, only the 144 patients undergoing a scheduled second procedure, 207 ⫾ 180 days (range, 15 to 2,156) after the first procedure, on ECC were screened for antiheparinPF4-antibodies before each surgery and for clinical signs of HIT II in their intermediate course up to the second or third approach. Of these 144 patients, 41 underwent also a third procedure, 372 ⫾ 273 days (range, 10 to 861) after second procedure and were screened again. Patients with second procedures less than 10 days after 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.07.002

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Abbreviations and Acronyms BW ⫽ body weight CoA ⫽ coarctation DILV ⫽ double inlet left ventricle DORV ⫽ double outlet right ventricle ECC ⫽ extracorporeal circulation ECT ⫽ ecarin clotting time HIT II ⫽ heparin induced thrombocytopenia type II HPIA ⫽ heparin-induced platelet activation assay HTX ⫽ heart transplantation IAA ⫽ interrupted aortic arch PF4 ⫽ platelet factor IV PTT ⫽ plasma thrombin time RVOT/PA ⫽ right ventricular outflow tract/Pulmonary artery TAPVD ⫽ total anomalous pulmonary venous drainage TCPC ⫽ total cavopulmonary connection TGA ⫽ transposition of the great arteries TOF ⫽ tetralogy of Fallot TV ⫽ tricuspid valve VSD ⫽ ventricular septal defect

their first surgery (n ⫽ 10) and patients who died shortly after their first surgery (n ⫽ 6) were excluded from the study. The congenital pathologies of the study patients were Table 1. Surgical Procedures in Patients Screened for Antiheparin PF4 Antibodies Before Repeat Cardiac Surgery With Extracorporeal Circulation Procedure Norwood 1 Hemifontan/Glenn RVOT-PA repair Shunt CoA (⫹VSD), IAA Fallot-Correction Total cavopulmonary connection Tricuspid valve reconstruction Unifocalization ⫹ shunt Truncus arteriosus correction TAPVD correction Arterial switch (⫹VSD) Heart transplant Re-VSD Miscellaneous

First

Second

Third

63 (43.5%) 15 (10.6%) 2 (1.2%) 17 (11.8%) 14 (9.4%) 3 (2.4%) 0

0 68 (47.1%) 15 (10.3%) 8 (5.7%) 3 (2.3%) 3 (2.3%) 10 (6.9%)

0 3 (8.3%) 7 (16.7%) 0 0 0 16 (38.9%)

0

10 (6.9%)

5 (11.1%)

3 (2.4%)

0

0

5 (3.5%)

0

0

5 (3.5%) 5 (3.5%)

0 0

0 0

0 0 12 (8.2%)

3 (2.3%) 7 (4.6%) 17 (11.5%)

63

as follows: hypoplastic left heart syndrome (n ⫽ 70); transposition of the great arteries ([TGA] simple, with ventricular septal defect [VSD], double inlet left ventricle or double outlet right ventricle, n ⫽ 20); tetralogy of Fallot (also with pulmonary atresia, n ⫽ 16); coarctation (also with VSD, n ⫽ 13); truncus arteriosus communis (n ⫽ 5); total anomalous pulmonary venous drainage (n ⫽ 5); tricuspid atresia (n ⫽ 5); VSD/pulmonary stenosis (n ⫽ 2); miscellaneous (n ⫽ 8). The surgical procedures are displayed in Table 1. Heparin-induced thrombocytopenia type II was suspected if a positive value (cutoff point, 28.5%) of the antiheparin-PF4-antibody was detected by a heparin-induced platelet activation assay (Asserachrom HPIA; Roche Diagnostics, Mannheim, Germany). Patients who tested positive for antiheparin-PF4antibody were treated specifically, as if they were HIT II positive: heparin contact before, during, and after ECC was avoided. During ECC, lepirudin (Refludan; Aventis, Bad Soden, Germany), a recombinant hirudine acting as a direct thrombin inhibitor, was used. Because the plasma thrombin time (PTT) is invalid in higher lepirudin dosages, the lepirudin concentration during ECC was monitored by the Ecarin clotting time (ECT, Pentapharm, Basel, Switzerland). The advantage of the ECT monitoring is the proportionality of the ECT to lepirudin concentrations of greater than 2 ␮g/mL [12]. Before surgery, an individual calibration graph was obtained using the patient=s blood: after adding lepirudin in concentrations of 1 ␮g/mL, 2 ␮g/mL, 3 ␮g/mL, and 4 ␮g/mL to the patient=s blood, the ECT values for these samples were determined. Lepirudin was added to the ECC priming (0.2 mg/kg body weight) and given intravenously (0.25 mg/kg body weight) before ECC start after having obtained the first ECT. During ECC, a lepirudin infusion was adjusted according to the relevant ECT, which was measured every 10 minutes. Target values were a minimum of 3.5 ␮g/mL and a maximum of 5 ␮g/mL patient blood. Thirty minutes before termination of the ECC, the lepirudin infusion was stopped, and the lepirudin was removed from the patient by ultrafiltration and stimulation of the diuresis. If bleeding continued, a cell-saving device primed with lepirudin (1 mg/L rinsing fluid) was used, further renal elimination of lepirudin was intensified, and increased efforts for subtle surgical hemostasis were made.

Results

0 0 10 (25%)

CoA ⫽ coarctation; IAA ⫽ interrupted aortic arch; PA ⫽ pulmonary artery; RVOT ⫽ right ventricular outflow tract; TAPVD ⫽ total anomalous pulmonary venous drainage; VSD ⫽ ventricular septal defect.

The incidence of antiheparin-PF4-antibody positivity (266 ⫾ 168 days after last surgery) during the screening period was 1.4% (2 of 144 patients). In these 2 patients, as well as in all other screened patients, no sign for previous HIT II could be found: neither a thrombopenia of less than 50% of the preoperative value 5 to 10 days after previous surgery, nor the generation of thrombosis or embolization combined with a positive antiheparin-PF4antibody could be proved. In the 2 patients positive for antiheparin-PF4-antibody, in whom heparin exposition was totally avoided, surgery was performed using lepirudin instead of heparin on ECC. Additionally, the cellsaving device suction was also primed with lepirudin.

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Table 2. Surgical Procedures, Testing for Heparin-Induced Thrombocytopenia II, and Perioperative Data in Patients Undergoing Extracorporeal Circulation (ECC) With Lepirudin Patient No.

Height (cm)/ Weight (kg)

Surgical Procedure

105/13 100/15 61/5.1 61/5.0

TCPC RVOT conduit Hemifontan Hemifontan

I II III IV

HPIA ⫽ heparin-induced platelet activation assay; connection.

Interval Between Last Heparin Exposure and HPIA test 13 20 47 2

days days days days

n.a. ⫽ not available;

Outside the screening period, 2 additional patients with antiheparin-PF4-antibodies could be found and were treated similarly. The last heparin exposure for the 4 patients positive for antiheparin-PF4 antibody was at the time of preoperative cardiac catheterization (2 to 47 days before surgery; Table 2). The first patient with a complex cardiac malformation (upstairs-downstairs ventricles, VSD, straddling of the left-sided atrioventricular valve, d-TGA, coarctation) underwent correction of the coarctation and pulmonary banding on March 13 and 18, 1997. After resection of a subaortic stenosis, an atrioseptectomy, isolation of the pulmonary bifurcation, and a modified Blalock-TaussigShunt, a residual subaortic stenosis had to be removed and the Blalock-Taussig-Shunt had to be enlarged in February 1998. A hemifontan procedure with patch plasty of the left ventricular outlet tract and the ascending aorta was done in March 1999. After a first positive value of antiheparin-PF4-antibodies, a total cavopulmonary connection was carried out on March 7, 2001. After total cavopulmonary connection, a reoperation became necessary on the seventh postoperative day owing to partial thrombosis of the lateral tunnel (Table 2). The second patient, who had undergone corrective surgery for tetralogy of Fallot in March 1997, needed first a pulmonary artery plasty in April 1997, then a homograft implantation and patchplasty of the left pulmonary artery in December 1997. Owing to a homograft stenosis, a xenograft was implanted in March 2003 after a first positive PF4 value 10 days earlier. (For a description of the anticoagulation regime with lepirudin, see Methods.) The procedure and the postoperative course were uneventful (Table 2). Patients 3 and 4 (outside the screening period) had hypoplastic left heart syndrome, and underwent an uneventful hemifontan procedure with lepirudin anticoagulation on ECC (Table 2).

Comment The first part of this study shows that the incidence of antiheparin-PF4-antibodies in children undergoing repeat cardiac surgery is low (1.4%). During the study period, HIT II could not be found in a single patient. Pooled data [1] indicate that HIT II is a rare (2.4% of all patients) but severe complication after adult cardiac sur-

HPIA Titer 36,7% 45,1% 33% n.a.

Duration of Perioperative Surgery Blood Loss and ECC (min) (4/24 hrs) 270/97 211/95 320/180 235/127

RVOT ⫽ right ventricular outflow tract;

50/150 mL 31/68 mL 22/128 mL 50/353 mL

Blood Transfusions 160 400 150 510

mL mL mL mL

TCPC ⫽ total cavopulmonary

gery: venous or arterial thromboses develop in 38% to 81% of HIT II patients, leading to a mortality rate of 28% [13]. Heparin-induced thrombocytopenia type II is a clinical diagnosis based on substantial platelet count falls (usually by more than 50%) [1] and on the development of thrombosis and skin lesions [4]. The clinical diagnosis can be confirmed by a positive antiheparin-PF4-antibody value in one of the commercially available enzyme immunoassays. The work of Chilver-Stainer and associates [14] shows that high antiheparin-PF4-antibody titers, detected in the same enzyme-linked immunosorbent assay test as used by us, are independently associated with an increased in vivo thrombin generation. Nonfunctional (insignificant) antibodies, which can also be detected by this enzyme-linked immunosorbent assay, seem to lead to low antiheparinPF4-antibody titers, which have a low retrospective probability score for HIT [14]. Generally, a negative antiheparin-PF4-antibody test rules out HIT II [15]. A positive antiheparin-PF4-antibody without clinical symptoms, however, does not necessarily prove HIT II to be the diagnosis [1], because seroconversion to antiheparin-PF4-antibody positivity after adult cardiac surgery occurs in 27% to 50% of patients [16]. This seroconversion is usually transient: a decline to nondetectable levels occurs after a median of 50 days [17]. That means that a patient after cardiac surgery coming to a second procedure with a positive antiheparin-PF4antibody value does not necessarily have HIT II. Therefore, the use of heparin [1] or of heparin combined with tirofiban, a platelet glycoprotein IIb/IIIa antagonist [18], instead of hirudin for anticoagulation management during ECC is discussed for patients after HIT II and without clinical symptoms independent from a positive antiheparin-PF4-antibody value. After having had positive experiences with lepirudin, our clinical strategy now avoids heparin exposure for patients positive for antiheparin-PF4-antibody who are potentially at risk of developing HIT. In these patients, a small amount of heparin is sufficient for the development of HIT II, because the boostering of an antibody reaction to heparin is not dose-dependent. This reaction to heparin could be caused by a preoperative cardiac catheterization in a child before repeat cardiac surgery. The second part of this study shows that in antiheparinPF4-antibody positive patients, the successful anticoagulation management during ECC with lepirudin, as first re-

ported for adult cardiac surgery by Riess and colleagues [6, 7], is possible also in pediatric cardiac surgery. After having built up a working group of surgeons and perfusionists being responsible for the management of HIT II patients, we have gained experiences with the use of lepirudin for the anticoagulation management on ECC in adult patients. Because the incorrect dosage of lepirudin could lead to either clotting of blood in the ECC or bleeding after surgery, one of the most important management steps is controlling the lepirudin level by the ECT. Based on these experiences in HIT II–positive adults, we dared to extend the lepirudin management also to children positive for antiheparin-PF4-antibody. In our practice, we see contraindications to lepirudin for anticoagulation on ECC in patients with renal dysfunctions and coagulation disorders. Because of the renal excretion of lepirudin, in patients with renal dysfunctions, hemofiltration/hemodialysis has to be used to remove lepirudin from the blood, which has been shown to be possible experimentally [19] as well as clinically [6]. Koster and coworkers showed the use of plasmapheresis filters to be more effective to eliminate from the patient=s blood than hemofilters [20]. In our pediatric patients, lepirudin could be removed by ultrafiltration on ECC or modified ultrafiltration after ECC. An alternative to lepirudin in patients with renal insufficiency could be bivalirudin, another r-hirudin currently under investigation, because of its mostly enzymatic metabolization. Bivalirudin has been shown to be effective in cardiac surgery with [21] and without [22] extracorporeal circulation. Danaparoid for the management of pediatric HIT II patients has also been described [23], but in adults, intraoperative clotting and postoperative bleeding occurred in many patients [1]. Our results can neither show a superiority of lepirudin over heparin as anticoagulation drug nor that there would have been any outcome difference if heparin had been used. However, the determination of a positive antiheparin-PF4 antibody value after heparin administration during cardiac catheterization shortly before repeat cardiac surgery justifies the suspicion of HIT II even without clinical signs and therefore the use of an alternative to heparin. Moreover, the high antiheparin PF4 titers seen in our patients are associated with an increased thrombin generation [14] placing these patients at a higher level of coagulation activation. In conclusion, the incidence of antiheparin-PF4antibodies in children undergoing repeated cardiac surgery is low (1.4%); clinical signs for HIT II could not be found in our patients throughout the screening period. In pediatric cardiac surgery patients who are antiheparin-PF4-antibody positive, the total avoidance of heparin is possible and accounts for an uneventful perioperative course.

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