Heparin-Induced Thrombocytopenia Workup
- Author: Sancar Eke, MD, FASN; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
Heparin-induced thrombocytopenia (HIT) has three characteristic features that can distinguish it from other causes of thrombocytopenia. First is the timing of the onset of thrombocytopenia; in most patients with HIT, the platelet count decrease begins from days 5 to 14 of heparin treatment. Second, the severity of the thrombocytopenia is usually mild to moderate, with platelet counts only rarely less than 15 x 109/L.
Third is the occurrence of large-vessel venous or arterial thrombosis in association with thrombocytopenia. Thrombosis precedes thrombocytopenia in up to 25% of patients with HIT.
All patients should have baseline platelet counts measured before heparin treatment is started. Guidelines from the American College of Chest Physicians (ACCP) suggest basing further platelet counts on the patient’s risk of HIT. For patients whose risk is considered to be greater than 1% (eg, patients receiving unfractionated heparin after cardiac or orthopedic surgery), the ACCP suggests monitoring the platelet count every 2 or 3 days from days 4-14 of heparin therapy (or until heparin is stopped, whichever comes first).
The ACCP suggests that platelet counts need not be monitored in patients receiving heparin whose risk of HIT is considered to be less than 1%. These include medical patients receiving low molecular weight heparin.
If the platelet count falls by over 50% of the baseline count, even if the nadir remains above 150 x 109/L, and/or a thrombotic event occurs, diagnostic tests should be performed. Diagnostic tests for HIT consist of immunoassays and functional assays.
Immunoassays identify antibodies against heparin/platelet factor 4 (PF4) complexes. Functional assays measure the platelet-activating capacity of PF4/heparin-antibody complexes. Functional assays have greater specificity than immunoassays but are time-consuming and not widely available; many institutions offer only immunoassays.
Silent deep venous thrombosis (DVT) is common in patients with HIT. Therefore, bilateral lower extremity compression ultrasonography may be considered in these patients, even in the absence of clinical evidence of lower-limb DVT.
In patients with HIT who experience thrombosis, different vascular imaging studies can be used to document the thrombotic lesions, including ultrasonography and angiography (see the images below). Multislice computed tomography (MSCT) scanning has been utilized in some patients with multiple thrombosis.
Immunoassays include solid-phase immunoassays (heparin/PF4 enzyme-linked immunosorbent assay [ELISA]), and particle gel immunoassays. Immunoassays are widely available and have a rapid turnaround time and high sensitivity (> 99%). However, they have poor specificity (30%-70%) because they also detect nonpathogenic antibodies.
The specificity of ELISA can be enhanced by taking into account the optical density of the result. Higher absolute optical density values correlate with a clinical diagnosis of HIT. Warkentin and colleagues reported that weaker optical density values (0.4 to < 1.00) indicated a 5% or lower probability of a strongly positive result on functional testing with the serotonin release assay (SRA), whereas an optical density value of 2.00 or more resulted in an approximately 90% probability of a strong SRA result.
Baroletti and colleagues found that in patients with clinically suspected HIT, a 1-unit increase in optical density values was associated with an approximate doubling in the odds of thrombosis by 30 days (odds ratio, 1.9; 95% confidence interval, 1.5-2.6; P=.0001). The proportion of patients with pulmonary embolism increased with higher values.
In a study of surgical intensive care unit patients, Berry and colleagues found that only 19% of patients with an optical density value of 0.4 or higher had a positive SRA result. Use of an optical density threshold of 2.0 proved more predictive of HIT, with a true positive rate of 65%.
One proposed procedure to improve the specificity of the ELISA involves the addition of excess heparin to the sample. With a positive ELISA, a decrease in the optical density by 50% or more after the addition of excess heparin confirms the presence of heparin-dependent antibodies.
Functional assays include the heparin-induced platelet aggregation assay (HIPA) and the serotonin release assay (SRA). Most laboratories that perform functional testing use HIPA, which is highly specific but which is also reported to be less sensitive than SRA. The availability of SRA is largely restricted to centers where HIT is a focus of research.
The SRA is based on HIT antibodies causing platelets to aggregate and release serotonin. For the test, platelets of normal donors are radiolabeled with carbon 14 (14 C)-serotonin and are washed; these platelets are then mixed with patient serum, along with low (therapeutic) and high heparin concentrations. The test is considered positive if the sample causes a greater than 20% serotonin release at a (therapeutic) dosage of 0.1 U/mL heparin.
The14 C-SRA is considered the "gold standard" assay for the detection of heparin-dependent antibodies in heparin-induced thrombocytopenia (HIT). The sensitivity of SRA has ranged from 69% to 94%, and its specificity of SRA may be as high as 100%.[45, 46, 47]
HIPA is a platelet-activation test in which the patient's serum is mixed with donor platelets in the presence of heparin. Aggregation of the donor platelets indicates the presence of antibodies to the heparin–PF4 complex. Chong and colleagues reported that the mean sensitivity of HIPA may vary from 39% to 81%, depending on the heparin concentration and the reactivity of the platelets used, while specificity ranged from 82-100%.
HIPA proved to be more sensitive than PF4 ELISA for laboratory confirmation of HIT, in a study involving serum samples from 146 patients examined for HIT. However, neither the HIPA nor the PF4 ELISA predicted thrombotic risk.
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|2 points||1 point||0 points|
platelet nadir 20-100 × 109/L
platelet nadir 10-19× 109/L
platelet nadir < 10× 109/L
|Timing of platelet count fall||Clear onset on day 5-10, or =1 d if heparin exposure within past 30 d||Consistent with day 5-10 fall, but not clear (eg, missing platelet counts); onset after day 10; or fall = 1 day if heparin exposure 30-100 days ago||Platelet count fall =4 d without recent heparin exposure|
|Thrombosis or other sequelae||New thrombosis (confirmed); skin necrosis; acute systemic reaction after IV UHF bolus||Progressive or recurrent thrombosis; erythematous skin lesions; thrombosis suspected but not proven||None|
|Other causes of thrombocytopenia||None apparent||Possible||Definite|