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Ann Thorac Surg 2001;71:678-683
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia

^a Service d’Anesthésie—Réanimation and E.A. 1896, Université Claude Bernard Lyon I, Lyon, France
^b Laboratoire d’Hématologie, Hôpital Cardiovasculaire et Pneumologique L. Pradel, Lyon, France

Accepted for publication May 25, 2000.

Address reprint requests to Dr Aouifi, Service d’anesthésie—Réanimation, Infirmerie Protestante de LYON, 1–3 Chemin du Penthod, 69300 Caluire et Cuire, France
e-mail: a.aouifi{at}free.fr

	Abstract

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Background. The use of cardiopulmonary bypass (CPB) in patients with a history of type II heparin-induced thrombocytopenia (HIT) may be associated with complications related to their anticoagulation management.

Methods. Between January 1997 and December 1999, among 4,850 adults patients who underwent cardiac surgery in our institution, 10 patients presented with preoperative type II HIT. In 4 patients, anticoagulation during CPB was achieved with danaparoid sodium. In 6 other patients, heparin sodium was used after pretreatment with epoprostenol sodium.

Results. No significant change in platelet count occurred in any patient. No intraoperative thrombotic complication was encountered. Total postoperative chest drainage ranged from 250 to 1,100 ml in patients pretreated with epoprostenol and 1,700 to 2,470 ml in patients who received danaparoid sodium during CPB (p < 0.05, Mann-Whitney U test).

Conclusions. During CPB, inhibition of platelet aggregation by prostacyclin may be a safe anticoagulation approach in patients with type II HIT.

	Introduction

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Heparin is one of the most commonly used anticoagulant drugs in cardiac patients. Unfortunately, a small number of patients receiving heparin develop a heparin-induced thrombocytopenia (HIT). Based on the severity of thrombocytopenia, HIT is differentiated into two types. In HIT type I, thrombocytopenia is moderate (>100 10⁹/L), early, asymptomatic, and transient, resolving spontaneously despite further heparin administration. In type II, thrombocytopenia is severe (<100 10⁹/L), persistent, and often associated with thrombo-embolic and hemorrhagic events [1].

During cardiac surgery, heparin is the standard anticoagulant for cardiopulmonary bypass (CPB). For this procedure, heparin has become essential because of its predictability effectiveness, rapid action, and reversibility with protamine. In patients scheduled for cardiac surgery with CPB, type II HIT is a rare but potentially dangerous state. Heparin use in this circumstance can lead to thrombo-embolic events, severe bleeding, and sudden death [2]. Because of these potentially catastrophic complications, alternative strategies avoiding reexposure to heparin or inhibiting platelet aggregation induced by heparin during CPB should be available to practitioners. In this report, we describe our experience of CPB anticoagulation in 10 patients with type II HIT who underwent cardiac surgery over the last 3 years. The different alternatives to heparin in these situations are described, and recommendations for intraperative anticoagulation are provided.

	Material and methods

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Between January 1997 and December 1999, among 4,850 adult cardiac surgical patients, 10 with preoperative documented HIT type II underwent a cardiac surgical procedure with CPB in our institution (0.2%). Age ranged from 53 to 84 years, and 6 patients were male. Characteristics of these patients are shown in Tables 1 and 2. HIT type II was confirmed in all patients by a positive result of platelet aggregation assay, which exhibits aggregation of normal donor platelets, by patient’s plasma in the presence of heparin. Concomitantly, plasma of all patients was screened for a potential cross-reaction with low molecular weight (LMW) heparin and danaparoid sodium.

In 4 patients (1–4), in the absence of positive cross-reaction, danaparoid sodium (Orgaran, Riom Laboratoires-CERM, Riom, France) was used for anticoagulation during CPB. Danaparoid sodium 3U/ml was added to the priming solution of CPB. Before commencing CPB, the 4 patients received an additional intravenous bolus (125 U/kg). Anti-Xa activity was checked prior to CPB, then 10, 30, and 60 minutes after institution of CPB. Celite activated clotting time (ACT) was measured concomitantly (Hemochron, Technidyne, Edison, NJ).

In the 6 other patients (5–10), anticoagulation during CPB was achieved with heparin sodium (Heparin Choay, Sanofi Wintrop, Gentilly, France), but administered following pretreatment with epoprostenol sodium (Flolan, Glaxo Wellcome, Paris, France). The anticoagulation regimen was as follows: continuous infusion of epoprostenol sodium started after induction of anesthesia at a rate of 5 ng/kg/min, infusion rate increased by stages of 5 µg/kg every 5 minutes, and when the infusion rate reached 30 ng/kg/min, a bolus of 300 U/kg of heparin was intravenously administered. When required, norepinephrine (0.05 to 0.1 µg/kg/min) was infused to maintain mean arterial pressure greater than 75 mmHg. CPB was started when ACT exceeded 480 seconds. After emergence from CPB, heparin was reversed with protamine (3 mg/kg). Fifteen minutes after protamine reversal, epoprostenol sodium infusion was reduced by stages of 5 ng/kg until stopped.

Antifibrinolytics were not used intraoperatively. During the postoperative period, 2 patients (2 and 8) who underwent mechanical valve replacement and 1 patient (9) who underwent mitral valvuloplasty were administered danaparoid sodium (150 U/h) intravenously, started on the 8th and the 12th postoperative hour, respectively.

On postoperative day 1, in the absence of active hemorrhage (chest drainage less than 20 ml/h during 2 consecutive hours), oral warfarin or intravenous aspirin was started, according to surgical indications.

	Results

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In patients receiving danaparoid sodium intraoperatively, anti-Xa activity ranged between 1.7 and 2.3 U/ml, and ACT between 196 and 370 seconds. In patients who were administered epoprostenol sodium and heparin, ACT remained greater than 520 seconds during CPB. No clotting occurred during CPB in any patient. Postoperatively, platelet count ranged between 28 and 173 10⁹/L except patient 4 who had a low preoperative platelet count (18 10⁹/L) which remained at 15 10⁹/L after CPB (Table 1).

Total postoperative bleeding ranged from 1,700 to 2,470 ml in the 4 patients receiving danaparoid sodium, and from 250 to 1,100 ml in the 6 patients treated with epoprostenol sodium and heparin (p < 0.05, Mann-Whitney U test). All patients receiving danaparoid sodium required transfusion of blood products. From 5 to 12 units of packed red cells were required to maintain hematocrit greater than 25%, and from 2 to 5 units of fresh frozen plasma were needed for each patient to reduce postoperative bleeding. In patients receiving epoprostenol, 2 to 4 units of packed red cells were transfused in patients 5, 6, 7, and 9 (Table 1). Patients 8 and 10 did not required any transfusion.

Patient 1, who underwent redo aortic valve replacement (AVR) developed multiple organ failure and died on the 45th postoperative day. Patients 2 and 3 required chest reexploration for bleeding on the 3rd and 15th postoperative day. Patient 4, who presented with infective endocarditis and refractory septic shock, died on the 8th postoperative hour.

	Comment

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HIT type II is due to an immune mediated reaction leading to thrombocytopenia between 4 to 14 days after exposure to heparin [1]. In 1992, Amiral and colleagues [3] showed that the heparin-platelet factor 4 (H-PF4) complex was the antigen responsible in 75% of cases. The antibody is an immunoglobulin (Ig), usually IgG, which recognizes the complex H-PF4 [4]. During type II HIT, antibodies to the H-PF4 complex induce platelet activation and aggregation through the platelet Fc receptor [3].

Incidence of type II HIT in patients scheduled for cardiac surgery with CPB is not precisely known. Previous data of the literature indicated an incidence ranging from 0.12% to 1.3% [5, 6]. This incidence was 0.2% in our institution. Whereas incidence of HIT type II in patients scheduled for CPB is low, postoperative prevalence of antibodies to H-PF4 after CPB is surprisingly high. In a prospective study measuring antibodies to H-PF4 on the 5th postoperative day in 111 patients, Bauer and associates [7] found that antibodies to H-PF4 were present in 51% of patients exposed to CPB. Nevertheless, in this study, the presence of antibodies was not necessarily associated with a platelet count decrease or a thrombo-embolic event.

Alternative therapeutic options in patients with HIT type II
In patients with HIT type II, there are several alternatives for anticoagulation during CPB: (a) use of heparin associated with a potent platelet inhibitor such as prostacyclin; (b) use of another anticoagulant such as danaparoid sodium or recombinant hirudin (r-hirudin); and (c) preoperative use of the defibrinogenating agent such as ancrod.

Prevention of heparin-induced platelet activation during CPB using prostacyclin was used during the 1980s [8]. Iloprost, an analogue of prostacyclin, was used during CPB by Addonizio and colleagues [9] in 3 patients with confirmed preoperative type II HIT. In these 3 patients, biological assays demonstrated the effectiveness of Iloprost for prevention of platelet activation by heparin during CPB. Subsequently, Iloprost was used safely during CPB, in patients with HIT, by several other authors [10, 11]. In 1990, Kappa and associates [11] reported the use of Iloprost in 9 patients scheduled for various types of cardiac surgery. In these 9 patients, anticoagulation was effective and safe without severe postoperative bleeding. Epoprostenol sodium, a prostaglandin (PGI₂), vasodilator, initially used in patients with pulmonary hypertension, is also a potent platelet inhibitor [12]. In our institution, since 1991, epoprostenol sodium was successfully used in association with heparin in patients with type II HIT requiring anticoagulation for hemodialysis, or vascular or cardiac surgery. In this report, we confirmed that epoprostenol sodium seems effective and safe with acceptable postoperative blood losses. Nevertheless, epoprostenol sodium, just as Iloprost, may induce hypotension which may be deleterious in hemodynamically unstable patients. This hypotension, due to a vasodilator action, may require the use of a vasoconstrictor such as norepinephrine.

During the last decade, danaparoid sodium and r-hirudin, were developed as two alternative drugs to heparin. Danaparoid sodium is an heparinoid comprising a mixture of polysulfated glycosaminoglycans (heparan sulfate 84%, dermatan sulfate 12%, and chondroitin sulfate 4%) [13]. It is a potent inhibitor of thrombin formation. This heparinoid was initially suggested as an alternative to heparin in medical patients with HIT for prevention of thrombo-embolic events [14]. The first use of danaparoid sodium during CPB was reported by Doherty and coworkers in 1990 [15]. In 1993, in an overview of 230 patients with HIT type II treated with danaparoid sodium, Magnani and colleagues [14] reported 19 patients who underwent cardiac surgery with CPB. In this review, the anticoagulant effect of danaparoid sodium during CPB was found to be effective, but with postoperative blood losses larger than those usually observed with heparin. Furthermore, several other case reports described the use of this anticoagulant during CPB [15–19] (Table 3). Unfortunately, two major pharmacological properties limit the use of this drug during CPB: the first one is the lack of a specific antidote, the second is its prolonged anti-Xa activity (25 hours approximately) [20]. The consequence is an excessive postoperative bleeding risk and need for transfusion of blood products as reported in the data of the literature (Table 3) and in our 4 patients. Another problem with danaparoid sodium is a possible cross-reaction with heparin which occurs in 10% of cases. A preoperative in vitro screening test is mandatory. This screening test should be performed at the same time as the in vitro assay for confirmation of HIT type II.

Ancrod is a defibrinogenating agent derived from the Malayan pit viper. It was used as an anticoagulant during CPB in a limited number of patients because of the lack of an effective neutralizing agent [25]. Moreover, the patient’s plasma fibrinogen must be decreased to 0.5 g/L before initiating CPB, preparation often requiring more than 12 hours, thus excluding emergencies. This drug is currently considered as a less favorable alternative to anticoagulation during cardiac surgery [10].

Management of anticoagulation for CPB in patients with HIT type II
The most essential decision in a patient with HIT type II is the absolute discontinuation of heparin including in the catheter flush solutions. Heparin-coated pulmonary catheter and CPB circuits must also be avoided [26]. Platelet transfusions are not indicated because this may induce or worsen thrombosis [10].

Because of the rare occurrence of HIT type II in patients scheduled for cardiac surgery with CPB, no study comparing the different alternative anticoagulation options is available. In the literature, most data are reported as case studies, therefore comparison between the different anticoagulant protocols is impossible. Nevertheless, based on these data, the following decisional approach may be proposed (Fig 1).

View larger version (30K): [in this window] [in a new window]   Fig 1. Algorithm for anticoagulation management in patients with HIT type II scheduled for cardiac surgery with CPB. (CPB = cardiopulmonary bypass; HIT = heparin-induced thrombocytopenia.)

When HIT type II is recent and the platelet aggregation assay still positive, it is preferable, when possible, to postpone the date of surgery until disappearance of H-PF4 antibodies as suggested by Warkentin and colleagues [28]. In patients requiring emergent cardiac surgery, CPB may be performed with one of the following protocols. The association of heparin with prostacyclin appears to have the better risk/benefit ratio, because of the easy protamine reversal and the limited postoperative blood losses. In patients who might poorly tolerate the hypotension associated with a prostaglandin’s administration, danaparoid sodium or r-hirudin may be used, but with excessive bleeding.

Conclusion
HIT type II in a patient scheduled for cardiac surgery with CPB is a rare but potentially life-threatening situation, which requires special intraoperative anticoagulation management. Various types of anticoagulation approaches are available such as prevention of platelet aggregation by prostacyclin or the use of danaparoid sodium or r-hirudin. The use of a combination of prostacyclin and heparin seems to be safe and effective. Intraoperative use of danaparoid is often associated with excessive bleeding and greater blood transfusion need.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The authors acknowledge Dr Rhys Evans from the Nuffield Department of Anaesthetics, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom, for help during the manuscript preparation.

	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 Aouifi, A. Articles by Lehot, J.-J. Search for Related Content PubMed PubMed Citation Articles by Aouifi, A. Articles by Lehot, J.-J. Related Collections Extracorporeal circulation