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Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

Treatment and Prevention of Heparin-Induced Thrombocytopenia*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) FREE TO VIEW

Theodore E. Warkentin, MD; Andreas Greinacher, MD; Andreas Koster, MD; A. Michael Lincoff, MD
Author and Funding Information

*From McMaster University (Dr. Warkentin), Hamilton, ON, Canada; Institute for Immunology and Transfusion Medicine (Dr. Greinacher), Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany; Deutsches Herzzentrum Berlin (Dr. Koster), Berlin, Germany; and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (Dr. Lincoff), The Cleveland Clinic Foundation, Cleveland, OH.

Correspondence to: Theodore E. Warkentin, MD, Room I-180A, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, General Site, 237 Barton St E, Hamilton, ON, L8L 2X2 Canada; e-mail: twarken@mcmaster.ca



Chest. 2008;133(6_suppl):340S-380S. doi:10.1378/chest.08-0677
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This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 × 109/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].

Figures in this Article
1.0 Recognition of HIT
1.1 Platelet Count Monitoring for HIT

1.1. For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients receiving heparin who have an estimated risk of HIT of 0.1 to 1.0%, we suggest platelet count monitoring over no platelet count monitoring (Grade 2C).

1.1.1 Platelet Count Monitoring of Patients Recently Treated With Heparin

1.1.1. For patients who are starting UFH or LMWH treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, we recommend obtaining a baseline platelet count and then a repeat platelet count within 24 h of starting heparin over not obtaining a repeat platelet count (Grade 1C).

1.1.2 Anaphylactoid Reactions After IV UFH Bolus

1.1.2. For patients in whom acute inflammatory, cardiorespiratory, neurologic, or other unusual symptoms and signs develop within 30 min following an IV UFH bolus, we recommend performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, over not performing a platelet count (Grade 1C).

1.1.3 Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH

1.1.3. For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

1.1.4 Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis (Highest Risk Group for HIT)

1.1.4. For patients who are receiving postoperative antithrombotic prophylaxis with UFH, ie, the patient population at highest risk for HIT (HIT risk > 1%), we suggest at least every-other-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

1.1.5 Platelet Count Monitoring in Patients in Whom HIT is Infrequent (0.1 to 1%)

1.1.5. For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH “flushes,” or medical/obstetrical patients receiving LMWH after first receiving UFH (estimated HIT risk, 0.1 to 1%), we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first), when practical, over less frequent platelet count monitoring (Grade 2C).

1.1.6 Platelet Count Monitoring When HIT is Rare (< 0.1%): UFH and LMWH

1.1.6. For medical/obstetrical patients who are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C).

1.1.7 Platelet Count Monitoring When HIT is Rare (< 0.1%): Fondaparinux

1.1.7. For patients who are receiving fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C).

1.1.8 Management of Patients in Whom Platelet Counts Are Not Monitored

1.1.8. In outpatients who will receive heparin prophylaxis or treatment, informed consent should include HIT and its typical sequelae (new thrombosis, skin lesions) and the patient should be advised to seek medical advice if these events occur (Grade 2C).

1.1.9 Screening for Subclinical HIT Antibody Seroconversion

1.1.9. In patients who receive heparin, or in whom heparin treatment is planned (eg, for cardiac or vascular surgery), we recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of HIT (Grade 1C).

1.1.10 When Should HIT Be Suspected?

1.1.10. For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C).

1.2 Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring After Cardiac Surgery

1.2. For postoperative cardiac surgery patients, we recommend investigating for HIT antibodies if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between postoperative days 5 and 14 (inclusive; day of cardiac surgery = day 0) [Grade 1C].

2.0 Treatment of HIT
2.1 Nonheparin Anticoagulants for Treating HIT (With or Without Thrombosis)

2.1.1. For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], bivalirudin [Grade 2C]) over the further use of UFH or LMWH therapy or initiation/continuation of a VKA (Grade 1B).

2.1.2. For patients receiving lepirudin, the initial lepirudin infusion rate should be no higher than 0.10 mg/kg/h (patients with creatinine < 90 μmol/L), with lower infusion rates for patients with higher serum creatinine levels (creatinine, 90 to 140 μmol/L: starting infusion rate, 0.05 mg/kg/h; creatinine, 140 to 400 μmol/L: starting infusion rate, 0.01 mg/kg/h; creatinine > 400 μmol/L: starting infusion rate, 0.005 mg/kg/h) [Grade 1C]. Furthermore, we recommend that the initial IV bolus either be omitted or, in case of perceived life- or limb-threatening thrombosis, be given at a reduced dose (0.2 mg/kg) [Grade 1C]. Further, we recommend that APTT monitoring be performed at 4-h intervals until it is apparent that steady state within the therapeutic range (1.5- to 2.0-times patient baseline [or mean laboratory] APTT) is achieved (Grade 1C).

2.1.3. When argatroban is used to treat patients who have heart failure, multiple organ system failure, or severe anasarca or who are postcardiac surgery, we suggest beginning the initial infusion at a rate between 0.5 and 1.2 μg/kg/min, with subsequent adjustments using the APTT, over the usual recommended starting dose of 2.0 μg/kg/min (Grade 2C).

2.1.4. When danaparoid is used to treat patients with strongly suspected (or confirmed) HIT, we recommend a therapeutic-dose regimen (see text) administered (at least initially) by the IV route over prophylactic-dose regimens or initial SC administration (Grade 1B).

2.1.5. For patients with strongly suspected or confirmed HIT, whether or not there is clinical evidence of lower-limb DVT, we recommend routine ultrasonography of the lower-limb veins for investigation of DVT over not performing routine ultrasonography (Grade 1C).

2.2 VKAs
2.2.1 Management of Direct Thrombin Inhibitor–VKA Overlap

2.2.1. For patients with strongly suspected or confirmed HIT, we recommend against the use of VKA (coumarin) therapy until after the platelet count has substantially recovered (ie, usually to at least 150 × 109/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low, maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) rather than with higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the INR has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B).

2.2.2 Reversal of VKA Anticoagulation

2.2.2. For patients receiving a VKA at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].

2.3 LMWH for HIT

2.3.1. For patients with strongly suspected HIT, whether or not complicated by thrombosis, we recommend against use of LMWH (Grade 1B).

2.4 Prophylactic Platelet Transfusions for HIT

2.4.1. For patients with strongly suspected or confirmed HIT who do not have active bleeding, we suggest that prophylactic platelet transfusions should not be given (Grade 2C).

3.0 Special Patient Populations
3.1 Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

3.1.1. For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend the use of UFH over a nonheparin anticoagulant (Grade 1B). 3.1.2. For patients with a history of HIT who are antibody positive by platelet factor 4 (PF4)-dependent enzyme immunoassay (EIA) but antibody negative by washed platelet activation assay, we recommend the use of UFH over a nonheparin anticoagulant (Grade 2C).

Remark: Preoperative and postoperative anticoagulation, if indicated, should be given with a nonheparin anticoagulant.

3.2 Patients With Acute or Subacute HIT Undergoing Cardiac Surgery

3.2.1. For patients with acute HIT (thrombocytopenic, HIT antibody positive) who require cardiac surgery, we recommend one of the following alternative anticoagulant approaches (in descending order of preference): delaying surgery (if possible) until HIT has resolved and antibodies are negative (then see Recommendation 3.1.1.) or weakly positive (then see Recommendation 3.1.2.) [Grade 1B]; using bivalirudin for intraoperative anticoagulation during cardiopulmonary bypass (if techniques of cardiac surgery and anesthesiology have been adapted to the unique features of bivalirudin pharmacology) [Grade 1B] or during “off-pump” cardiac surgery (Grade 1B); using lepirudin for intraoperative anticoagulation (if ECT is available and patient has normal renal function and is judged to be at low risk for postcardiac surgery renal dysfunction) [Grade 2C]; using UFH plus the antiplatelet agent epoprostenol (if ECT monitoring is not available or renal insufficiency precludes lepirudin use) [Grade 2C]; using UFH plus the antiplatelet agent, tirofiban (Grade 2C); or using danaparoid for intraoperative anticoagulation for off-pump coronary artery bypass surgery (Grade 2C) over performing the surgery with UFH when platelet-activating anti-PF4/heparin antibodies are known to be present in a patient with acute or recent HIT. 3.2.2. For patients with subacute HIT (platelet count recovery, but continuing HIT antibody positive), we recommend delaying surgery (if possible) until HIT antibodies (washed platelet activation assay) are negative, then using heparin (see Recommendation 3.1.1.) over using a nonheparin anticoagulant (Grade 1C). If surgery cannot be delayed, we suggest the use of a nonheparin anticoagulant (see Recommendation 3.2.1.) over the use of UFH (Grade 2C).

3.3 Percutaneous Coronary Interventions

3.3.1. For patients with strongly suspected (or confirmed) acute HIT who require cardiac catheterization or percutaneous coronary intervention (PCI), we recommend a nonheparin anticoagulant (bivalirudin [Grade 1B], argatroban [Grade 1C], lepirudin [Grade 1C], or danaparoid [Grade 1C]) over UFH or LMWH (Grade 1B).

3.3.2. For patients with previous HIT (who are antibody negative) who require cardiac catheterization or PCI, we suggest use of a nonheparin anticoagulant (see Recommendation 3.3.1.) over UFH or LMWH (Grade 2C).

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse effect of heparin that is important because of its strong association with venous and arterial thrombosis.14 Patients treated with heparin in whom HIT develops constitute a cohort with substantially increased thrombotic risk, both in relative (odds ratio [OR] for thrombosis, 20 to 4015) and absolute (thrombosis risk, 30 to 75%110) terms, depending on the patient population affected.

Because the diagnosis is based on both clinical and serologic grounds, clinicians should consider HIT a clinicopathologic syndrome.1114 Thus, neither thrombocytopenia or thrombosis without the presence of heparin-dependent antibodies, nor the isolated presence of antibodies without thrombocytopenia, thrombosis, or other clinical sequelae, meet the criteria for HIT. Rather, clinicians make a diagnosis of HIT when any of the following events occurs in association with the presence of “HIT antibodies” detected by in vitro assays: (1) an otherwise unexplained platelet count fall (defined by various investigators as a minimum platelet count fall of 30%,16 40%,17 or 50%2—even if the platelet count nadir remains > 150 × 109/L (note: the “baseline” platelet count is not necessarily the preheparin platelet count, but rather the highest platelet count during the 2-week period that follows initiation of heparin therapy and that immediately precedes the platelet count decline indicating HIT); (2) venous or arterial thrombosis (most often, deep venous thrombosis [DVT], pulmonary embolism [PE], limb artery thrombosis, thrombotic stroke, myocardial infarction, adrenal hemorrhagic necrosis [indicating adrenal vein thrombosis]); (3) skin lesions at heparin injection sites,18; or (4) acute systemic (anaphylactoid) reactions (eg, fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest) that occur after IV heparin bolus administration.,7 Diagnostic specificity can be further increased by use of a sensitive washed platelet activation assay; a positive platelet activation assay is much more specific for clinical HIT than a positive platelet factor 4 (PF4)-dependent immunoassay.1923 With such a clinicopathologic viewpoint, clinicians can diagnose clinical HIT even when the patient’s platelet count does not fall by as much as 30% (eg, a patient with heparin-induced necrotizing skin lesions and adrenal necrosis associated with formation of platelet-activating anti-PF4/heparin antibodies,18).21,24 Indeed, in about 25% of HIT patients, a thrombotic event during heparin treatment precedes the subsequent HIT-associated platelet count fall.,1,16

The neoepitopes recognized by HIT antibodies are located on PF4, and are formed when PF4 binds to heparin.2527 HIT antibodies activate platelets intravascularly, causing release of platelet microparticles and increased thrombin generation. However, only a subset of anti-PF4/heparin antibodies activate platelets,1920,28 which explains the greater diagnostic specificity of certain platelet activation assays (eg, platelet serotonin release assay [SRA], heparin- induced platelet activation (HIPA) assay] for HIT compared with the PF4-dependent EIA.,1920,23,29 There is a correlation between the degree of reactivity in the EIA, expressed in optical density (OD) units, and the presence of platelet-activating anti-PF4/heparin antibodies. Thus, the greater the magnitude of a positive EIA test result, the greater the likelihood that the patient has HIT, given a certain pretest probability. However, a very strong EIA test result does not necessarily mean that platelet-activating IgG antibodies are present; conversely, only about 5 to 10% of sera showing reactivity 0.4 to 1.0 OD U in an EIA nonetheless contain strong platelet-activating antibodies.29

This chapter is organized into sections on the recognition, treatment, and prevention of HIT. The scope of our recommendations include platelet count monitoring for HIT as well as management of HIT, both in patients detected by thrombocytopenia alone (“isolated HIT”) and in patients who present with HIT-associated thrombosis. The interrelatedness of platelet count monitoring and treatment recommendations is clear when one considers that “isolated HIT” (a patient population with substantial risk of thrombosis) by definition can be detected only by platelet count monitoring. Furthermore, even in patients with thrombosis complicating HIT, the availability of serial platelet counts often provides the key information to prompt consideration of the diagnosis of HIT. Table 1 ) lists the inclusion and exclusion criteria for the studies used to formulate our recommendations.

1.1 Platelet Count Monitoring for HIT

HIT occurs most commonly in certain patient populations, such as postoperative patients who receive standard, unfractionated heparin (UFH) for ≥ 1 week (for review, see Lee and Warkentin6). One definition classifies an adverse reaction as “common” if its incidence is > 1%.30 In other clinical settings, the estimated risk of HIT can be described as “uncommon” (0.1 to 1%) or “rare” (< 0.1%).30 As described later, there is evidence that initial isolated HIT has a substantial risk of evolving to symptomatic and fatal thrombosis. Further, prospective cohort studies (with historical controls) suggest that antithrombotic therapy reduces the risk of thrombosis in patients with isolated HIT. In addition, HIT can lead to life- and limb-threatening complications, a risk that could increase with delay in diagnosis or increase in heparin dose (to treat unrecognized HIT-associated thrombosis), or through use of warfarin. These considerations suggest that routine platelet count monitoring for HIT is appropriate in at least some clinical situations, and that the greater the risk of HIT, the stronger the rationale for regular monitoring.

Another consideration that supports a role for platelet count monitoring is that HIT antibody seroconversion and resulting “typical-onset” HIT usually occur during specific time periods following initiation of heparin, namely days 5 to 10 (seroconversion and initial platelet count fall) and days 7 to 14 (reaching a threshold defining thrombocytopenia), when the first day of the immunizing heparin exposure is considered to be “day 0.”12,67,3132 (Day 4 can be included within the period of platelet count monitoring for HIT because it can provide a comparative preimmunization reference point.) Further, “rapid-onset HIT” (in which the platelet count fall begins within 24 h of starting heparin) is strongly associated with recent heparin exposure (within the past 100 days, and especially the last 30 days).3132

The frequency of HIT among patients exposed to heparin is highly variable, and is influenced by the heparin preparation (bovine UFH > porcine UFH > low-molecular-weight heparin [LMWH]),1920,3341 the type of heparin-exposed patient population (postsurgery > medical > pregnancy),1920,4146 duration of heparin exposure,7 and patient sex (female > male).41 Thus, whether to perform platelet count monitoring, and the intensity of such monitoring, depends on these considerations, particularly heparin and patient type and the duration of heparin use. Therefore, it is appropriate to perform platelet count monitoring in certain clinical situations, and to focus platelet count monitoring during those times when HIT usually occurs. Furthermore, the rationale for platelet count monitoring is stronger when monitoring is relatively easy (ie, in a hospital inpatient), and weaker when monitoring is more difficult (ie, out-patient settings. Table 2 summarizes the various risk factors for HIT, and classifies risk into three different groups: high (> 1.0%), intermediate (0.1 to 1.0%), and low (< 0.1%).,12,4,6,15,17,1920,3471

A potential downside of platelet count monitoring is that patients with a decrease in platelet counts for reasons other than HIT may be wrongly suspected of having this diagnosis. As the alternative nonheparin anticoagulants have a relatively high risk of bleeding, there is the potential for treatment-related adverse events as a consequence of platelet count monitoring.

Underlying Values and Preferences: The following recommendations regarding monitoring of platelet count share the same underlying values and preferences, as follows. The recommendations place a high value on the possible benefits of early diagnosis and consequent early treatment of HIT to prevent sequelae and a lower value on the burden and cost of monitoring platelet counts, including the consequences of further investigation and management of the high proportion of patients with a significant fall in platelet count who do not have HIT and the risks associated with unnecessary withdrawal of heparin and unnecessary use of alternative agents with a higher bleeding risk.

Recommendation

1.1. For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients receiving heparin who have an estimated risk of HIT of 0.1 to 1.0%, we suggest platelet count monitoring over no platelet count monitoring (Grade 2C).

1.1.1 Platelet Count Monitoring of Patients Recently Treated With Heparin

“Rapid-onset HIT” refers to patients who have a large platelet count fall attributable to HIT antibodies within 24 h of starting heparin.3132 Contrary to popular assumption, this phenomenon is not caused by an anamnestic immune response, but rather results from the administration of heparin to a patient who has already-circulating HIT antibodies that resulted from a recent heparin exposure.3132 As a general rule, exposure within the past 100 days (and especially within the last month) is associated with the phenomenon of rapid-onset HIT.

Recommendation

1.1.1. For patients who are starting UFH or LMWH treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, we recommend obtaining a baseline platelet count and then a repeat platelet count within 24 h of starting heparin over not obtaining a repeat platelet count (Grade 1C).

1.1.2 Anaphylactoid Reactions After IV UFH Bolus

Rarely, patients develop acute inflammatory (eg, fever, chills) or cardiorespiratory (eg, hypertension, tachycardia, dyspnea, chest pain, cardiorespiratory arrest) symptoms and signs within 30 min following an IV heparin bolus.7,47Also termed acute systemic reactions, these can also mimic acute PE (pseudo-pulmonary embolism48) and strongly suggest acute in vivo platelet activation secondary to HIT. This presentation mandates a prompt platelet count measurement, as an abrupt platelet count fall in this clinical context supports the diagnosis of HIT. The platelet count drop is frequently transient,,2 and thus a delay in determining the platelet count, especially if heparin is stopped, may result in a missed diagnosis.

Recommendation

1.1.2. For patients in whom acute inflammatory, cardiorespiratory, neurologic, or other unusual symptoms and signs develop within 30 min following an IV UFH bolus, we recommend performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, over not performing a platelet count (Grade 1C).

1.1.3 Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH

For patients receiving porcine UFH in therapeutic doses, by either the IV or subcutaneous (SC) route, for the treatment of venous or arterial thrombosis, the risk of HIT has been estimated to be at most about 1%,6 based on a review of studies of the frequency of HIT in patients receiving porcine UFH for venous thromboembolism.4,36,4962 However, the two most recent studies4,36 identified only 1 patient with HIT among 594 treated with therapeutic-dose UFH, suggesting that the frequency among this patient population is likely < 1%.

Recommendation

1.1.3. For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

1.1.4 Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis (Highest Risk Group for HIT)

Patient groups at the highest risk of HIT (1 to 5%) include postoperative orthopedic, cardiac, and vascular surgery patients who are receiving UFH for 1 to 2 weeks,15,17,1920,33,6367 and, likely, other postsurgery patient populations.

Recommendation

1.1.4. For patients who are receiving postoperative antithrombotic prophylaxis with UFH, ie, the patient population at highest risk for HIT (HIT risk > 1%), we suggest at least every-other-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

While we gave a strong recommendation overall in favor of performing platelet count monitoring when the risk of HIT was judged to be ≥ 1% (see Recommendation 1.1), our recommendation for the specific intensity of platelet count monitoring in this and other patient populations (see also Recommendations 1.1.3 and 1.1.5) have been given a weak (Grade 2) recommendation because no study exists comparing outcomes using any particular platelet count monitoring strategy. Our suggestion to perform every-other-day monitoring takes into account the observation that platelet count declines in HIT, when they occur, are relatively rapid (median of 2 to 3 days from the postoperative peak to a ≥ 50% platelet count decline).12,7

1.1.5 Platelet Count Monitoring in Patients in Whom HIT is Infrequent (0.1 to 1%)

There are several patient groups in which the risk of HIT can be classified as “uncommon” (ie, 0.1 to 1%). These include medical (including patients with acute coronary syndrome) or obstetrical patients receiving prophylactic-dose UFH4,6,46,6062,6870; postoperative patients receiving LMWH12,6,17,1920,63,66; postoperative/critical care patients receiving UFH flushes6,71; and, theoretically, medical patients receiving LMWH after having received one or more preceding doses of UFH. In some settings (eg, patients receiving outpatient LMWH), it may be impractical to obtain platelet counts. Thus, less frequent (or no) platelet count monitoring may be appropriate in these patients, especially if the risk is thought to be closer to 0.1% than 1% (eg, postoperative patients receiving LMWH) and if the patient is instructed to contact the physician promptly if signs or symptoms of venous thromboembolism (the most common complication of HIT) occur or painful skin lesions develop at the heparin injection sites (see also Recommendation 1.1.8).

Recommendation

1.1.5. For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH “flushes,” or medical/obstetrical patients receiving LMWH after first receiving UFH (estimated HIT risk, 0.1 to 1%), we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first), when practical, over less frequent platelet count monitoring (Grade 2C).

1.1.6 Platelet Count Monitoring When HIT is Rare (< 0.1%): UFH and LMWH

In medical and obstetrical patients receiving LMWH, the risk of HIT appears to be rare (< 0.1%).3637,39,4245 For example, only one possible case43 of HIT was observed among 1,167 pregnancies treated with LMWH in three studies4244; a more recent review45 of LMWH use during 2,777 pregnancies identified no cases of HIT. Although fewer data exist with respect to medical patients receiving LMWH or UFH as flushes (eg, oncology patients with indwelling catheters),,7273 the experience of the authors is that HIT is rare in this setting. However, one prospective, multicenter study38of LMWH administered to medical patients reported the frequency of HIT to be 0.8%. Limitations of this study suggest, however, that it provides an overestimate of HIT incidence: (1) not all patients underwent testing with the more specific platelet activation assays, and (2) some of the clinical features (eg, early onset of thrombocytopenia) were not characteristic of this adverse drug reaction. Furthermore, the data represent a statistical outlier compared with other studies,39,41 and in our view further studies are required before recommending that platelet count monitoring be performed routinely in medical patients receiving LMWH.

Recommendation

1.1.6. For medical/obstetrical patients who are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C).

Underlying Values and Preferences: This recommendation places a lower value on the rare diagnosis and early treatment of HIT to prevent sequelae and a higher value on the burden and cost of monitoring platelet counts.

1.1.7 Platelet Count Monitoring When HIT is Rare (< 0.1%): Fondaparinux

Fondaparinux is an indirect (antithrombin- mediated) inhibitor of factor Xa modeled after the pentasaccharide region of heparin. A syndrome resembling immune HIT was not reported in any of the regulatory trials for this anticoagulant in various clinical settings (eg, orthopedic surgery,74treatment of venous thromboembolism7576). However, anti-PF4/heparin antibodies—some with platelet-activating properties—have been observed to occur in association with fondaparinux thromboprophylaxis in a frequency similar to that seen with the LMWH enoxaparin.7778 Unlike the situation with UFH or enoxaparin, these antibodies—as well as antibodies obtained from patients with typical HIT—do not bind well to PF4 in vitro in the presence of fondaparinux, even though they recognize well the epitopes on PF4 in the presence of UFH or LMWH.,7781 Further, several dozen patients with putative HIT have been reported to have shown platelet count recovery during administration of fondaparinux.8284 It therefore seems that the risk of inducing a syndrome resembling immune HIT is negligible. To our knowledge, only one possible case of HIT that occurred in association with postoperative fondaparinux thromboprophylaxis has been reported after 4 years in the marketplace.85 In our view, this negligible frequency of immune thrombocytopenia indicates that routine platelet count monitoring for HIT should not be performed.

Recommendation

1.1.7. For patients who are receiving fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C).

1.1.8 Management of Patients in Whom Platelet Counts Are Not Monitored

Clinicians should consider informing patients receiving UFH or LMWH about the potential for the adverse effect of HIT. For patients not under close platelet count monitoring, clinicians should describe the most common resulting signs and symptoms, ie, new thrombosis and painful skin lesions at the heparin injection sites. Outpatients should be advised to seek medical advice immediately if these events occur. This will increase awareness of HIT in both the patient and the treating physician.

Recommendation

1.1.8. In outpatients who will receive heparin prophylaxis or treatment, informed consent should include HIT and its typical sequelae (new thrombosis, skin lesions) and the patient should be advised to seek medical advice if these events occur (Grade 2C).

1.1.9 Screening for Subclinical HIT Antibody Seroconversion

Prospective studies of HIT and HIT antibody formation12,6,1920,3436,67,86 indicate that HIT occurs in a minority of patients who form anti-PF4/heparin antibodies. The serologic profile in about 99% of patients with clinical HIT is positive testing in both of two sensitive and complementary assays: (1) platelet activation (or “functional”) assay using washed platelets (eg, 14C-SRA, HIPA test), or (2) PF4-dependent EIA.,1920,87 However, even though both assays are sensitive in detecting HIT antibodies, neither is completely specific for the HIT syndrome (although the functional assays are far more specific than the EIA).13 Consequently, serology is more effective in ruling out a possible diagnosis of HIT than in confirming the diagnosis, ie, the negative tests have a very low likelihood ratio, but positive tests only a moderately high likelihood ratio. However, the “strength” of a positive test result provides useful diagnostic information regarding the likelihood of HIT. For example, a strong positive test result (eg, > 90% serotonin release or > 2.0 absorbance units) was associated with a high likelihood ratio for HIT in patients after orthopedic surgery (approximately 100), whereas a weak positive test result (eg, 0.40–1.00 absorbance units in one study using an in-house PF4-dependent EIA that detected IgG class antibodies) was associated with a relatively low risk for HIT.,19,21,29 For patients after cardiac surgery, the corresponding risks for HIT for “strong” and “weak” serologic results are likely to be lower.21,29 The risk of HIT is even lower when using commercial EIAs that detect antibodies of all three Ig classes. The diagnostic interpretation of these laboratory tests must be made in the context of the clinical estimation of the pretest probability of HIT.13,21,88

Further, prospective data indicate that an increased risk of thrombosis occurs in the group of patients whose platelet count has fallen in relation to HIT antibody formation (ie, those with clinical HIT) rather than in patients who develop antibodies without a significant platelet count decline.12 In our view, it is not useful to perform anti-PF4/heparin antibody testing in the absence of clinical indication of HIT, by either an unexpected fall in the platelet count or an unexpected clinical event. Thus, routine platelet count monitoring, rather than routine anti-PF4/heparin antibody studies, is most useful (and most practical) to identify patients who are at risk for developing thrombosis because of immunization triggered by heparin therapy.

In addition, there is no evidence that routine testing for anti-PF4/heparin antibodies prior to cardiac or vascular surgery—in the absence of thrombocytopenia or thrombosis or other clinical evidence of HIT—leads to identification of clinically significant antibodies or improves patient outcomes. In our view, such routine testing is much more likely to identify subclinical antibodies that do not pose increased risk for perioperative complications attributable to the intraoperative or postoperative use of heparin.

Recommendation

1.1.9. In patients who receive heparin, or in whom heparin treatment is planned (eg, for cardiac or vascular surgery), we recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of HIT (Grade 1C).

1.1.10 When Should HIT Be Suspected?

Retrospective and prospective studies suggest that > 90% of patients with clinical HIT have a platelet count fall that is > 50% during their heparin treatment.2,12 In patients with HIT who have lesser degrees of platelet count decline, almost all are identified because of thrombotic complications or other sequelae, such as heparin-induced skin lesions or anaphylactoid reactions following IV bolus UFH.21 The pretest probability of HIT should also be influenced by the temporal features of the platelet count fall and by the likelihood of other possible alternative diagnoses to explain the thrombocytopenia (eg, perioperative hemodilution, sepsis/multiorgan system dysfunction, cancer-associated coagulopathy, glycoprotein IIb/IIIa antagonist administration, clearance of previously transfused platelets).,21,89 PE poses a special problem: Whereas HIT is strongly associated with PE (OR, ∼ 40),7 PE itself can be associated with prominent thrombocytopenia (with associated consumptive coagulopathy) even in the absence of HIT antibodies,8990 thus emphasizing the important diagnostic role of laboratory testing for HIT antibodies.

Clinicians should consider a diagnosis of HIT when thrombocytopenia (defined subsequently) occurs with a temporal pattern consistent with heparin-induced immunization, ie, platelet count fall that begins 5 to 10 days (or thrombocytopenia that occurs 7 to 14 days) after starting a course of heparin therapy (first day of heparin = day 0), or when thrombosis or other sequelae of HIT occur in patients treated (or recently treated) with heparin.21 The pretest estimation of the probability of HIT is also influenced by the pattern of the platelet count fall and by the likelihood of other possible alternative diagnoses to explain the thrombocytopenia.21 The strong association between HIT and thrombosis indicates that clinicians should suspect HIT and draw a platelet count (and compare the result with previous values) in a patient who develops symptomatic venous or arterial thrombosis while receiving heparin prophylaxis or treatment, or within several days after heparin prophylaxis or treatment. A recent study16 found that in approximately one quarter of patients recognized with HIT, HIT-associated thrombosis preceded the development of thrombocytopenia by 1 day or a few days. In such cases, administration of higher doses of heparin to treat the thrombosis can “unmask” HIT.,91

About two thirds of HIT patients evince typical-onset HIT, ie, the platelet count begins to fall 5 to 10 days after starting heparin,3132 although thrombocytopenic levels (eg, > 50% fall or to < 150 × 109/L) are usually not reached until a few days later (about 7 to 14 days after beginning heparin). In about 25 to 30% of patients, the platelet count falls abruptly on beginning a course of heparin.,31 Such rapid-onset HIT occurs in patients who recently (within the previous 100 days) have been exposed to heparin,3132 and represents abrupt onset of platelet activation in a patient who has residual circulating HIT antibodies related to the recent prior heparin exposure.

In about 3 to 5% of patients with HIT, the onset of thrombocytopenia begins several days after heparin has been stopped (delayed-onset HIT).9298 This last syndrome is consistent with a transient autoimmune nature of HIT, as these patients have PF4/heparin-reactive antibodies that can activate platelets even in the absence of heparin.92,99 Sometimes even relatively minor exposures to heparin (≤ 5,000 U), particularly when given in a perioperative or inflammatory setting, have resulted in this syndrome. In December 2006, the US Food and Drug Administration (FDA) notified health-care professionals of revisions to the WARNINGS section of the prescribing information for heparin to inform clinicians of the possibility of delayed onset of HIT.

Definition of Thrombocytopenia in HIT: The majority of postoperative patients who acquire HIT sustain an otherwise unexplained ≥ 50% fall in the platelet count from the postoperative peak during the second week following surgery.2 This reduction occurs on a background of the normal pattern of a rising platelet count expected between postoperative days 4 to 14 (transient postoperative thrombocytosis).,12 Thus, in postoperative HIT, the serial platelet counts form an “inverted V” as the initial platelet count recovery that begins about 2 to 3 days following surgery transforms unexpectedly to a falling platelet count a few days later.12,7 In contrast, in medical patients, the platelet count fall begins or accelerates from day 5 onwards, usually without a preceding profile of a rising platelet count.4 On occasion, the platelet count declines by < 50% even though the clinical and serologic findings otherwise strongly suggest HIT-associated thrombosis.12,18

Although there are fewer data on an appropriate definition of HIT applicable to medical patients,4 it appears that a proportional (> 50%) fall in platelet count beginning between days 5 and 14 of heparin therapy is appropriate. In our opinion, such a threshold avoids trivial platelet count declines that might be detected if an absolute threshold, such as 150 × 109/L, is used to define thrombocytopenia, especially as transient thrombocytosis does not often occur in medical patients.

We are making a strong recommendation regarding the approach to defining thrombocytopenia in HIT because there is good evidence that a proportional fall in platelet count of ≥ 50% is superior to an absolute threshold of 150 × 109/L for the detection of HIT, at least in postoperative patients (improved sensitivity for HIT without loss of diagnostic specificity).2,7 However, no single definition of thrombocytopenia is appropriate in all clinical situations.

Recommendation

1.1.10. For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C).

1.2 Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring After Cardiac Surgery

The risk of symptomatic venous thrombosis is relatively low in postcardiac surgery patients, even when no antithrombotic prophylaxis is given (although subclinical DVT can be detected in 20% of patients).100 Many cardiac surgery centers give antithrombotic prophylaxis with UFH (in North America more than in Europe) or LMWH (Europe more than North America). Even if anticoagulant prophylaxis is not routinely given, individual patients who have undergone cardiac surgery may receive anticoagulants because of a prosthetic mechanical valve or unexpected complications such as prolonged postoperative atrial fibrillation, thrombotic stroke, or prolonged immobilization.

The risk of anti-PF4/heparin antibody formation is especially high in this population of cardiac surgery patients, ranging from 35 to 65% by days 7 to 10, even when postoperative anticoagulant prophylaxis with heparin is not given17,19,6567,101 or if “off-pump” surgery is performed.35 More importantly, the absolute risk of clinical HIT in such patients who receive UFH following surgery ranges from 1 to 3%.6,17,6567,102103 Finally, this patient population has a relatively high burden of atherosclerosis, and appears to be at a disproportionately higher risk for life- and limb-threatening arterial complications compared with other patient populations.7,16

An ongoing nonrandomized comparison17,66 between UFH and LMWH antithrombotic prophylaxis after cardiac surgery found a substantially lower frequency of HIT with LMWH use than with UFH use (11/437, or 2.5%, vs 8/1,874, or 0.4%; p < 0.0001). However, there were differences in the patient populations that led to one or the other drug being selected for use. Thus, whether LMWH reduces the risk of HIT in this patient population—though likely—remains unproven. Further, HIT antibodies resulting from UFH therapy frequently cross-react with LMWH, and because patients receiving LMWH after cardiac surgery invariably received UFH during cardiac surgery, there is the potential for HIT to occur more frequently with LMWH in this patient population than in other clinical settings. However, because (to our knowledge) there are no formal studies proving that routine anticoagulant prophylaxis, either with UFH or LMWH, is safe and effective following cardiac surgery, it is difficult to provide any firm recommendations.

Given the known high risk of HIT in this patient population, we believe that monitoring for HIT is especially important if surgeons prescribe postoperative UFH or LMWH.102 A practical problem in monitoring for HIT after cardiac surgery is that major hemodilution occurs both during and in the first several days following cardiac surgery. This perioperative platelet count decrease typically attains its nadir 2 days after surgery. However, HIT is rare in the first 4 days after cardiac surgery, even in patients who have received heparin during the preoperative period. This is because HIT resulting from heparin exposure during angiography or for treatment of acute coronary syndrome is infrequent (< 1%), whereas postoperative dilutional thrombocytopenia occurs universally. Thus, it is difficult on clinical grounds to identify the occasional case of HIT beginning soon after cardiac surgery (in which immunization resulted from preoperative heparin exposure). In contrast, HIT is a relatively likely explanation for a platelet count fall ≥ 50% that begins from postoperative day 5 onwards. This is because the circumstances of cardiac surgery are a frequent stimulus for HIT antibody generation, and because the typical onset of HIT (beginning 5 to 10 days after cardiac surgery) coincides with the time period in which the platelet count typically is rising to thrombocytotic levels following perioperative hemodilution. Accordingly, in patients who have undergone cardiac surgery, clinicians should consider a fall in the platelet count ≥ 50% that occurs between postoperative days 5 and 14 (inclusive) to represent potential HIT and should prompt laboratory investigations for HIT antibodies (day of cardiac surgery = day 0).2,17,102,104

Recommendation

1.2. For postoperative cardiac surgery patients, we recommend investigating for HIT antibodies if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between postoperative days 5 and 14 (inclusive; day of cardiac surgery = day 0) [Grade 1C].

HIT is a prothrombotic condition that is associated with increased in vivo thrombin generation (as evidenced by the presence of elevated levels of thrombin-antithrombin complexes105) and thus can be considered an acquired, hypercoagulability syndrome.13 However, unlike other acquired hypercoagulability syndromes (eg, antiphospholipid antibody syndrome, malignancy-associated thrombosis), HIT is transient, with recovery of platelet counts to normal levels within days or weeks, and disappearance of the pathogenic HIT antibodies within weeks or a few months.,31 Thus, there is important potential benefit (over the risk) of optimal antithrombotic management over the relatively brief period of the patient’s life in which this paradoxical adverse event has occurred.

Marked in vivo thrombin generation helps explain several clinical aspects of HIT, including its association with venous and arterial thrombosis, the occurrence of decompensated (hypofibrinogenemic) disseminated intravascular coagulation (DIC) in 5 to 10% of HIT patients, and the risk for progression of DVT to venous limb gangrene (or, less often, “classic” nonacral coumarin-induced skin necrosis) in some patients with HIT who are treated with warfarin or other VKAs (see Section 2.2).106115 Finally, recognition of the role for in vivo thrombin generation in HIT provides a rationale for current therapies that emphasize reduction of thrombin generation,,11,105 either via direct inhibition of thrombin (eg, argatroban, lepirudin, bivalirudin) or by inhibiting factor Xa indirectly (eg, danaparoid, fondaparinux).

In making recommendations for the management of HIT, we have chosen to combine the approach to patients with “isolated HIT” and HIT-associated thrombosis. There are three reasons for this approach. First, from the point-of-view of pathophysiology, patients with isolated HIT and HIT-associated thrombosis have similar disease processes, as shown by platelet count nadirs (median, about 50 to 60 × 109/L for each group), and similar elevations of thrombin-antithrombin complexes. Second, the time course of thrombosis in HIT is a continuum, with approximately equal numbers of patients being recognized with symptomatic thrombosis (1) during the initial period of a falling platelet count; (2) after crossing a threshold defining thrombocytopenia but while heparin treatment remains ongoing; and (3) after discontinuation of heparin because of thrombocytopenia.12,9,16 Third, and most importantly, among patients who are recognized as having isolated HIT (subsequently confirmed serologically), and who are managed by simple discontinuation of heparin, or substitution of heparin by warfarin, the risk of symptomatic thrombosis ranges from 25 to 50%, including an overall risk of fatal thrombosis of about 5%.12 These event-rates resemble those in other clinical situations in which antithrombotic management is generally considered mandatory (eg, after hip fracture).

Treatment Recommendations Depend on the Likelihood of HIT: Unlike other conditions (eg, hip fractures), however, the diagnosis of HIT may not be initially clear, especially since HIT might not be the only potential explanation for thrombocytopenia and/or thrombosis in patients receiving heparin. Furthermore, only about 30 to 60% of the patients with anti-PF4/polyanion antibodies by EIA also have detectable heparin-dependent platelet-activating antibodies (using a sensitive platelet activation assay); this suggests that a false diagnosis of HIT is possible in about one third to two thirds of patients who are antibody positive by EIA.23,29,116117 Thus, it is important to emphasize that the recommendations we have made are appropriate for patients in whom the diagnosis of HIT is strongly suspected on clinical grounds (pending laboratory confirmation), or has already been confirmed by (usually) strong positive test results for HIT antibodies in the appropriate clinical context of intermediate or high pretest probability.

In clinical settings in which HIT is considered unlikely, it may be appropriate to continue heparin or (in settings of antithrombotic prophylaxis) to give usual prophylactic doses of an alternative anticoagulant, eg, prophylactic-dose danaparoid (750 U bid or tid SC),117119 prophylactic-dose fondaparinux (2.5 mg od SC),74 or prophylactic-dose recombinant hirudin (15 mg bid SC).120 We suggest to continue heparin in patients with a low likelihood of HIT requiring therapeutic-dose anticoagulation because the risk of bleeding complications is high when alternative anticoagulants are used in therapeutic doses (as the risk of major bleeding is probably higher than the risk of HIT-associated thrombosis). In contrast, the risk of major bleeding is low when an alternative anticoagulant is given in prophylactic doses. It might therefore be safer to switch to an alternative agent instead of maintaining heparin in this situation.

Scoring systems to help physicians estimate the pretest probability of HIT have been developed.12,21,24 Prospective and retrospective evaluations of one scoring system, the “4 T’s,” indicates that low scores have very low likelihood ratios and thus make HIT very unlikely, whereas a high score confers moderate to high risk of HIT.24,104,121

2.1 Nonheparin Anticoagulants for Treating HIT (With or Without Thrombosis)

Table 3 lists five agents that clinicians can consider for treatment or prevention of HIT-associated thrombosis, and presents pharmacokinetic information, including site of organ clearance.84,122126 Of these, only three (argatroban, lepirudin, bivalirudin) are approved for treatment of HIT in the United States (although bivalirudin is approved only for patients with HIT, or at risk of HIT, undergoing PCI).122124 A fourth agent, danaparoid, is currently approved for thrombosis prophylaxis but neither approved for HIT nor currently available in the United States. Danaparoid is, however, approved (for HIT and/or non-HIT indications) and available for treatment and prevention of HIT-associated thrombosis in Canada, Europe, Australia, New Zealand, Japan, and Korea.125

A fifth agent, fondaparinux,84,126 is a pentasaccharide that inactivates factor Xa in an antithrombin-dependent manner. As described above, it does not “cross-react” in vitro with HIT antibodies (ie, it does not react with PF4 in such a way as to cause sites for HIT antibody binding).,77,7981 Therefore, theoretically it could be effective for treatment of HIT, although its reported use in this indication to date is limited to case reports and small case series, often without convincing serologic support for the diagnosis of HIT.8284 Furthermore, there is uncertainty whether the usual prophylactic or therapeutic doses of fondaparinux would be effective in a patient with severe HIT-associated hypercoagulability.85,105 As both prophylactic- and therapeutic-dose protocols and approvals exist for fondaparinux in various non-HIT settings, fondaparinux (like danaparoid) may be appropriate in those patients encountered in clinical practice in whom the patient is judged to be at relatively low risk of having HIT, but in whom ongoing use of UFH or LMWH is not desired.

The evidence for the efficacy of nonheparin anticoagulants for HIT is not based on large randomized controlled trials (RCTs), due to the infrequent occurrence of serologically confirmed HIT and the clinical heterogeneity of affected patients. Indeed, only one RCT has evaluated HIT treatment: this open-label study compared danaparoid (plus warfarin) with dextran-70 (plus warfarin).127In addition, several retrospective cohort studies and case series have assessed danaparoid therapy.128136 In contrast, prospective cohort studies (with historical controls) have been performed for the two direct thrombin inhibitors (DTIs), lepirudin137142 and argatroban143144 (with several subsequent subanalyses also reported for argatroban145158). Among these prospective cohort studies, the primary efficacy endpoint was a composite end point consisting of new thrombosis, limb amputation, and all-cause mortality. This end point may overestimate the occurrence of new apparent thrombosis or thrombosis growth, as deaths and limb amputations could be related to clinical factors already established when an alternative anticoagulant therapy is begun.5 Indeed, more favorable hazard ratios for outcomes of argatroban treatment of HIT were reported when a “thrombotic end point” that emphasized new thrombotic events and their sequelae was evaluated in a recent argatroban substudy.153 In addition, retrospective postmarketing studies of DTI therapy for HIT have been reported, both for lepirudin and for argatroban (discussed subsequently; see Sections Lepirudin Dose and Monitoring Recommendations Deviating From the Package Insert Recommendations, and Argatroban Dose Recommendations).

Antihirudin antibodies are commonly generated during treatment with lepirudin;159161 reports of anaphylaxis162165 in patients reexposed to lepirudin (as high as 1 in 625 in patients re-exposed to lepirudin)160 led the European Agency for the Evaluation of Medicinal Products (EMEA) to recommend that nonhirudin anticoagulants be considered in patients who have previously been exposed to lepirudin (Public Statement of EMEA, October 2002).

Considerations in Choice and Dosing of Alternative Anticoagulation for HIT: The following factors should be taken into consideration when selecting the appropriate anticoagulant among the five main options (lepirudin, argatroban, bivalirudin, danaparoid, fondaparinux).

  • Most experience with HIT treatment is with danaparoid (outside the United States), argatroban, and hirudin (lepirudin); for these three drugs, American College of Chest Physicians dosing recommendations for management of HIT (Table 3) differ somewhat from manufacturer recommendations, with generally higher dosing recommended for danaparoid and lower dosing recommended for hirudin and argatroban. For bivalirudin (outside the setting of PCI) and fondaparinux, dosing, efficacy, and safety for the management of HIT are not established.

  • For non-HIT situations, most experience is with fondaparinux (VTE prevention/treatment; acute coronary syndrome treatment) and bivalirudin (PCI).

  • Due to the severe hypercoagulability of HIT, low-dose (prophylactic) regimens effective in non-HIT situations, such as DVT prophylaxis with danaparoid or fondaparinux, may not be similarly effective in acute HIT.

  • In the absence of renal or hepatic dysfunction, the relative elimination half-lives are: bivalirudin < argatroban < lepirudin ≪ fondaparinux < danaparoid. However, the advantages of a short half-life (eg, in a patient with bleeding or who requires an invasive procedure) must be balanced against the greater risk of rebound hypercoagulability and thrombosis in acute HIT.

  • In non-HIT patients, lepirudin increases risk of bleeding over heparin when used in therapeutic doses, whereas danaparoid, fondaparinux, and bivalirudin do not increase risk of bleeding compared with heparin (argatroban has undergone minimal evaluation in non-HIT settings).

  • In renal failure, argatroban is safer than hirudin; danaparoid and bivalirudin can be used with moderate dose reductions and increased anticoagulant monitoring; fondaparinux is not recommended in this situation.

  • In hepatic insufficiency/failure, the half-life of argatroban is prolonged; although the half-lives of hirudin, danaparoid, fondaparinux, and bivalirudin are not significantly prolonged in these patients, they too may need dose reduction and increased anticoagulant monitoring.

  • Factors increasing the activated partial thromboplastin time (APTT)—eg, decompensated DIC, hepatic dysfunction, antiphospholipid syndrome, VKA therapy—can lead to underdosing or inappropriate discontinuation of APTT-monitored therapy (eg, DTIs); in contrast, danaparoid and fondaparinux dosing is not influenced by the APTT.

  • The DTIs raise the INR (and can interfere with other functional clotting assays) as follows: argatroban > bivalirudin > hirudin, whereas danaparoid and fondaparinux have no effect; accordingly, overlapping VKA therapy is safest with danaparoid and fondaparinux. Especially with argatroban, VKA therapy should be postponed pending substantial resolution of thrombocytopenia.

  • In thrombocytopenic patients judged to be at low risk of HIT, and in whom no definite indication for therapeutic-dose anticoagulation exists, the safest approach likely is low-dose danaparoid or fondaparinux (pending results of HIT antibody testing).

Treatment of HIT-Associated Thrombosis

DTIs in HIT With Thrombosis: Lepirudin, Argatroban, Bivalirudin: Table 4a summarizes the results of the efficacy and major bleeding endpoints for the lepirudin137141 and argatroban143144 prospective cohort studies of patients with HIT complicated by thrombosis, including their respective historical control data (in addition, Table 4b summarizes the results for lepirudin and argatroban for treatment of “isolated HIT,” which are discussed in a later section). For both agents, pooled data from their respective prospective cohort studies (lepirudin: HAT-1, -2, and -3 trials; argatroban: Arg-911 and -915/915X trials) are also shown, including the efficacy results (composite end point [new thrombosis, limb amputation, all-cause mortality; maximum, one event per patient], and the individual end points of new thrombosis and limb amputation), taken from start of treatment to day 35 (lepirudin) or day 37 (argatroban). Major bleeding rates for both agents are also shown.

Risk ratios (pooled data compared with historical controls) for the composite end point were 0.48 (lepirudin) and 0.75 (argatroban), and for new thrombosis the RRs were 0.28 (lepirudin) and 0.45 (argatroban). The corresponding absolute event rates (categorical analysis) were 19.2% (lepirudin) and 42.3% (argatroban) for the composite end point, and 7.0% (lepirudin) and 15.5% (argatroban) for new thrombosis. A large (n = 496) postmarketing study of lepirudin showed an even lower absolute frequency of thrombosis (5.2%).

Significant differences in the entry criteria and conduct of the trials occurred. For example, patients entered into the lepirudin trials needed to be positive for HIT antibodies (by HIPA test), whereas argatroban patients were entered based on a clinical diagnosis (only 65% of patients were shown to have HIT antibodies in the Arg-911 study, and the data for the Arg-915/915X studies are not reported). Moreover, patients received lepirudin for a mean of 15.8 days, but argatroban only for 6.6 days. A greater percentage of patients in the lepirudin trials were transitioned to a VKA, compared with patients in the argatroban trials (at least 83% vs 62%). Particularly as observation periods in the studies were relatively long (35 and 37 days for lepirudin and argatroban, respectively), the longer duration of lepirudin therapy, and the greater likelihood of transition to VKA, could explain its greater apparent efficacy.

Limb amputation represents a relatively “hard” end point. Comparing limb amputation rates among the trials, there is a lower amputation rate among patients who received lepirudin, compared with argatroban (12/214 [5.6%] vs 51/373 [13.7%]; p = 0.0022 by Fisher exact test, two-tailed). Further, the RR values for limb amputation were 0.70 for lepirudin (compared with historical controls), but were 1.26 for argatroban, ie, the limb amputation rates tended to be greater than the corresponding historical controls for the latter agent.