HITTS

Heparin Induced Thrombotic Thrombocytopaenia Syndrome (HITTS or HIT)

OVERVIEW

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

PATHOPHYSIOLOGY

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

HIT Type II

• 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

CLINICAL FEATURES

Onset

• 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

Thrombocytopaenia

• 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 AND SCORING SYSTEM

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?

INVESTIGATIONS

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

COMPLICATIONS

• 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%)

AN APPROACH

• 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

LITFL

• ICU Mind Map — Heparin-Induced Thrombocytopenia

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.