Heparin-Induced Thrombocytopenia Differential Diagnoses

Updated: Jul 19, 2023
  • Author: Sancar Eke, MD, FASN; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Diagnostic Considerations

Diagnosis of heparin-induced thrombocytopenia (HIT) can be challenging, and both underdiagnosis and overdiagnosis pose potential dangers. Failure to diagnose HIT increases the risk of thrombosis, amputation, or death, while misdiagnosis can result in major hemorrhage (in thrombocytopenic patients treated with alternative anticoagulants) or thrombosis (if heparin treatment is suspended unnecessarily). [41] Consequently, pretest scoring systems have been devised to guide diagnosis of HIT.

4Ts score

The 4Ts is a pretest clinical scoring system for HIT that is widely used in clinical practice. [41, 42]  The title refers to four characteristics of HIT:

  • Thrombocytopenia
  • Timing of thrombocytopenia relative to heparin exposure
  • Thrombosis or other sequelae of HIT
  • Likelihood of other (oTher) causes of thrombocytopenia

See the HIT 4T's score calculator, and the Table below. 

Table. 4Ts score [39, 43] (Open Table in a new window)



2 points

1 point

0 points


>50% fall


platelet nadir 20-100 × 109/L

30%-50% fall


platelet nadir 10-19× 109/L

< 30% fall


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 at heparin injection sites; anaphylactoid reaction after IV heparin bolus; adrenal hemorrhage

Progressive or recurrent thrombosis; erythematous skin lesions; thrombosis suspected but not proven


Other causes of thrombocytopenia

None apparent



Total scores and corresponding probability of HIT are as follows:

  • 0-3: Low probability
  • 4-5: Intermediate probability
  • 6-8: High probability

A systematic review and meta-analysis by Cuker and colleagues found that a low-probability 4Ts score was a robust means of excluding HIT, with a negative predictive value of 0.998 (95% confidence interval [CI], 0.970-1.000). These researchers proposed that in patients with a low-probability 4Ts score, it may be possible to exclude HIT without further laboratory testing and continue heparin. [41]

Cuker and colleagues reported that the positive predictive value of an intermediate 4Ts score was 0.14 (95% CI, 0.09-0.22) and that of a high-probability score was 0.64 (95% CI, 0.40-0.82). [41] In other studies, the 4Ts model has demonstrated a positive predictive value of 9%–17%. [44] Jevtic and colleagues recommend that patients with a 4Ts score greater than 3 should undergo prompt antibody screening and, if that is positive, a platelet activation assay. [5]

Overdiagnosis of HIT in surgical patients with critical illness has been reported. [45] A retrospective study in surgical intensive care unit patients by Berry and colleagues found that 8.6 % of patients with low-probability 4Ts scores were positive for HIT on laboratory testing, and 57% of patients with high-probability scores of 6-8 were HIT negative. These researchers concluded that testing or treatment for HIT should not depend on the 4Ts score alone. [46]

HIT expert probability score

The HIT expert probability score (HEP) is a more detailed system developed to improve on the diagnostic utility of the 4Ts score. Testing in a validation cohort showed that the HEP model was 100% sensitive and 60% specific for determining the presence of HIT, and demonstrated better correlation with serologic HIT testing and better interobserver agreement than the 4Ts score. Nevertheless, the researchers cautioned that prospective multicenter validation is warranted. [44]

Other problems to be considered

Other conditions that may be considered in the differential diagnosis of HIT include the following:

  • Septicemia with disseminated intravascular coagulation (DIC)
  • Liver disease with hypersplenism
  • Other medications
  • Immune thrombocytopenia (ITP)
  • Other thrombocytopenic disorders (eg, posttransfusion purpura)
  • Hemodilution (eg, following massive blood transfusions)

Medications known to cause thrombocytopenia include the following:

  • Platelet glycoprotein (gp) IIb/IIIa inhibitors (eg, abciximab,eptifibatide, tirofiban)
  • Quinine
  • Quinidine
  • Sulfonamides (sulfa drugs)
  • Sulfalike drugs
  • Chlorothiazide
  • Chloroquine
  • Rifampicin
  • Gold salts

Differential Diagnoses