Heparin Induced Thrombotic Thrombocytopaenia Syndrome (HITTS or HIT)


HIT is a major issue in ICU because:

  • heparin (UFH) or LMWH is nearly universal in ICU patients
  • thrombocytopenia is common (up to 50%)
  • complications of HIT can be severe

Two types

  • HIT type I, a benign non-immune condition
  • HIT type II, an immune-mediated syndrome caused by an antibody to the PF4/heparin complex — what we mean when we say “HIT”

Incidence of HIT type II

  •  1-5% with UFH
  • < 1% with LMWH


Platelet Factor 4

  • PF4 is released on platelet activation -> binds anionic glycosaminoglycans on cell surfaces ->  inhibit the formation of megakaryocytes and angiogenesis + modulate immune response.
  • PF4 is released after trauma, inflammation, surgical trauma, and in cancer

HIT Type I

  • 10-30% of patients within 4 days after exposure to heparin
  • Heparin binds to PF4 ->  decreases cAMP ->  mild platelet aggregation and thrombocytopenia
  • platelet counts rarely decrease below 100,000/μl
  • mild and self-limiting


  • formation of a PF4/heparin complex -> triggers an immune response -> IgG binds  PF4/heparin complexes -> clustering of platelet Fc-receptors (FcχRIIa, FcχRIIIa) -> platelet activation -> arterial and venous thrombosis
  • HIT antibodies may bind to Fc receptors on monocytes -> tissue factor -> thrombosis
  • also endothelial damage -> increased von Willebrand factor and soluble thrombomodulin -> thrombosis

Not all patients who have heparin antibodies develop platelet activation and clinically relevant HIT

  • at most 5% to 30%, of patients who form HIT-IgG will develop clinical HIT



  • typically 5-10 days post heparin
  • consider other causes if later than 10 days (especially sepsis, also drugs + others)
  • rapid onset can occur if prior exposure to heparin (can mimic PE)
  • delayed onset can occur after heparin stopped


  • usually falls to values between 40,000 to 80,000/μl
  • <10% fall to <20,000

Complications can occur before, or without, thrombocytopaenia


Risk factors

  • amount of heparin exposure (therapeutic > prophylactic; UFH > LMWH)
  • amount of PF4 release: surgical and trauma patients > medical

Scoring system for likelihood pretest probability – 4Ts

  • Thrombocytopaenia severity
  • Timing of onset of platelet decrease (recent exposure increases risk)
  • Thrombosis (recent proven increases risk)
  • Thrombocytopaenia due to other reasons likely?


Antigen assays – e.g. ELISA

  • PF4/polyanion EIA
  • detects antibodies reactive against the PF4/Heparin complex (IgM, IgG and IgA)
  • IgG is the most sensitive for disease
  • high sensitivity (90-98%) and low specificity (65%) with positive result = 0.4 optical density untis
  • > 1.0 optical density units = more likely to be HIT (higher specificity ~83%)
  • increase in clinical condition thus delay until danaparoid or lepirudin is therapeutic and platelet count has recovered

Functional assays

  • Heparin-induced platelet activation (HIPA) and serotonin release assays
  • very high specificity
  • technically demanding (selected platelet donors, washed platelets, internal controls, radioactivity), high turn-around time, poor availability


  • venous thrombosis — DVT 50%, PE 25%, venous sinus thrombosis
  • arterial thrombosis — arterial, mesenteric, stroke, MI, acute leg ischemia, etc
  • skin necrosis at sites heparin is injected (usually ~8 days post-heparin starting)
  • acute systemic reactions after IV bolus (may look like anaphylaxis or PE)
  • decompensated DIC
  • death (10-30%)


  • stop heparin, including ‘heparin locks’ and coated catheters
  • avoid platelet transfusion
  • do not wait for laboratory confirmation if high degree of suspicion
  • if uncomplicated and low degree of suspicion await laboratory confirmation
  • alternatives to heparin: direct thrombin inhibitors (e.g. lepirudin, bivalirudin) and factor Xa inhibitors (e.g. danaparoid, fondaparinux)
  • a positive ELISA alone does not mean the patient has HIT
  • avoid warfarin in HIT until the platelet count has recovered (risk of thrombosis due to Protein C and S deficiency; risk of skin necrosis)

References and Links


Journal articles and textbooks

  • Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care. 2011;15(2):211. doi: 10.1186/cc9993. Epub 2011 Mar 22. Review. PubMed PMID: 21457505; PubMed Central PMCID: PMC3219407.

CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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