Heparin-induced thrombocytopenia

At a Glance

Heparin-induced thrombocytopenia (HIT) should be suspected if the platelet count decreases by 50% (at least 30%) during or within 2 weeks after administration of unfractionated heparin or low molecular weight heparin or fondaparinux, especially if associated with a new thrombosis. The platelet count typically starts falling 5-14 days after the start of heparin.

Patients who were pre-exposed to heparin within the previous 4 weeks may have circulating PF4/heparin antibodies. In these patients, the platelet count falls within hours after re-exposure. In a subset of these patients who receive a heparin bolus, generalized reactions, which are caused by immune complexes, may occur.

Because HIT is a prothrombotic condition, bleeding complications are rare. In addition, the platelet count in HIT usually does not decline below 20G/L. In patients with very low platelet counts and especially in bleeding patients, other causes of thrombocytopenia are much more likely than HIT. Clinical scoring systems are helpful in assessing the probability that HIT is the cause for the low platelet count. The 4 T-score results in 0-8 points. HIT should be considered unlikely if the resulting score is less than or equal to 3 points. If the 4 T-score is 4-6 points, HIT is moderately or very likely (7-8 points) and laboratory work-up should be initiated to rule out HIT (See Table 1).

Table 1.
Score 2 1 0
Thrombocytopenia (acute) >50% platelet fall (nadir ≥20 x109/l) 30-50% platelet fall (or >50% fall due to surgery); or nadir 10-19 x109/l <30% platelet fall; or nadir ≤10 x109/l
Timing of platelet count fall, thrombosis, or other sequelae (first day of heparin course=day 0) Onset between days 5 and10 or ≤1 day (if heparin exposure within past 30 days) Consistent with day 5-10 fall, but not clear (e.g. missing platelet counts or ≤ 1 day with heparin exposure within the past 31-100 days; or platelet count fall after day 10) Platelet count fall ≤ 4 days without recent heparin exposure
Thrombosis or other sequelae (e.g., skin lesions, ASR) New thrombosis, skin necrosis; acute systemic reaction after IV heparin bolus Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis (not yet proven); asymptomatic upper-limb DVT None
Other cause of thrombocytopenia No explanation (besides HIT) for platelet count fall is evident Possible other cause is evident Definite other cause is present

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Patients should only undergo testing if clinical features reasonably suggest a diagnosis of HIT. The “pathological” criterion is the detectability of “HIT antibodies” in acute patient serum or plasma. HIT is caused by heparin-dependent platelet-activating antibodies that, in almost all patients, recognize complexes of platelet factor 4 (PF4) bound to heparin. There are two types of assays: antigen assays measuring binding of antibodies against PF4/heparin complexes and functional assays measuring heparin dependent platelet activation by the patient serum.

Sensitivity of enzyme-immunoassays (EIAs) for anti-PF4/heparin antibodies is very high (~99%). A negative result of a HIT antibody test generally rules out HIT. However, the high sensitivity of the PF4/heparin EIAs causes the problem of detecting clinically-insignificant anti-PF4/heparin antibodies, which can be present coincidentally in patients with thrombocytopenia caused by non-HIT factors. This leads to “overdiagnosis” of HIT, which has become a serious clinical issue.

Diagnosis for HIT is optimized by combining the anti-PF4/heparin EIA with a functional (platelet activation) test. Platelet activation assays (especially using “washed” platelets, such as the serotonin-release assay (SRA) or the heparin-induced platelet activation (HIPA) test), are much more specific for HIT. Only about 50% of those who test EIA-positive also test positive in a washed platelet activation assay. Functional assays based on platelet-rich plasma or whole blood are less sensitive with potential for false-negative results. If the first-line test is an immunoassay, the functional assay could be restricted to patients testing positive in the EIA.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Patients should be tested for IgG class antibodies only, as only this isotype class activates platelets.

The strength of a positive EIA test result (expressed in optical density (OD) units) correlates strongly with the presence of platelet-activating antibodies and the risk of thrombosis. A weak-positive result (e.g., an OD <1.0 in the EIA together with a low 4T-score) is very unlikely in HIT.

Showing inhibition of antibody binding in the presence of high heparin concentrations (100 IU/mL) increases specificity of the EIA. (CAUTION: Strong platelet-activating antibodies may not be inhibited by high heparin.)

What Lab Results Are Absolutely Confirmatory?

There is no laboratory test absolutely confirmatory of HIT. The strength of HIT testing is exclusion of HIT. A negative EIA excludes HIT by 99%; a negative washed platelet functional assay excludes clinically relevant antibodies by more than 90%. The best approach, currently, is to combine the clinical score with the laboratory test result.

Additional Issues of Clinical Importance

After a negative antigen test, routine repeat testing a few days later is not indicated, unless a new platelet count decline or thrombosis occur. Such testing risks detecting clinically-irrelevant antibodies, which is especially relevant after major surgery and in intensive care unit (ICU) patients.

Over-diagnosis of HIT is potentially dangerous, because it may lead to withholding of certain diagnostic and therapeutic interventions not only during the acute event, but also at future admissions. Further, the diagnosis of HIT usually prompts treatment with alternative anticoagulants, which may increase bleeding risk.

Errors in Test Selection and Interpretation

HIT antibodies are transient. Testing a blood sample obtained several weeks after the clinical manifestation of HIT can cause false-negative results.

The most common mistake made in the interpretation of test results for HIT is interpretation of a positive antigen test as confirmation of HIT. These assays can only exclude HIT. Especially anti-PF4/heparin IgM and IgA antibodies do not confirm HIT. A positive antigen assay requires confirmation by a functional assay.