HIT or Miss: Is a Gel Immunoassay Better Than the 4Ts Score?

A fraction of patients taking the anticoagulant heparin will develop heparin-induced thrombocytopenia (HIT) – an adverse drug reaction caused by IgG platelet-activating antibodies that bind to platelet factor 4-heparin (PF4-H) complexes on platelets’ surfaces that can trigger devastating venous and arterial thromboembolic complications.

Rapidly determining whether or not a patient has HIT is critical in identifying patients who can continue to receive heparin or who need alternative anticoagulation therapies. The current standard for this determination is the 4Ts score, which scores patients’ likelihood of developing HIT based on four criteria: thrombocytopenia, timing of platelet count fall, thrombosis, and other potential causes of thrombocytopenia. The ASH Choosing Wisely campaign recommends not testing or treating for suspected HIT in patients who have a low 4Ts score, based on its high negative predictive value (99.8%).

According to a team of Canadian investigators, though, a low 4Ts score may be insufficient to exclude HIT; instead the researchers, led by lead investigator Lori-Ann Linkins, MD, of McMaster University in Hamilton, Ontario, have developed an alternative algorithm that rules out HIT with a “high level of confidence.”

The crux of their strategy is the addition of the PF4-H/PaGIA immunoassay to the 4Ts HIT testing protocol. The main benefit of the immunoassay is its speed, the researchers explained, adding that “it can be performed by most laboratories within an hour.”

When used by itself, the PF4-H/PaGIA immunoassay may over-diagnose HIT; combined with the 4Ts score, though, results from the assay might “allow patients who are in the lower-risk group to continue heparin without need for further testing, whereas other patients would receive protective non-heparin anticoagulant therapy while awaiting the result of further testing to confirm or rule out HIT,” the researchers wrote.

Dr. Linkins’ group conducted a prospective management study in 526 patients suspected of having HIT (mean age = 66.5 years) who presented at one of four hospitals from January 2008 to February 2013. All patients were evaluated for their 4Ts score, then underwent a PF4-H/PaGIA test and the standard test that evaluates for HIT, the serotonin-release assay (SRA).

While waiting for the SRA results to either confirm or rule out HIT, all participants, including those with a low 4Ts score (regardless of PF4/H-PaGIA result) or intermediate 4Ts score plus a negative PF4/H-PaGIA result, received alternative anticoagulant therapy: prophylactic danaparoid or fondaparinux (26.2%), danaparoid or fondaparinux therapeutic dose (13.5%), argatroban (1.9%), and “other” (i.e., warfarin, rivaroxaban; 2.7%). After SRA results were returned, patients with confirmed HIT continued to be treated with one of these alternative anticoagulant strategies, while those with negative SRA results were switched to heparin.

Thirty-two patients (6.1%) were confirmed HIT-positive (based on a positive SRA result). The frequency of SRA-confirmed HIT according to heparin exposure was 4.9 percent for those who received heparin, 6.3 percent in those who received low-molecular-weight heparin, and 12.6 percent in those who received both.

Among all subjects, HIT was confirmed in: 1.9 percent of patients with a low 4Ts score, 6.7 percent of patients with an intermediate score, and 36.6 percent of patients with a high score.

When Dr. Linkins and colleagues combined results from the two HIT determination methods, they found that the pretest probability for all 4Ts scores was reduced by a negative PF4/H-PaGIA result: from 1.9 to 0 percent (95% CI 0-1.3%) in the low group; from 6.7 to 0 percent (95% CI 0-2.7%) in the intermediate group; and from 36.6 to 0 percent (95% CI 0-14.3%) in the high group.

A positive PF4/H-PaGIA result, on the other hand, increased the pretest probability of HIT to 15.4 percent (95% CI 5.9-30.5%), 42.3 percent (95% CI 23-4-63.1%), and 88.2 percent (95% CI 63.6-98.5%) in each of the groups, respectively.

Based on these results, Dr. Linkins and colleagues developed a treatment algorithm to guide therapy according to 4Ts score and PF4/H-PaGIA result (TABLE).

The primary outcome of the study was the frequency of management failure, defined as SRA-based HIT-positive patients who had one of the following combinations of results: low 4Ts score and negative PF4/H-PaGIA result, low 4Ts score and positive PF4/H-PaGIA result, or intermediate 4Ts score and negative PF4/H-PaGIA result. Six patients (1.1%) were identified as management failures – all of whom had a low 4Ts score and a positive PF4/H-PaGIA result. Reasons for failure included incorrect 4Ts score and correct 4Ts score with mitigating features. The investigators pointed out that these complex clinical factors made it difficult even for the experts in the study to assign the correct 4Ts score.

Dr. Linkins told ASH Clinical News that these challenging patients would benefit most from the addition of a sensitive HIT assay to exclude HIT rather than relying on the 4Ts score alone, because these patients may have more than one cause of thrombocytopenia.

When asked could these study findings, and others like it, eventually lead to changes to the Choosing Wisely guidelines on HIT assessment, Dr. Linkins said it is too soon to tell. The Choosing Wisely recommendation works well if a patient has a straightforward history and presentation, she noted, while more complex patients would benefit from more sensitive testing, such as the gel immunoassay examined in the current study.

Ultimately, a low or intermediate 4Ts score plus negative PaGIA results excluded HIT, whereas any other combination of results justified use of alternative anticoagulants until HIT could be excluded, the authors concluded. However, they warned that the results from the more sensitive assay do need to be turned around in “real time,” and that could be a downside to this algorithm. In fact, one of the study’s limitations was that not all patients could have the assay done and returned in a timely fashion.

“The ideal turnaround time for a sensitive rapid laboratory assay that can exclude HIT would be less than 24 hours,” Dr. Linkins explained. “Many of the assays currently available on the market are capable of that, but [they] are batched and do not run on a daily basis due to cost. It must be emphasized that the purpose of a rapid assay is to exclude HIT and not to diagnose it.”


Linkins L-A, Bates SM, Lee AYY, et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood. 2015 April 29. [Epub ahead of print]

TABLE. Recommendations for Management of Patients with Suspected HIT

4Ts Score

PF4/H-PaGIA Result

Management Recommendations



HIT unlikely: continue heparin or LMWH if needed


HIT possible: discontinue heparin and consider alternative anticoagulant


HIT unlikely: continue heparin or LMWH if needed


HIT likely: discontinue heparin; strongly consider alternative anticoagulants


HIT likely: discontinue heparin; strongly consider alternative anticoagulants