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

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.

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.

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.

HIT is an adverse immune-mediated drug reaction that is associated with a high risk of venous and arterial thrombosis.^3‐6 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,^14‐16 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%).^{13,14,21‐24} Women have approximately twice the risk of developing HIT as men.¹⁸Table 2^25‐35 presents the incidence of HIT in various patient populations.

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,^51‐55 the best studied of which is the 4Ts score (Fig 1).^56‐59 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.

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