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Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles |

Treatment and Prevention of Heparin-Induced ThrombocytopeniaTreatment of HIT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Lori-Ann Linkins, MD; Antonio L. Dans, MD; COL Lisa K. Moores, MC, USA, FCCP; Robert Bona, MD; Bruce L. Davidson, MD, MPH, FCCP; Sam Schulman, MD, PhD; Mark Crowther, MD
Author and Funding Information

From the Department of Medicine (Drs Linkins, Schulman, and Crowther), McMaster University, Hamilton, ON, Canada; the College of Medicine (Dr Dans), University of the Philippines Manila, Manila, Philippines; The Uniformed Services (Dr Moores), University of Health Sciences, Bethesda, MD; School of Medicine (Dr Bona), Quinnipiac University, North Haven, CT; and the University of Washington School of Medicine (Dr Davidson), Seattle, WA.

Correspondence to: Lori-Ann Linkins, MD, Department of Medicine, McMaster University, Juravinski Hospital, Rm-M0118, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: linkinla@mcmaster.ca


Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


Chest. 2012;141(2_suppl):e495S-e530S. doi:10.1378/chest.11-2303
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Background:  Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke.

Methods:  The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.

Results:  Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C).

Conclusions:  Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Figures in this Article

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.1.1. For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C).

2.1.2. For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C).

3.1. In patients with HITT, we recommend the use of nonheparin anticoagulants, in particular lepirudin, argatroban, and danaparoid, over the further use of heparin or LMWH or initiation/continuation of a vitamin K antagonist (VKA) (Grade 1C).

3.2.1. In patients with HITT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C).

Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect, may influence the choice of agent.

3.2.2. In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C).

3.3. In patients with HIT and severe thrombocytopenia, we suggest giving platelet transfusions only if bleeding or during the performance of an invasive procedure with a high risk of bleeding (Grade 2C).

3.4.1. In patients with strongly suspected or confirmed HIT, we recommend against starting VKA until platelets have substantially recovered (ie, usually to at least 150 × 109/L) over starting VKA at a lower platelet count and that the VKA be initially given in low doses (maximum, 5 mg of warfarin or 6 mg phenprocoumon) over using higher doses (Grade 1C).

3.4.2. We further suggest that if a VKA has already been started when a patient is diagnosed with HIT, vitamin K should be administered (Grade 2C).

Remarks: We place a high value on the prevention of venous limb gangrene and a low value on the cost of the additional days of the parental nonheparin anticoagulant.

3.5. In patients with confirmed HIT, we recommend that that the VKA be overlapped with a nonheparin anticoagulant for a minimum of 5 days and until the INR is within the target range over shorter periods of overlap and that the INR be rechecked after the anticoagulant effect of the nonheparin anticoagulant has resolved (Grade 1C).

4.1. In patients with isolated HIT (HIT without thrombosis), we recommend the use of lepirudin or argatroban or danaparoid over the further use of heparin or LMWH or initiation/continuation of a VKA (Grade 1C).

4.2. In patients with isolated HIT (HIT without thrombosis) who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C).

Remarks: Other factors such as drug availability, cost, and ability to monitor the anticoagulant effect may influence the choice of agent. The dosing considerations are the same as for patients with HITT (see section 3.2). For a recommendation on choice of nonheparin anticoagulants in the setting of renal insufficiency, see Recommendation 3.2.2.

5.1.1. In patients with acute HIT (thrombocytopenic, HIT antibody positive) or subacute HIT (platelets recovered, but still HIT antibody positive) who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants and over heparin plus antiplatelet agents (Grade 2C).

5.1.2. In patients with acute HIT who require nonurgent cardiac surgery, we recommend delaying the surgery (if possible) until HIT has resolved and HIT antibodies are negative (see section 6.1) (Grade 2C).

Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the anticoagulant effect may influence the choice of agent. For recommendations for patients with a past history of HIT (>. 3 months previous) who require cardiac surgery, see section 6.1.

5.2. In patients with acute HIT or subacute HIT who require percutaneous coronary interventions, we suggest the use of bivalirudin (Grade 2B) or argatroban (Grade 2C) over other nonheparin anticoagulants.

Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may influence the choice of agent.

5.3.1. In patients with acute or subacute HIT who require renal replacement therapy, we suggest the use of argatroban or danaparoid over other nonheparin anticoagulants (Grade 2C).

Remarks: We acknowledge that the cost of argatroban may be prohibitive at some clinical centers. We further suggest that if the prothrombotic state of HIT appears to have resolved (as seen by normalization of the platelet count), saline flushes during dialysis would be a reasonable option. This suggestion is based on the presumed pathogenesis of thrombosis in this condition and not on the results of clinical trials.

5.3.2. In patients with a past history of HIT who require ongoing renal replacement therapy or catheter locking, we suggest the use of regional citrate over the use of heparin or LMWH (Grade 2C).

5.4. In pregnant patients with acute or subacute HIT, we suggest danaparoid over other nonheparin anticoagulants (Grade 2C). We suggest the use of lepirudin or fondaparinux only if danaparoid is not available (Grade 2C).

Remarks: Other factors, such as drug availability, cost, and ability to monitor the anticoagulant effect, may influence the choice of agent.

6.1.1. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac surgery, we suggest the use of heparin (short-term use only) over nonheparin anticoagulants (Grade 2C).

6.1.2. In patients with a history of HIT in whom heparin antibodies are still present who require cardiac surgery, we suggest the use of nonheparin anticoagulants (see Recommendation 5.1.1) over heparin or LMWH (Grade 2C).

6.2. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac catheterization or percutaneous coronary interventions, the recommended treatment is the same as in Recommendation 5.2.

6.3. In patients with a past history of HIT who have acute thrombosis (not related to HIT) and normal renal function, we suggest the use of fondaparinux at full therapeutic doses until transition to a VKA can be achieved (Grade 2C).

This article offers recommendations on diagnosis and management of heparin-induced thrombocytopenia (HIT). Table 1 describes the question definition (ie, population, intervention, comparator, and outcome) addressed by the recommendations.

Table Graphic Jump Location
Table 1 —[Introduction] Treatment and Prevention of HIT: Question Definitions

HIT = heparin-induced thrombocytopenia; HITT = heparin-induced thrombocytopenia with thrombosis; LMWH = low-molecular-weight heparin; PCI = percutaneous coronary intervention; PICO = population, intervention, comparator, and outcome; VKA = vitamin K antagonist.

We adhered to the general approach to developing recommendations described in the methodology article of these guidelines.1 We searched the PubMed English language literature from January 1976 to June 2010 using the following search terms: “heparin-induced thrombocytopenia,” “clinical trial,” “cohort,” “randomized clinical trial,” “argatroban,” “lepirudin,” “hirudin,” “bivalirudin,” “fondaparinux”, “diagnosis,” “laboratory assay,” “clinical prediction rule,” “platelet count monitoring,” “coronary artery bypass,” “cardiac surgery,” “cardiopulmonary bypass” (CPB), “angioplasty,” “transluminal percutaneous coronary,” “treatment,” “venous limb gangrene,” “platelet transfusion,” “renal replacement therapy,” “hemodialysis,” “hemofiltration,” “pregnancy,” “re-exposure,” and “recurrence.”

The primary efficacy outcome measures of interest were new thrombosis, limb amputation, major bleeding, and death (due to thrombosis or bleeding). In the cohort studies with historical controls, outcome events were counted if they occurred after treatment with the nonheparin anticoagulant was initiated, and from the date heparin was discontinued in the control group.

1.1 Value and Preferences

Based on the relevant literature and the value and preference rating exercise conducted by the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines panel,2 we infer that from the patient’s perspective, a venous thromboembolic event (eg, pulmonary embolism [PE], proximal DVT) carries similar weight as a major bleeding event (eg, gastrointestinal bleeding event), and that a stroke carries 2.5 times the weight of a major bleeding event.

1.2 Overview of HIT
1.2.1 Pathogenesis of HIT:

HIT is an adverse immune-mediated drug reaction that is associated with a high risk of venous and arterial thrombosis.36 Heparin exposure leads to the formation of IgG antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) and heparin that form on the surface of platelets.7,8 These complexes bind to the FcɣIIa (IgG) receptors of platelets,9,10 resulting in platelet activation and release of procoagulant, platelet-derived microparticles.11,12 The end result is marked generation of thrombin and the formation of venous and arterial thromboses that are the clinical hallmark of HIT.

Risk factors for HIT include duration and type of heparin exposure,13 patient population,1416 severity of trauma,17 and gender.18 Differences in the stoichiometry of heparin/PF4 complexes are believed to explain the 10-fold higher likelihood of HIT in patients who receive unfractionated heparin (UFH) compared with patients who receive low-molecular weight heparin (LMWH) or fondaparinux.19,20 Patients who undergo cardiac or orthopedic surgery and receive UFH have a higher risk of HIT (1%-5%) than medical or obstetric patients (0.1%-1%).13,14,2124 Women have approximately twice the risk of developing HIT as men.18Table 22535 presents the incidence of HIT in various patient populations.

Table Graphic Jump Location
Table 2 —[Overview of HIT] Incidence of HIT According to Patient Population and Type of Heparin Exposure

See Table 1 legend for expansion of abbreviations.

a 

Case reports only.

1.2.2 Clinical Features:

Thrombocytopenia (defined as a platelet count < 150 × 109/L) is the most common clinical manifestation of HIT and occurs in 85% to 90% of patients.4 If this definition is broadened to include a proportional fall in the platelet count (eg, 30%-50% fall even if the nadir remains > 150 × 109/L), this increases to 90% to 95% of HIT cases.4,5,27 The characteristic onset of the platelet count fall in HIT is 5 to 10 days after initiation of heparin (first day of heparin = day 0), particularly when heparin is administered perioperatively (typical-onset HIT).36 “Rapid-onset HIT” refers to an abrupt platelet count fall (within 24 h) that occurs in patients who already have circulating HIT antibodies because of recent exposure to heparin (usually within the past month, occasionally as long as 100 days earlier).36,37 Occasionally, thrombocytopenia can occur as long as 3 weeks after cessation of heparin (delayed-onset HIT).38 Although thrombocytopenia is the most common presenting feature of HIT, in up to 25% of patients with HIT the development of thrombosis precedes the development of thrombocytopenia.3,5

The pattern of thrombocytopenia following cardiac surgery using heparin is worthy of special mention. Although approximately 50% of patients who undergo cardiac surgery will develop HIT antibodies, only 1% to 2% will develop clinical HIT (thrombocytopenia with or without thrombosis).14 In general, the platelet count falls by approximately 38% immediately after CPB (and continues to decline for the first 1-2 postoperative days before rising in a continuous fashion to a level above the preoperative count).39,40 The following two patterns of thrombocytopenia should alert clinicians to the possibility of HIT following cardiac surgery: a fall in platelet count that begins > 4 days postoperatively (day of surgery = day 0), and thrombocytopenia that persists for > 4 days after surgery.41

The most common complication of HIT is venous thrombosis; 17% to 55% of untreated patients who present with thrombocytopenia develop DVT and/or PE.6,14,42 Arterial thrombotic events, including limb artery thrombosis, thrombotic stroke, and myocardial infarction (MI), also occur, but less often (from 3%-10%).6,43 After cardiac surgery, the majority of HIT-related thrombotic events are arterial.44,45 Approximately 5% to 10% of patients with HIT die, usually as a result of thrombotic complications.6,42

Less common manifestations of HIT include venous limb gangrene (5%-10% of patients with HIT with DVT treated acutely with a vitamin K antagonist [VKA] [eg, warfarin]),46 necrotizing skin lesions at heparin injection sites,47,48 adrenal hemorrhagic necrosis (due to adrenal vein thrombosis), and acute systemic reactions within 30 min of an IV heparin bolus injection (eg, fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest).48 HIT can be complicated by disseminated intravascular coagulation severe enough to deplete fibrinogen.38,49 Despite severe thrombocytopenia (but with a nadir rarely < 20 × 109/L), petechiae or other signs of bleeding are rarely seen.3

HIT is recognized as a clinicopathologic syndrome because diagnosis is based on the combination of a compatible clinical picture and the presence of platelet-activating anti-PF4 antibodies.50 Clinical prediction rules to assist physicians with determining the probability that a patient has HIT have been developed,5155 the best studied of which is the 4Ts score (Fig 1).5659 Evidence is emerging that patients with a low 4Ts score have a very low probability of HIT (0%-3%).51,56 However, many patients (24%-61%) with a high 4Ts score prove not to have HIT.51,56 Clinical assessment plays an essential role in the diagnosis of HIT for two reasons: (1) there is commonly a delay before the results of laboratory testing for HIT are available, and management decisions must be made immediately (the rate of thrombosis prior to treatment is approximately 5% per day)60; and (2) isolated HIT antibodies are both frequent and not diagnostic of HIT.

Figure Jump LinkFigure 1. 4Ts score. *Timing of clinical sequelae, such as thrombocytopenia, thrombosis, or skin lesions. **Two points if necrotizing heparin-induced skin lesions even if thrombocytopenia not present. (Modified with permission from Warkentin and Linkins.59)Grahic Jump Location
1.2.3 Laboratory Diagnosis of HIT:

A large number of laboratory assays are currently used to diagnose HIT. A recent survey of specialized coagulation laboratories in North America identified eight different assays and wide discrepancies in practice between centers using the same assay.61 The assays can be divided into two major categories according to the end point they measure: (1) antigen assays that detect the presence of HIT antibodies, and (2) functional assays that detect evidence of platelet activation (by HIT antibodies) in the presence of heparin.62 Only a small proportion of patients who form HIT antibodies (seroconversion) will develop thrombocytopenia, and a smaller proportion will develop HIT-associated thrombosis. Antigen assays, the most commonly used being enzyme-linked immunosorbent assays (ELISA) that test for antibodies that are reactive against PF4/heparin or PF4/polyvinyl sulfonate, are very sensitive for HIT because they detect seroconversion.15,63 However, not all of the antibodies these assays detect are capable of causing clinical HIT; hence, the specificity of these assays is only moderate. In contrast, functional assays, such as the serotonin release assay (SRA) and heparin-induced platelet activation (HIPA), are sensitive and specific for HIT because they only detect antibodies that are capable of activating platelets.15

The washed platelet SRA and HIPA are generally accepted as the reference standard assays for HIT. However, they are only available at a few centers because they are technically difficult, require human platelets from known reactive donors, and, in the case of the SRA, require working with radiation.64,65 Most clinical centers use commercially available ELISAs because they do not have these limitations. The primary drawback of the ELISAs is their potential to overdiagnose HIT by detecting antibodies that are not pathogenic. ELISAs that only detect IgG antibodies appear to have better specificity for HIT (IgM and IgA antibodies are unlikely to cause HIT).15,66

In patients recovering from HIT, there can be a lag time of several weeks between full platelet recovery and disappearance of the HIT antibodies (subacute HIT), particularly when using the ELISA for serologic testing. These patients are still at risk for developing rapid-onset HIT on heparin re-exposure (unless the washed platelet SRA or HIPA is negative and the ELISA is only weakly positive or strongly positive because of non-platelet-activating IgM or IgA antibodies).

A class of commercial antigen assays that are designed to have a faster turnaround time than the ELISA (approximately 15 min vs 3.5 h [or days, if batched]) have entered the market. One of these assays, the ID-PaGIA Heparin/PF4 antibody test (DiaMed), is a gel centrifugation assay that uses the binding of antibodies to antigen-coated (PF4/heparin) high-density, red polystyrene beads.67 This method can be performed in any blood bank that utilizes a gel centrifugation system for red cell antibody screening. The operating characteristics for this assay are reviewed in section 1.2.4.

1.2.4 Commercial Antigen Assays Compared With Reference Standard Assays for Diagnosis of HIT:

To determine the accuracy of the commercially available antigen assays for HIT, we searched the literature for studies that: (1) compared the operating characteristics of these assays with at least one of the reference standard assays (ie, SRA or HIPA), and (2) used blood samples collected prospectively from consecutive patients with suspected HIT. The three studies that met our criteria evaluated two antigen assays: GTI-PF4 (Genetics Testing Institute [GTI]) and ID-PaGIA Heparin/PF4 antibody test (DiaMed AG)56,68,69(Table 3). Both of these assays detect all classes of immunoglobulin. The sensitivity of the GTI-PF4 assay was 100% (if negative, HIT ruled out), whereas the specificity (82%-85%) was lower. Thus, many patients with positive tests, particularly those with moderate or low pretest probability, will not have HIT. The sensitivity of the PaGIA is lower than the GTI-PF4 (94%-95%), and the specificity is higher (88%-92%) than the GTI-PF4.

Table Graphic Jump Location
Table 3 —[Overview of HIT] Comparison of Commercial Antigen Assays With Reference Standard Assays

ELISA = enzyme-linked immunosorbent assay; FN = false negative; FP = false positive; GTI = Genetics Testing Institute; HIPA = heparin-induced platelet activation; NPV = negative predictive value; PF4 = platelet factor 4; PPV = positive predictive value; Sens = sensitivity; Spec = specificity; SRA = serotonin release assay; TN = true negative; TP = true positive. See Table 1 legend for expansion of other abbreviation.

In summary, both of these antigen assays can exclude a diagnosis of HIT, but neither assay is ideal as a stand-alone test to confirm the diagnosis of HIT. A negative ELISA or PaGIA in a patient with a low pretest probability of HIT excludes the diagnosis of HIT. A positive ELISA or PaGIA in a patient with a low pretest probability of HIT should not be interpreted as diagnostic for HIT and requires confirmation with a functional assay.

1.2.5 Commercially Available ELISA Using Manufacturer’s Optical Density Threshold Compared With an Elevated Optical Density Threshold:

There is a correlation between the strength of the reaction with an ELISA (measured using optical density units [OD]) and the likelihood of clinical HIT.70,71 Three studies have addressed the question (retrospectively) of whether raising the OD threshold that is used to define a positive result with an ELISA would improve the specificity of the assay.69.70,72 All three used the GTI-PF4 assay, which detects all classes of immunoglobulin (positive threshold set at 0.40 OD) (Table 4). Two of the studies showed that raising the OD threshold to 1.0 increased the likelihood of a positive SRA result (specificity increased from 85% to 95%)69 and increased the likelihood of new thromboembolic events (24% of patients at a threshold of 0.40 OD had a new thrombotic event compared with 59% at a threshold of 1.0 OD).70 The third study showed that increasing the threshold of the GTI-PF4 to 1.20 OD and combining it with an intermediate or high 4Ts score identified all of the same HIT-positive patients as the SRA alone.72

Table Graphic Jump Location
Table 4 —[Overview of HIT] Studies Comparing Different OD Threshold Levels for Commercial ELISAs

IQR = interquartile range; OD = optical density; TEC = thromboembolic complication.

a 

Includes 16 patients identified by the classic HIT definition and an additional 16 patients (one of the additional patients had a TEC).

b 

Recent platelet count < 150 × 109/L, platelet count of ≥ 50% in setting of heparin therapy or a prior history of HIT.

c 

Includes the 15 patients initially diagnosed with HITT and eight patients with HIT who developed thrombosis within 30 d of diagnosis with HIT.

In summary, it appears that the combination of a threshold > 1.0 OD with a high clinical suspicion for HIT (eg, intermediate or high 4Ts score) may have a similar accuracy for diagnosing HIT as the reference standard assay (SRA). However, this strategy requires validation in prospective studies.

For laboratories using the GTI-PF4 ELISA, we suggest reporting the quantitative value of the test result, together with the threshold used to define a positive result, over reporting the result only as positive or negative. For clinicians ordering the GTI-PF4 ELISA to determine whether a patient has HIT, we suggest taking into consideration both the pretest probability of HIT and the quantitative level of the GTI-PF4 ELISA result. A GTI-ELISA result between 0.40 and 1.0 OD in a patient with a low or moderate pretest probability for HIT should, if possible, be confirmed with a functional assay.