Heparin-induced thrombocytopenia (HIT)

David Goldemund M.D.
Updated on 07/11/2023, published on 19/01/2022


  • heparin-induced thrombocytopenia (HIT) represents one of the most serious complications of heparin therapy. Patients are at significantly increased risk of thromboembolism (30-50% of cases)
    • the incidence of HIT among these patients ranges from <0.1% to 7%, depending on the type of heparin (UFH > LMWH), duration of drug exposure, and patient population (e.g., surgical vs. medical)
  • type I and II are distinguished (see table)
    • type I HIT – a non-immune mediated, probably caused by a direct effect of heparin on platelet activation; does not pose an increased risk to patients
    • type II HIT – an immune-mediated complication of heparin therapy
      • heparin interacts with platelets to release platelet factor 4 (PF4). A heparin/PF4 complex on the platelet surface may induce the production of specific antibodies (most often IgG, less commonly IgM and IgA). These antibodies activate platelets, leading to thrombocytopenia and a prothrombotic state.
      • rapid antibody production to PF4 occurs after heparin administration in previously sensitized patients
  • patients with HIT develop thrombotic complications (HITTSHIT with the Thrombotic Syndrome) – the so-called “white thrombus syndrome,” which is probably caused by in vivo platelet activation
    • the majority of thrombotic events occur in the venous system (DVT, PE), with a smaller proportion affecting the arteries (MI, stroke/TIA)
Type II HIT – usually develops within 4-14 days; cases within 12 h after administration were reported

  • serious complications occurring in approx. 0.5-5% of patients treated with heparin
  • platelet count usually drops to  < 100 000/μL due to antibody reaction to heparin-PF4 complex
    • antibodies persist in the blood for approx. 50-80 days
  • high risk of thromboembolic complications!
Type I HIT – usually transient, occurs within 1-5 days after the initiation of heparin therapy
  • affects up to 30% of patients; the exact mechanism is unknown but likely involves a direct effect of heparin on platelet activation
  • platelet count usually drops by 10-30%, rarely below 150 000/μL
  • clinically insignificant, discontinuation of heparin therapy is generally not required
  • DDx can be challenging

HIT prevention and screening

  • keep heparin therapy as short as possible
  • monitoring is not required if heparin is administered for < 4 days or in patients considered to have a low risk of HIT (<0.1%) (ASH guidelines 201)
    • low-risk patients:   medical and obstetric patients receiving LMWH, patients receiving LMWH after minor surgery or minor trauma, and any patients receiving fondaparinux
  • otherwise, monitor platelet counts every 2-3 days if heparin administration lasts ≥ 4 days (until day 14 or until heparin is discontinued)

    • in high-risk patients (surgical and trauma patients receiving UFH), the ASH guideline panel suggests monitoring the platelet count at least every other day
  • for patients who have received UFH/LMWH within the past 30 days, check the platelet count before UFH/LMWH administration and repeat 24 hours later
  • in general, the risk is significantly lower with the use of LMWHs   [Walenga, 2004]

Clinical presentation

  • thrombocytopenia, or a 30-50% decrease in platelet count from baseline values
    • commonly occurs between days 5-12 following initiation of heparin therapy; rarely, it may manifest several hours after the heparin administration
  • hypercoagulable state
    • DVT, PE
    • cardioembolism, peripheral vascular occlusion
    • MI, stroke

Consider HIT in cases of unexplained thromboembolic events after heparin exposure. The platelet count must not drop below 100.000; a decrease of >50% from baseline is sufficient to diagnose HIT!

Diagnostic evaluation

Content available only for logged-in subscribers (registration will be available soon)


  • immediately discontinue heparin (LMHW, UFH, including flushes from IV lines !)
  • do not administer warfarin until the platelet count is normalized (≥ 150 x 109/l)!
  • consult a hematologist
  • avoid administration of platelet concentrates!
    • consider only in acute bleeding or high-risk patients (e.g., after recent surgery) (ASH Guidelines 2018)
  • start non-heparin anticoagulants at a therapeutic dose; continue until platelet counts normalize  (ASH guidelines 2018)
    • argatroban or bivalirudin are preferred for severe conditions thanks to their short half-lives
    • fondaparinux or DOACs are preferred in stable patients
    • use parenteral medication for pulmonary embolism
  • consider IVIG in severe refractory cases
  • routine placement of an IVC (inferior vena cava) filter is not recommended Inferior vena cava filter  (ASH Guidelines 2018)
Indirect anti-Xa inhibitors


  • the first-choice drug
  • rarely, a cross-reactivity with antibodies occurs   [Tardy-Poncet, 2009]
    • absence of any increase in platelet count after 3-5 days of danaparoid therapy and/or the occurrence of a new thrombotic event should lead to danaparoid cross-reactivity suspicion

FONDAPARINUX (Arixtra)  → see here

  • off-label use
  • the dose is higher than that used in prophylactic therapy (see table below)
  • fondaparinux anti-Xa assay can be used to monitor fondaparinux therapy
  • it measures the inhibitory effect of the fondaparinux-AT complex on FXa
    • an optical method based on the principle of chromogenic substrates without the addition of exogenous antithrombin
    • the analysis depends on the amount of AT in the plasma
  • sampling should be drawn 3-4 hours after drug administration when the highest anti-Xa activity is reached (peak steady-state plasma concentration)
    • prophylactic dose 2.5 mg SC once daily … 0.39 – 0.50 mg/L (μg/mL)
    • therapeutic dose 7.5 mg SC once daily  …  1.2 – 1.26 mg/L (μg/mL)
Direct anti-Xa inhibitors

ARGATROBAN (Argatroban, Acova)

BIVALIRUDIN (Angiox, Angiomax)

DOACs (Direct Oral AntiCogulants)
  • administer warfarin only after the platelet count normalizes
  • prefer DOACs
Epoprostenol (FLOLAN)
  • epoprostenol is a prostaglandin; it reduces the tendency of platelets to clot and also helps to dilate blood vessels ⇒ ↓BP
  • prevents platelet activation induced by HIT antibodies  [Yamamoto, 2006]
  • if UFH needs to be administered during, e.g., cardiac surgery, then:
    • initial dose 5 ng/kg/min, increase by 5 ng/kg/min over 20-30 min, target dose 30 ng/kg/min
    • after reaching the target dose, heparin can be administered at the standard dose
    • at the end of the procedure, administer the calculated dose of protamine
    • then reduce the dose of epoprostenol (gradually 5 ng/kg/min, discontinue within 20-30 minutes
argatroban  IV
normal organ function → initial dose 2 μg/kg/min IV infusion over 3 hours
hepatopathy (bilirubin > 1.5 mg/dL) → 0.5-1.2 μg/kg/min
heart failure, anasarca, cardiac surgery → 0.5-1.2 μg/kg/min
Frequent monitoring of aPTT is recommended, aiming for 1.5-3 times the baseline value
danaparoid IV bolus (Magnani, 2012)
<60 kg, 1500 IU as IV bolus

60-75 kg, 2250 IU
75-90 kg, 3000 IU
>90 kg, 3750 IU
followed by an IV infusion of 400IU/h for 4 h and then 200 IU/h (in renal insufficiency 150 IU/h) for 4-7 days or until platelet count recovery
danaparoid-specific anti-Xa activity 0.5-0.8 IU/mL
bivalirudin IV normal organ function → 0.15 mg/kg/h  (ClCR > 60mL/min)
hepatopathy / renal dysfunction – consider dose reduction  (0.08-0.1 mg/kg/h in patients with ClCr 30-60 ml/min, and 0.03-0.05 mg/kg/h with ClCr <30 ml/min)  (Kiser, 2008)
check aPTT; aim for 1.5-3 times the baseline value
SC <50 kg → 5 mg once daily
50-100 kg → 7.5 mg once daily
>100 kg → 10 mg once daily
PO isolated HIT: 5 mg  twice daily
HITT: 10 mg twice daily for 7 days, then 5 mg twice daily
PO isolated HIT: 15 mg twice daily till platelet count normalizes
HITT: 15 mg twice daily for 21 days, then 20 mg once daily
PO HIT: 150 mg twice daily till platelet count normalizes (dose adjustments based on renal function)
HITT: 150 mg twice daily after  > 5 days of non-heparin parenteral anticoagulation

You cannot copy content of this page