Heparin-Induced Thrombocytopenia and Cardiac Surgery Jerrold H

Heparin-induced thrombocytopenia and cardiac surgery Jerrold H. Levy and Anne M. Winkler

Emory University School of Medicine, Atlanta, Georgia, Purpose of review USA Heparin-induced thrombocytopenia (HIT) is an important, increasingly recognized Correspondence to Jerrold H. Levy, MD, Emory antibody-mediated complication of heparin therapy occurring in approximately 0.5–5% University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA of patients receiving heparin for at least 5 days. HIT is a prothrombotic disorder that Tel: +1 404 778 3934; fax: +1 404 778 5194; typically presents with a 50% platelet count drop, thrombotic event manifesting usually e-mail: [email protected] 5–14 days after starting heparin, or both. HIT antibodies usually decrease to negative Current Opinion in Anaesthesiology 2010, titers/levels within 3 months. When there is clinical suspicion of HIT, heparin should be 23:74–79 discontinued and alternative anticoagulation should be considered, as well as laboratory evaluation for HIT. Recent ﬁndings HIT immunoassay results should be used for clinical decision-making about initial anticoagulation management. Recent data reevaluate the importance of absolute titers of HIT antibodies as a risk factor for clinical occurrence. Although laboratory assays are routinely used, current data suggest that increasing optical densities are more likely associated with a positive 14C-serotonin release assay and HIT. HIT is also associated with a greater risk for adverse events, so even though alternative anticoagulation is used, clinicians should be aware of this hypercoagulable syndrome. Summary For patients with HIT, alternative anticoagulation is available, but for cardiovascular surgery, if the operation cannot be delayed until HIT antibodies have become negative, alternative anticoagulation strategies are recommended, although patients with HIT are at a greater risk for adverse outcomes.

Keywords anticoagulation, cardiac surgery, heparin-induced thrombocytopenia, hypersensitivity, thrombosis

Curr Opin Anaesthesiol 23:74–79 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 0952-7907

in platelet alpha granules. Heparin–PF4 antibodies are Introduction generated when heparin and PF4 bind, creating a con- Heparin-induced thrombocytopenia (HIT) is an formational change on PF4 that exposes new antigenic immune-mediated prothrombotic event resulting from binding sites called epitopes [4]. The antibody produ- platelet activation by an antibody formed during heparin cing HIT is an immunoglobulin (Ig)G antibody that therapy. Clinically, HIT manifests as an unexplained binds heparin–PF4 complexes on platelet surfaces to more than 50% decrease in the platelet count, often to form immune complexes. The platelets in turn are 9 less than 100 Â 10 /l that can be associated with throm- activated by the Fc domain of the IgG via FcgIIa bosis [1 ,2,3 ,4 ]. When heparin is administered peri- receptors. Consequently, platelets release membrane operatively, the incidence of HIT is the highest. When fragments (microparticles) that are prothrombotic and HIT is strongly suspected, heparin should be stopped promote thrombin generation/platelet activation. HIT and suitable treatment should be started immediately, antibodies also activate monocytes, bind to endothelial even before laboratory conﬁrmation, especially if a post- cells, and further augment the procoagulant state. About operative thrombotic event occurs. This review will dis- 7–50% of heparin-treated patients form heparin–PF4 cuss the pathophysiology, diagnosis, and treatment of antibodies; however, HIT occurs in approximately 1–5% HIT, in addition to alternative anticoagulation strategies. of patients receiving unfractionated heparin and less than 1% of patients receiving low-molecular- weight heparin [3,5]. Cardiac transplant/neurosurgical Pathogenesis/frequency patients have an increased risk of developing HIT (11 HIT is mediated by antibodies that develop to a complex and 15%, respectively) [6,7]. Cardiovascular surgery of heparin–platelet factor 4 (PF4), a basic protein stored patients are especially at risk of producing the antibodies

0952-7907 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/ACO.0b013e328334dd2f

[8]. HIT antibodies circulate only temporarily (half-life an ELISA OD of more than 1.40 units – weak positive 3months)[9].Thepresenceandthelevelofthe results (0.04–1.00 OD) excluded a diagnosis of HIT in antibodies, irrespective of thrombocytopenia, are associ- most cases [23]. Further, ‘high-titer negative’ ELISA ated with increased adverse events in different groups of results may become positive on retesting after several patients from acute coronary syndromes to cardiovascu- days. Functional tests include the SRA and heparin- lar surgery [10,11,12]. HIT increases the risk of throm- induced platelet activation test. These tests detect bosis (odds ratio 37), and the overall thrombotic risk with heparin-dependent, platelet-activating antibodies and HIT is 38–76% [13,14]. Thrombosis appears coincident are considered the gold standard for the laboratory diag- with, or slightly before, the decline in platelet count noses of HIT because of high sensitivity/speciﬁcity but [13]. require specialized laboratories [19,20,21,22].

Diagnosis Treatment HIT should be suspected if the platelet count drops by The recommended treatment for patients with strongly 50% or new thrombosis occurs 5–14 days after initiating suspected or confirmed HIT is discontinuation of heparin heparin therapy [1,2]. Thrombocytopenia due to other and beginning of a nonheparin, alternative anticoagulant causes, including an intraaortic balloon pump with mech- such as a direct thrombin inhibitor (e.g. lepirudin, arga- anical destruction, sepsis, or other drug-induced causes of troban, and bivalirudin) or danaparoid [1,2]. In addition, thrombocytopenia, should be excluded [4]. In cardiac documentation of the patient’s HIT status including a patients, IIb/IIIa platelet inhibitors are important causes sign on the patient’s bed chart stating ‘No heparin: HIT’, of drug-induced thrombocytopenia [4]. Other con- or both, may help prevent unintended heparin exposure. founding issues include cardiopulmonary bypass (CPB) Different direct thrombin inhibitors are approved in the in which a 40–60% decrease in platelet count occurs United States for use in HIT patients without thrombosis because of dilution and consumption. HIT after CPB (argatroban), HIT patients with thrombosis (lepirudin often has a biphasic pattern that decreases after CPB- and argatroban), and patients with or at risk of HIT related thrombocytopenia corrects or a persistently low/ undergoing percutaneous coronary intervention (PCI) decreasing platelet count more than 4 days postopera- (argatroban and bivalirudin). Lepirudin and argatroban tively [15,16]. HIT can manifest with a ‘rapid onset’ are also available in some other countries for use in within minutes to hours of heparin exposure associated patients with HIT in the noninterventional setting. with systemic responses caused by preexisting antibodies The direct thrombin inhibitors do not resemble heparin, due to prior exposure [17]. These reactions manifest as do not cross-react with heparin–PF4 antibodies, and hypersensitivity/anaphylaxis and include hypotension, cannot promote HIT. Danaparoid, a heparinoid with pulmonary hypertension, tachycardia 2–30 min after minimal cross-reactivity with heparin–PF4 antibodies, heparin bolus [4], or all. HIT can also occur days to was one of the first agents approved but was widely weeks after exposure (delayed onset HIT) in patients unavailable. Fondaparinux is a selective factor Xa inhibi- presenting with thrombosis [18]. tor with a low risk for antibody formation; however, fondaparinux has not been prospectively studied in HIT, and data are limited. Laboratory confirmation Laboratory testing for HIT includes antigen assays and Managing HIT should include stopping heparin and con- functional platelet activation assays [19,20,21,22]. Anti- tinued alternative anticoagulant coverage to prevent gen assays such as the ELISA and rapid particle gel thrombotic complications [1,2,3]. However, the risk immunoassay detect polyclonal antibodies to complexes of excessive bleeding especially recently after cardiac or of PF4 and heparin or complexes of PF4 and other other surgery should be carefully considered, as bleeding is polyanions [19,20,21,22]. The most commonly used also associated with adverse outcomes. Low-molecular- commercial ELISAs detect IgG, IgM, and IgA anti- weight heparins should be avoided because they cross- bodies, and are sensitive for detection of heparin–PF4 react with heparin–PF4 antibodies and worsen HIT antibodies but are not specific for HIT. However, newer [1,2,3]. Heparin should be avoided, at least as long as commercial assays have been developed that detect heparin–PF4 antibody testing is positive [1,2,3,4]. IgG antibodies, thus increasing clinical specificity The British Committee for Standards in Haematology [19,20,21,22]. Although ELISA results can be reported recommends the use of a heparin alternative for most as positive or negative, optical density (OD), antibody patients needing anticoagulation with previous HIT titer based on the OD, or all are important for clinical [24]. Avoiding heparin is feasible in many patients but decision-making. The likelihood of a positive 14C-sero- may be challenging in a few clinical situations, for example tonin release assay (SRA) increases proportionally with cardiovascular surgery (discussed below). For patients with increased ODs – most cases of HIT were associated with current or previous HIT who need cardiac surgery, the

surgery should be delayed, if possible, until heparin–PF4 clinicians now use bivalirudin (see below). Direct throm- antibodies are negative [1,2]. If heparin use is unavoid- bin inhibitors, particularly argatroban, prolong the inter- able or planned, the heparin exposure should be limited national normalized ratio (INR), and methods for monitor- to the surgery itself, with alternative anticoagulation ing the argatroban-to-coumarin transition using the INR or used preoperatively and postoperatively as needed chromogenic factor Xa assay should be followed [32]. [1,2,3,4].

Preoperative and postoperative alternative Preoperative and postoperative alternative anticoagulation therapies: bivalirudin anticoagulation therapies: lepirudin Bivalirudin is a low-molecular-weight protein developed Lepirudin, a recombinant form of hirudin, is the most by adapting hirudin that is cleared by renal elimination potent agent with side effects that include an 18% inci- and by circulating proteases. Bivalirudin is used exten- dence of major bleeding and potential for anaphylactic sively in the cardiac catheterization setting and in reactions on reexposure [25–27]. Bleeding risk is related to patients with or at risk of HIT during PCI. Bivalirudin serum creatinine levels, and dosing adjustments should be was evaluated in an open-label, prospective study of 52 made with renal dysfunction [24]. Recommended lepir- patients with or at risk of HIT [33]. The primary end- udin dosing is a 0.4 mg/kg initial bolus, followed by a point of major bleeding occurred in one (2%) patient. 0.15 mg/kg/h infusion (reduced in renal injury) adjusted Clinical success, defined as a lack of death, emergency to keep an activated partial thromboplastin time (aPTT) bypass surgery, or Q-wave infarction, occurred in 48 1.5–2.5 times baseline. A lower first infusion of 0.1 mg/kg/h (96%) of 50 evaluable patients. The recommended dose without a bolus may reduce the bleeding risk. is a 0.75 mg/kg initial bolus followed by an infusion of 1.75 mg/kg/h (reduced in renal impairment). Notable added experience exists with this drug in non-HIT Preoperative and postoperative alternative patients, and it is the agent most extensively studied anticoagulation therapies: desirudin and used in cardiac surgery (see below). Desirudin, another recombinant hirudin, has been extensively studied in orthopedic and cardiac settings [28]. As a prophylaxis in patients undergoing hip replacement Preoperative and postoperative alternative surgery, desirudin was significantly more effective in anticoagulation therapies: danaparoid reducing the incidence of deep vein thrombosis than Danaparoid is a glycosaminoglycan used since 1982 for either unfractionated or low-molecular-weight heparin. patients with HIT and is the only alternative anticoagu- The two recombinant hirudins for clinical use include lant evaluated in a randomized controlled trial in HIT desirudin and lepirudin. Desirudin is approved for throm- that included dextran 70 as the comparator, which is now bosis prophylaxis following orthopedic hip replacement considered inappropriate therapy [34]. In 1478 clinical surgery and lepirudin for anticoagulation in patients with experiences with danaparoid in HIT, event rates were HIT and thromboembolic complications [29]. Both com- 16.2% for mortality, 9.7% for thrombosis, and 8.1% for pounds differ from each other in their N-termini; desir- major bleeding [35]. Other studies report its use, but it is udin possesses a valine–valine and lepirudin possesses a currently unavailable for clinical use. leucine–threonine structure. Otherwise, the desirudin and lepirudin are similar, with molecular weights of 6.96 and 6.98 kDa, respectively [29]. Preoperative and postoperative alternative anticoagulation therapies: fondaparinux Fondaparinux is a synthetic pentasaccharide with mini- Preoperative and postoperative alternative mal in-vitro cross-reactivity with HIT sera [36]. It is anticoagulation therapies: argatroban approved in the United States and elsewhere for prophy- Argatroban is a hepatically metabolized, small molecule laxis and treatment of venous thromboembolism. Pro- (molecular weight 526 Da) developed from L-arginine. spective, controlled studies in HIT with small numbers The small size minimizes the risk for antibody formation. have been reported [37]. In addition, there are a few The recommended initial dose is an infusion of 2 mg/kg/ reports of HIT associated with fondaparinux and minimal min (0.5 mg/kg/min if hepatic impairment), adjusted to approaches to reverse its bleeding effects. achieve an aPTT 1.5–3 times baseline. However, a lower dose (0.5 mg/kg/min) should be considered in patients with heart failure, multiple organ system failure, or fluid over- Managing heparin-induced thrombocytopenia load, but dose adjustment for renal failure is not required patients for cardiovascular surgery [30,31]. Although argatroban is also approved for use in If patients are HIT positive based on current criteria, and patients with or at risk of HIT undergoing PCI, most based on recent understanding about antibody titers, and

cardiac surgery cannot be delayed, nonheparin anticoa- using CPB [41] or undergoing coronary artery bypass gulation during the surgery is recommended [1,2, grafting without CPB [42]. Bivalirudin was administered 3,4]. A previous clinical report [4] included a review to 206 patients, providing anticoagulation with a safety of danaparoid or heparin with the short-acting platelet profile similar to that of heparin. Bivalirudin dosing in inhibitors epoprostenol, iloprost, or tirofiban as alterna- surgery without CPB is similar to that used in PCI. tive agents. A retrospective analysis [38] of 57 patients Cautions when using this agent include intraoperative with HIT for cardiovascular surgery with CPB was techniques to prevent blood from being stagnant when reported using lepirudin anticoagulation. Lepirudin using bivalirudin, which is metabolized by enzymes 0.20 mg/kg was added to the priming solution. A present in blood exposed to wound or foreign surfaces. 0.25 mg/kg intravenous bolus followed by continuous Therefore, direct retransfusion of shed pericardial/med- infusion of 0.5 mg/min was started before cannulation. iastinal blood into the cardiotomy container should be During CPB, lepirudin was monitored using the ecarin avoided with the use of bivalirudin to avoid systemic clotting time. Target values were 350–400 s. Fifty-four activation and circulation of thromboemboli. Alterna- (95%) patients fully recovered without evidence of tively, shed pericardial blood can be processed via cell thromboembolism. Four (7%) patients, each with renal salvage systems when using bivalirudin. impairment, had excessive bleeding associated with pro- longed lepirudin elimination. Argatroban has been reported during cardiac surgery, on the basis of a retro- Antibody negative spective analysis of 21 published adult cases with a If heparin–PF4 antibodies are negative after a HIT history of HIT, heparin allergy, or antithrombin episode, guidelines recommend heparin over non- deficiency [39]. Other studies have reported its use for heparin anticoagulants during cardiac surgery [1,4]. cardiovascular surgery, but bivalirudin has been more The risk of complications, including bleeding associated extensively studied for this application as noted below. with nonheparin anticoagulants, during cardiac surgery may exceed the risk of recurrence of HIT with brief heparin reexposure [1,2,3,4]. Added concerns with Bivalirudin alternative anticoagulants for cardiac surgery include Bivalirudin has become the agent most used to replace limited experience and the lack of a reversal agent heparin in patients with HIT requiring cardiac surgery. An [1,2]. Heparin use should be confined to the intra- early case series [40] reported four patients with suspected operative period, with alternative anticoagulation used HIT who underwent coronary artery bypass grafting using preoperatively and postoperatively as needed [1]. As CPB and bivalirudin anticoagulation. Patients received a previously discussed, heparin–PF4 antibodies are tran- 1.5 mg/kg loading dose before cannulation and continuous sient. In one study [9] of 144 patients with HIT, the 2.5 mg/kg/h infusion during CPB. Anticoagulation was median time to a negative antibody result after an initial monitored using activated clotting times with a target of positive result was 50 days by activation assay and 85 days 500 s. Anticoagulation during CPB was effective, and total by antigenic assay. operating times were acceptable. One patient experienced excessive postoperative bleeding. Conclusion Larger, prospective studies compared bivalirudin with HIT is an antibody-mediated prothrombotic disorder heparin in non-HIT patients undergoing cardiac surgery that should be considered if a patient experiences a

Table 1 Direct thrombin inhibitors for clinical use Drug Dose Availability Indications Monitoring

Bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/h Available in the United States, PCI or in patients with HIT ACT infusion for the duration of PCI, with 0.3 mg/kg Europe, and Canada based on ACT; cardiothoracic surgery dosing depends on on vs. off pump [40,41,42] Argatroban 2 mg/kg/min initial infusion adjusted to Available in the United States Prophylaxis and treatment of aPTT and 10 mg/kg/min when aPTT is 1.5–3Â thrombosis in HIT and ACT (PCI) baseline (HIT); 25 mg/kg/min infusion PCI in patients with HIT and 350 mg/kg bolus until ACT > 300 s Lepirudin 0.4 mg/kg bolus dose and 0.15 mg/kg Available in the United HIT and prevention of further VTE aPTT infusion to target aPTT of 1.5–2.5 times States and Europe Desirudin 15 mg subcutaneously q12 h (orthopedic) Approved in the United States Total hip arthroplasty (HIT) None and Europe for hip arthroplasty ACT, activated clotting time; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention; VTE, venous thromboembolism.

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