4Ts versus 3Ls: heparin induced thrombocytopenia probability scoring

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Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

The Pre-brief

  • Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction to heparin that places patients at increased risk for venous or arterial thrombosis.
    • HIT is generally suspected at the bedside when there is a characteristic 50% drop in platelet count following 5-10 days of heparin exposure, but other causes of thrombocytopenia must be considered.
  • Pre-test probability scoring for HIT is a key component in management and is described further below. 


HIT antibodies (IgG class) bind to multimolecular complexes of platelet factor 4 (PF4) and heparin on platelet surfaces, resulting in platelet activation when the IgG molecules interact with the platelet Fc receptors. Platelet-derived microparticles are generated, which enhance coagulation reactions. HIT antibodies can activate endothelium and monocytes, exacerbating the procoagulant response. Activation of platelets and increased production of thrombin could explain the high risk of arterial and venous thrombosis in HIT.

Risk factors for HIT

The incidence of HIT is 10 times higher in patients receiving unfractionated heparin (UFH) compared to low-molecular-weight heparin (LMWH): 1-5% versus 0.1-1%, respectively. Both prophylactic and therapeutic doses of UFH carry the same risk. Patients undergoing major surgery, especially cardiac surgery, have a higher risk (1-3%) of developing HIT than general intensive care patients (0.4%). HIT rarely occurs in obstetrical patients or those exposed to heparin flushes only (<0.1%).

Management of HIT

The 2018 American Society of Hematology recommends the following management algorithm for HIT. Notably, the 4T score is utilized to assess the pre-test probability for HIT which is a major determinant in whether further workup and treatment of HIT is pursued.

The 4Ts score is the most widely utilized HIT pretest probability scoring system. The degree and timing of thrombocytopenia, development of thrombosis, and potential for other causes of thrombocytopenia are incorporated into the numerical score which correlates to low, intermediate, and high probability risk categories of HIT. A meta-analysis demonstrated that low probability scores (≤3) have a good negative predictive value (NPV) 0.998 (95% CI, 0.970-1.000), but the positive predictive value (PPV) for high and intermediate scores are less useful at 0.64 (95% CI, 0.40-0.82) and 0.14 (95% CI, 0.15-0.31), respectively.

“LLL score” in cardiopulmonary bypass patients

There are challenges with applying the 4Ts Score to patients who underwent cardiopulmonary bypass (CPB) since CPB itself is associated with thrombocytopenia and critically ill patients may have other potential causes for thrombocytopenia. Lillo-Le Louët et al. described a model to estimate the probability of HIT in patients who underwent CPB. The authors found three independent risk factors for the development of HIT: biphasic platelet count (e.g. initial fall immediately after bypass, then a rise of at least 30% over the next 5 days followed by a second fall in platelet count), an interval of ≥5 days from CPB to the first day of suspected HIT, and a bypass duration of ≤118 minutes. Based on these findings, they developed the scoring system (LLL) below with a PPV of 62% and a NPV of 97%.

Although the American Society of Hematology recommends use of the 4Ts Score in the management of HIT, it may be reasonable to concurrently assess the Lillo-Le Louët score for patients who have undergone CPB to assist with treatment decisions.

Treatment of HIT

Historically, direct-thrombin inhibitors (e.g. argatroban, bivalirudin) have been the cornerstone of initial HIT treatment in critically ill patients with an eventual bridge to warfarin once platelet counts recover to >150,000. Since direct-thrombin inhibitors interfere with INR values, transitioning to warfarin is complex and almost always a logistical nightmare on the general medical floor. Fortunately, in the most updated HIT guidelines, direct oral anticoagulants (e.g. rivaroxaban, apixaban, etc.) have emerged as a preferred HIT treatment regimen for otherwise medically stable patients.


    • Patients who develop HIT are at an increased risk of developing venous or arterial thrombosis.
    • The 4Ts Score is the most widely used pre-test probability scoring tool.
      • Patients with suspected HIT who underwent CPB may benefit from an assessment with the Lillo-Le Louët score as it has a good NPV and takes into account CPB-associated thrombocytopenia.
  • Direct thrombin inhibitors are appropriate initial management for critically ill patients with HIT.
  • Long-term anticoagulation may be maintained with either direct oral anticoagulants or warfarin.


  • Warkentin TE. Heparin-induced thrombocytopenia: diagnosis and management. Circulation. 2004; 110(18):e454-8.
  • Lillo-Le Louet A, Boutouyrie P, Ahenc-Gelas M, et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thomb Hemost. 2004; 2: 1882-88.
  • Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018; 2(22):3360-3392.
  • Hogan M, Berger JS. Heparin-induced thrombocytopenia (HIT): Review of incidence, diagnosis, and management. Vascular Med. 2020; 25(2):160-73.


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