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
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
||Timing of Onset
||Other Causes of Thrombocytopenia
||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
||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
||Platelet count decreases <30%
Platelet nadir <10 x 109/L
|≤4 days after start of heparin, with no recent heparin exposure
||Definite other cause
aA score is assigned for each category or variable, and the total 4Ts score (far right column) is the sum of all scores.
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:
||Patients undergoing cardiac or orthopedic surgerya
||Medical or obstetric patients
|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
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 for 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 to 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.
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 basis of 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 assaya
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 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 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 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.
Platelet Count Monitoring
Platelet counts serve as a surrogate for ongoing platelet activation. Platelet count monitoring is useful to guide clinical decision-making after a confirmed diagnosis of HIT, both to evaluate for 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.