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Department of *Anesthesiology and
Laboratory Medicine,
Division of Hematology, and
Division of Cardiovascular Surgery,
||Mayo Clinic, Rochester, Minnesota
Address correspondence and reprint requests to Gregory A. Nuttall, MD, Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905. Address e-mail to nuttall.gregory{at}mayo.edu
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Abstract |
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IMPLICATIONS: We report a case series of 12 patients with a clinical history of type II heparin-induced thrombocytopenia and describe their hematologic management during cardiac surgery with cardiopulmonary bypass.
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Introduction |
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RIIA-receptors, inducing strong platelet activation and aggregation (2). These antibodies can also bind to PF4 on endothelial cell proteoglycans, thereby promoting endothelial injury. These combined events can lead to a precipitous reduction in circulating platelet counts, frequently to <30 x 109/L, and life-threatening venous and arterial thrombosis, which can result in limb and organ ischemia (3,4). The profound thrombocytopenia usually resolves once heparin exposure has ceased. Even small doses of heparin, such as prophylactic doses, flush solutions, and heparin-bonded catheters can induce HITT type II (4,5). Anticoagulation is a significant concern for patients with HITT type II being prepared for cardiac surgery with or without cardiopulmonary bypass (CPB). We report our experience with 12 patients clinically diagnosed with HITT type II presenting for cardiac surgery requiring CPB.
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Methods |
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All of the patients had been diagnosed with HITT type II using clinical criteria. Each patient had a decrease in platelet count to <100 x 109/L associated with heparin administration, which increased after heparin cessation. Two patients had thrombotic episodes associated with thrombocytopenia. Because HITT type II is an antibody-mediated disorder, the antibody may resolve over time. Therefore, a patient with a history of HITT type II may no longer have measurable amounts of the antiheparin antibody (6). Each patient had the presence of the HITT type II antibodies determined by enzyme-linked immunosorbent assay (ELISA) for heparin-PF4 complex using goat antihuman antibody that directly detects the heparin-induced antibodies before surgery. Six of 12 patients had a positive ELISA for the heparin-PF4 complex antibodies immediately before surgery. The other six patients had a negative ELISA for the heparin-PF4 complex antibodies immediately before surgery.
All patients received a moderate-dose opioid-based anesthetic, supplemented with benzodiazepines, muscle relaxants, and inhaled anesthetics. A Terumo 5 x 25-membrane oxygenator (Terumo Cardiovascular Systems, Elkton, MD) was used in a Sarns 9000 CPB machine (Sarns Inc, Ann Arbor, MI) at a flow of 2.4 L · min-1 · m2. The CPB circuit was primed with 1.5 L of plasmalyte, 10 mEq of sodium bicarbonate (NaHCO3), and 0.5 g/kg of mannitol. All patients had arterial and nonheparin-bonded pulmonary artery catheters placed before CPB, and all flushing solutions were free of heparin. In all patients, antifibrinolytic therapy was administered using either full-dose aprotinin (2 x 106 kallikrein inhibitory units [KIU] [280 mg] followed by a maintenance infusion of 500,000 KIU/h (70 mg/h), with a bypass prime of 2 x 106 KIU [280 mg]) or tranexamic acid (10-mg/kg load followed by 1 mg · kg-1 · h-1). Our practice for antifibrinolytic use is aprotinin for repeat sternotomies and complex procedures and tranexamic acid for primary procedures. Allogeneic red blood cells were transfused when the hemoglobin concentration became <8 g/dL after discontinuation of CPB and <7 g/dL during CPB. Transfusion of allogeneic fresh frozen plasma, platelets, or cryoprecipitate was based on clinical evidence of bleeding and supporting laboratory studies (thromboelastography [TEG®; Haemoscope Co, Skokie, IL] maximum amplitude <48 mm, platelet count <102,000 x 109/L, prothrombin time >16.6 s, activated partial thromboplastin time [aPTT] >57 s, or fibrinogen level <144 mg/dL) (7).
Patients who were negative for the HITT type II antibodies underwent cardiac surgery with CPB, and heparin was only administered for anticoagulation during CPB. No heparin or heparin flush was administered after CPB. Porcine heparin was administered to patients as an initial bolus of 300 U/kg and 10,000 U in the priming volume of the oxygenator. Additional heparin (5000 U) was administered when the activated clotting time (ACT) was <450 s in patients not receiving aprotinin. For patients receiving aprotinin, additional heparin was administered when the kaolin ACT was <450 s or the celite ACT was <750 s. After discontinuation of CPB, the initial protamine sulfate dose was 0.013 mg/U of heparin administered. Heparin neutralization was regarded as adequate if the postprotamine ACT value was within 10% of the preheparin ACT value. Additional protamine (20–50 mg) was added at the discretion of the attending anesthesiologist if the ACT had not returned to this range. Intraoperative blood salvage and reinfusion of shed mediastinal blood was used in all cases. Ultrafiltration was not used with any of these patients.
If those patients who had HITT type II antibodies confirmed by ELISA were unable to have their cardiac surgery delayed until the antibodies disappeared, recombinant hirudin (r-hirudin or Lepirudin) was used as the anticoagulant during CPB. The r-hirudin concentration was monitored by measurement of the ECT on the Thrombolytic Assessment System (TAS) point-of-care analyzer (PharmaNetics Inc, Morrisville, NC). Before surgery, a sample of blood was collected in 3.2% sodium citrate tubes, and an in vitro titration of r-hirudin was performed to develop an individual patient calibration curve for the ECT. In those patients already on r-hirudin before surgery, when possible, the patient’s r-hirudin was discontinued for a 24-h period to collect the in vitro titration sample without previous r-hirudin contamination of the sample. To minimize the effects of hemodilution and depletion of procoagulant through contact activation of the CPB circuit, the citrated whole-blood samples were supplemented 1:1 with standard human plasma. This ensures adequate prothrombin and fibrinogen concentrations for precise ECT measurements when the r-hirudin concentrations are larger than 2 µg/mL. All measurements were performed in duplicate.
The dose of r-hirudin was a 0.25 mg/kg bolus before CPB, 0.20 mg/kg in CPB pump prime, and a continuous infusion of 0.5 mg/min after the bolus and throughout CPB (8). The bolus and infusion of hirudin were administered early enough to insure an adequate hirudin concentration of more than 3.5 µg/mL per ECT monitoring (8). Supplemental bolus doses of hirudin and increases in the hirudin infusion occurred to maintain hirudin concentrations larger than 3.5 µg/mL per ECT. The ECT was performed every 15–30 min throughout CPB. There is no Food and Drug Administration (FDA) approved antagonist to hirudin. The r-hirudin infusion was discontinued 15–30 min before termination of CPB. Because r-hirudin has a molecular weight (6980 Da) that is small enough to be effectively hemofiltered with certain large flux hemodialyzers, hemofiltration (Hemoconcentrator HC05, 0.5 m (2), cutoff point 65,000 Da; Terumo Cardiovascular Systems) and forced diuresis with furosemide and mannitol were performed on rewarming or near the termination of CPB to assist in the rapid removal of circulating r-hirudin (9). Fresh frozen plasma was also transfused to antagonize hirudins’ anticoagulant effect after CPB if bleeding and laboratory tests supported this intervention. Perioperative blood salvage (cell saver) was not used in these patients because of the concern of re-transfusing blood with hirudin.
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Discussion |
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HITT type II is a clinical diagnosis that is supported by laboratory tests (4). HITT type II is identified by the following clinical criteria: a massive decrease in platelet count with exposure to heparin, thromboembolism, resolution of thrombocytopenia after cessation of heparin exposure, and detection of heparin-dependent antibodies. Various laboratory tests can be used to verify the diagnosis of HITT type II (5,10). The two most common tests are the heparin-induced platelet aggregation assay (HIPAA) by platelet-rich plasma aggregometry and ELISA for heparin-PF4 complex using goat antihuman antibody that directly detects the heparin-induced antibodies.
Although the prevalence of antibodies to the heparin-PF4 complex by ELISA may be as frequent as 61% at five days after cardiac surgery, the incidence of clinical HITT type II in cardiac surgery patients is estimated to be 1.3% (11,12). Yet, if HITT develops in this setting, both the morbidity and mortality can be frequent. Walls et al. (11) reported a 51% incidence of thromboembolic complications with an accompanying mortality of 37% in patients with HITT after CPB. Therefore, heparin administration in any form should be avoided if possible in patients with documented HITT type II antibodies. However, heparin is the preferred anticoagulant for CPB. Therefore, in patients with circulating heparin-PF4 antibodies, the urgent or emergent necessity for cardiac surgery remains problematic. The FDA has approved the use of r-hirudin for anticoagulation in patients with documented HITT type II. Hirudin is a highly selective thrombin inhibitor that does not inhibit other serine proteases. It was originally derived from the saliva of leaches. Although hirudin is available as an anticoagulant for CPB, appropriate dosing and anticoagulation monitoring are not fully standardized. The following dosing regimen for hirudin administration during CPB has been shown to be effective (1,8): 0.25-mg/kg hirudin bolus before CPB, 0.20 mg/kg in CPB pump prime, and continuous infusion 0.5 mg/min after bolus and throughout CPB.
With the use of hirudin instead of heparin, which is the conventional method of anticoagulation monitoring, the ACT is not applicable. Instead, there is an effective point-of-care test to measure hirudin levels during CPB based upon the FDA approved coagulation device called the "TAS." The test cartridge for the TAS that measures hirudin levels is the ECT (1). The mechanism by which the ECT measures hirudin concentrations is by ecarin, derived from snake venom, converting prothrombin to meizothrombin. Because hirudin inhibits meizothrombin’s conversion of fibrinogen to fibrin, the time it takes for clot formation to occur is directly related to the hirudin concentration in the plasma. Previous investigations have maintained hirudin concentrations more than 3.5 µg/mL throughout the duration of CPB. The ECT cartridge has recently received a HDE from the FDA (HDE-h9900012), and a compassionate use IRB approval or a research protocol is required for its use. Before CPB, an in vitro titration of hirudin using the patient’s blood is required to develop a titration curve for the ECT test’s response to various hirudin concentrations.
The previous studies of hirudin use for CPB, from which we derived our clinical care protocol, have been retrospective studies performed primarily in Germany (1,8). These studies have demonstrated good success with the use of hirudin anticoagulation during CPB with ECT guidance in larger numbers of patients. Because hirudin is eliminated primarily through renal excretion, we also augmented hirudin elimination through the use of ultrafiltration and forced diuresis, as reported in the previous studies.
It is now recognized that HITT type II is a transient immune response to the conformationally altered PF4 heparin complex triggered by heparin administration that results in thrombocytopenia in addition to a prothrombotic state and thromboembolic events (6). The immune response begins to wane after eliminating further heparin exposure, and the antibodies that mediate HITT type II often are no longer detectable after several months (6). Therefore, a patient with a very significant history of HITT type II may no longer have the PF4 complex antibody after several months. Six of the 12 patients with clinical histories of HITT type II did not have detectable anti-PF4 antibodies by ELISA. Brief exposure to heparin was used for CPB and reversed after CPB with protamine because of the absence of antibodies. No further heparin was administered after that time, and heparin was excluded from the flush systems for any invasive catheters to prevent any heparin from being in the patient, should anti-PF4 antibodies redevelop in response to heparinization during CPB. None of these patients developed detectable thromboembolic phenomenon after surgery. The blood loss and transfusion requirements in these patients were consistent with our general population of cardiac surgical patients.
Because the kidney removes hirudin, patients with renal failure or insufficiency may benefit from the use of an alternative anticoagulant. Koster et al. (13,14) recently reported on the use of the combination of the short acting platelet glycoprotein IIb/IIIa inhibitor tirofiban (load 10 µg/kg followed by an infusion of 0.15 µg · kg-1 · h-1), followed with standard-dose unfractionated heparin to accomplish CPB in 10 patients who had renal impairment. The patients were placed on hirudin infusions upon arrival to the intensive care unit adjusted to an aPTT of 40–60 seconds. There were no thrombotic complications, and the patients had very little bleeding and allogeneic blood transfusion requirements. A new FDA-approved specific thrombin inhibitor, bivalirudin, is less dependent on renal function for drug clearance (normal renal function, t1/2 = 25 minutes; severe renal impairment, t1/2 = 57 minutes)1 than hirudin. This drug could also be used in the same way as hirudin for anticoagulation in patients with or without renal insufficiency who require CPB, although there are no published studies using this drug in CPB (15,16).
There are limitations to our case series. The diagnosis of HITT type II is based on both clinical and pathologic criteria. The most common clinical abnormality is thrombocytopenia, which is often complicated by thrombosis. Only one of our ELISA negative patients had a previous positive ELISA with the initial diagnosis of HITT. Therefore, a possibility is that those patients with a negative ELISA may never have had HITT, and the clinical diagnosis was incorrect. The accuracy of the confirmatory tests for HITT type II is not perfect. In our protocol, we chose to use the ELISA for the heparin-PF4 complex antibodies immediately before surgery as the determinant for whether to use heparin as the anticoagulant during CPB. The ELISA is very sensitive but has a frequent false-positive rate (12). There have been reports of false negatives with this assay also. An alternative assay that is popular in Europe is a functional assay based on the platelet activating properties of the HITT antibody in platelet-rich plasma aggregometry or HIPAA. The HIPAA is difficult to perform and user dependent. It also has a frequent false-positive rate. Another limitation of our study is that a large number of our patients had impaired renal function. As a result, hirudin clearance was impaired, and these patients had large blood loss and allogeneic transfusion requirements. Use of the newer alternative anticoagulants listed above would be beneficial in this population. We also had a much larger amount of bleeding and transfusion than previously reported by Koster et al (13,14). The patients described in this manuscript were very sick (many with hepatic and renal insufficiency), and this may have resulted in the large amount of bleeding and blood transfusion. Another cause for the large blood loss and allogeneic transfusion requirements in the hirudin treated patients may be that intraoperative auto infusion was not used in these patients. Use of intraoperative auto infusion has been shown to reduce allogeneic blood use (17).
In conclusion, patients with HITT type II who require cardiac surgery and CPB constitute a significant challenge. Cooperation between multiple specialties is critical to successfully manage these patients. This is a case series of patients who, because of FDA requirements, were cared for under a defined protocol of care. With the proper anticoagulation and monitoring, this population can successfully undergo cardiac surgery and CPB.
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Footnotes |
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