Heparin-Induced Thrombocytopenia - HIT

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect of heparin treatment. On exposure to heparin, some patients form antibodies that target complexes of platelet factor 4 (PF4) and heparin. Only a subset of patients with detectable antibodies develop HIT syndrome. Although HIT is a thrombocytopenic disorder, it results in a prothrombotic condition of platelet activation that can lead to life-threatening complications, including pulmonary embolism, limb necrosis, stroke, and acute myocardial infarction. Without treatment, up to 50% of patients can experience thrombotic events. Diagnosis of HIT is based on clinical assessment and laboratory results. Primary laboratory tests for HIT include immunologic assays, such as an enzyme-linked immunosorbent assay (ELISA), and functional, platelet-activation assays, such as the serotonin release assay (SRA). It is recommended that a clinical scoring system, such as the 4Ts system, be used to determine the pretest probability of HIT in a patient before laboratory testing is performed.

Quick Answers for Clinicians

What are the risk factors for heparin-induced thrombocytopenia?

Risk factors for heparin-induced thrombocytopenia (HIT) include the duration of heparin treatment, type of heparin administered (unfractionated heparin [UFH] versus low-molecular-weight heparin [LMWH]), dose, patient population, and patient sex (females are at greater risk of developing HIT than males). Of the two heparin types, UFH is associated with greater risk (10-fold higher) than is LMWH. Patients undergoing major surgery and trauma patients are at increased risk for HIT compared with medical patients (ie, those undergoing minor surgery or general medical treatment).

Which clinical scoring systems are recommended to assess the likelihood of heparin-induced thrombocytopenia?

The American Society of Hematology (ASH) recommends the 4Ts clinical scoring system, which is widely used to assess pretest probability for heparin-induced thrombocytopenia (HIT). This system takes into account the severity and timing of thrombocytopenia, the presence of thrombosis or other complication(s), and the likelihood of another cause of thrombocytopenia. Laboratory testing is typically not performed in patients with low scores (unless missing information could affect score reliability) due to the 4Ts system’s high negative predictive value for HIT. Laboratory testing is performed in patients with intermediate or high 4Ts scores due to the system’s poor positive predictive value. In patients who undergo laboratory testing, the combination of the clinical score and test results is used to determine the likelihood of HIT.

Which tests are useful for diagnosing heparin-induced thrombocytopenia?

In patients with an intermediate or high pretest probability of HIT, an enzyme-linked immunosorbent assay (ELISA) to detect heparin-platelet factor 4 (PF4) immunoglobulin G (IgG) antibodies is the first diagnostic step. If the ELISA is positive, testing with a functional assay, such as the serotonin release assay (SRA), may be helpful to confirm the diagnosis of HIT.

Is heparin-induced thrombocytopenia testing useful when vaccine-induced immune thrombotic thrombocytopenia is suspected following COVID-19 vaccination?

Although vaccine-induced immune thrombotic thrombocytopenia (VITT) is distinct from heparin-induced thrombocytopenia (HIT), VITT is similarly associated with platelet-activating antibodies against platelet factor 4 (PF4), and testing for the two conditions overlaps. When VITT is suspected (severe symptoms typically occur 4-42 days postvaccination), initial laboratory testing includes:

HIT (anti-PF4) antibody detection by enzyme-linked immunosorbent assay (ELISA)
CBC with platelet count and peripheral smear
Prothrombin time (PT) test
Activated partial thromboplastin time (aPTT) test
Fibrinogen test
D-dimer test

Specimens for antibody testing should be collected before initiation of intravenous immunoglobulin (IVIG) therapy. One or more functional assays (eg, serotonin release assay) may be used as a follow-up to a positive HIT antibody result.

Indications for Testing

Laboratory testing for HIT is appropriate to:

Diagnose patients with thrombocytopenia after exposure to heparin, particularly those with an intermediate or high probability of HIT based on a clinical scoring system or risk factors
Guide clinical decision-making in patients with a current or previous diagnosis of HIT

Laboratory Testing

Diagnosis

HIT is a clinicopathologic diagnosis that requires combined evaluation of clinical examination and laboratory test results. Use of a clinical scoring system, such as the 4Ts system, is recommended to establish the need for diagnostic laboratory testing in HIT (see table below). Clinical scoring can determine which patients do not need further testing, thereby avoiding the use of expensive and potentially risky nonheparin anticoagulants (such as argatroban) while awaiting test results for these patients.

4Ts Scoring System
Score^a	Thrombocytopenia	Timing of Onset	Thrombosis	Other Causes of Thrombocytopenia	Total Score
Score^a	Category or Variable				Total Score
2	Platelet count decreases >50% Platelet nadir ≥20 x 10⁹/L	5-10 days after start of heparin, or ≤1 day (previous heparin exposure within 30 days)	New thrombosis, or skin necrosis at heparin injection sites, or acute systemic reaction after IV heparin	No other apparent cause	6-8 (high)
1	Platelet count decreases 30-50% Platelet nadir 10-19 x 10⁹/L	>10 days after start of heparin, or time frame of onset is unclear	Progressive or recurrent thrombosis	Possible other cause	4-5 (intermediate)
0	Platelet count decreases <30% Platelet nadir <10 x 10⁹/L	≤4 days after start of heparin, with no recent heparin exposure	No thrombosis	Definite other cause	0-3 (low)
^aA score is assigned for each category or variable, and the total 4Ts score (far right column) is the sum of all scores. IV, intravenous Sources: Salter, 2016; Greinacher, 2015

Both the American College of Chest Physicians (ACCP) and the American Society of Hematology (ASH) offer guidance about risk in various populations:

ACCP HIT Risk by Underlying Medical Condition for Patients Receiving UFH
1-5%	Patients undergoing cardiac or orthopedic surgery^a
0.1-1%	Medical or obstetric patients
ASH HIT Risk by Underlying Medical Condition and Type of Heparin
High risk (>1.0%)	Patients treated with UFH (or a combination of UFH and LMWH, or UFH and fondparinux) following major surgery or major trauma
Intermediate risk (0.1-1.0%)	Medical or obstetric patients treated with UFH Patients treated with LMWH following major surgery or major trauma
Low risk (<0.1%)	Medical or obstetric patients treated with LMWH Patients treated with LMWH after minor surgery or minor trauma Patients treated with fondparinux
^aRisk of HIT is 10 times higher with UFH than with LMWH. LMWH, low-molecular-weight heparin; UFH, unfractionated heparin Sources: Linkins, 2012; Cuker, 2018

Initial Tests

Platelet Counts

Baseline and serial platelet counts are recommended in patients with a HIT risk of at least 0.1% and are used to determine clinical pretest probability. ASH recommends evaluation for HIT using serial platelet counts every 2-3 days for intermediate-risk patients and at least every other day for high-risk patients, beginning on the day of heparin initiation if the patient has been treated with heparin in the preceding 30 days, or on day 4 after heparin exposure in patients who have not received heparin in the previous 30 days. Platelet-count monitoring should continue until day 14 or until cessation of heparin treatment, whichever comes first. For patients estimated to have a low risk of HIT, monitoring of platelet counts is not recommended.

The platelet-count decrease in HIT generally occurs over a period of 1-3 days and is evaluated in comparison with the highest platelet count obtained after heparin treatment began. Thrombocytopenia in HIT typically manifests 5-10 days after heparin is started, but rapid-onset and delayed-onset presentations are also possible. Rapid onset of thrombocytopenia may occur in patients treated with heparin within the past 30 days.

Specific Tests

Recommended HIT Diagnostic Testing Strategy
No HIT-Specific Testing Indicated	Immunologic Assay Indicated	Functional Assay Indicated
In patients with a low clinical probability of HIT on the basis of the 4Ts score (score of ≤3), do not order lab tests HIT testing may be warranted in patients with a low-probability 4Ts score if there is uncertainty about the score (such as in the case of missing information) or in patients in whom the 4Ts score may be invalid (such as patients with thrombocytopenia due to recent chemotherapy)	In patients with an intermediate or high 4Ts score (score of ≥4), discontinue heparin and start alternative anticoagulant; order immunologic assay	In patients with a positive immunologic assay, continue alternative anticoagulant and order a functional assay; however, a functional assay may not be needed in patients with a high 4Ts score and strongly positive immunologic assay^a In patients with a negative immunologic assay, do not order a functional assay and reassess choice of anticoagulant
^aAn analytical model developed by ASH indicated that patients with a high 4Ts score and strongly positive immunologic assay result would not be incorrectly diagnosed with HIT (ie, there would be no false-positive diagnoses of HIT in this population), and therefore a functional assay is likely not required. Source: Cuker, 2018

Immunologic Assays

Immunologic assays such as ELISAs are highly sensitive for HIT-related antibodies and are therefore helpful to exclude a HIT diagnosis in conjunction with pretest probability. ELISA immunoglobulin G (IgG) testing has a high negative predictive value. HIT is very unlikely in patients with a negative antibody test. Using an ELISA that measures only clinically relevant IgG antibodies but not IgA and IgM antibodies can improve the specificity and positive predictive value of the test. Higher optical density (OD) values in an ELISA are associated with an increased likelihood of positive functional assay results and clinical HIT; however, OD values vary by assay. Because not all patients with a positive ELISA will have HIT, functional assays are useful to further evaluate certain samples with positive ELISA results.

Functional Assays

Functional assays for HIT include platelet activation assays such as SRAs. These assays are generally used as second-line tests after immunologic assays for confirmation of a HIT diagnosis.

The SRA is considered the gold standard test for HIT diagnosis because of its high sensitivity and specificity. The test measures the serotonin released from platelets, which correlates with the degree of platelet activation induced by the PF4-heparin antibody complex. SRAs can sometimes be falsely positive due to non-HIT-related platelet-activating antibodies; performing the test in conjunction with an ELISA helps to avoid false-positive SRA results.

Monitoring

Platelet Count Monitoring

Platelet counts serve as a surrogate measure for ongoing platelet activation. Platelet count monitoring is useful to guide clinical decision-making after a confirmed diagnosis of HIT, both to evaluate patients for platelet count recovery and because vitamin K antagonists such as warfarin should not be given until the platelet count is >150,000/µL.

Functional and Immunologic Assays

HIT tests (both functional and immunologic assays) are used to evaluate patients with a history of HIT who may be reexposed to heparin (eg, those who need cardiac surgery); these assays can be used to determine whether HIT antibodies are still present before the use of heparin. However, heparin exposure is generally to be avoided in patients with a history of HIT unless warranted by a specific clinical situation in which alternative anticoagulation is considered inferior to heparin.