Heparin-Induced Thrombocytopenia (HIT) (BSH 2024)

 See bottom of page for a notes on Type I HIT and Other HIT Disorders

Type II HIT Pathophysiology

 

Heparin is a bioproduct produced from pig intestines --> why so many problems with antibody formation.

Exposure to heparin may --> Heparin binding to Platelet Factor 4 (PF4)

Heparin-PF4 may then act as an immunogen —> prompting primarily IgG antibodies

Heparin-PF4-IgG complexes then bind to platelets + monocytes (via FcyRIIa receptors) —> causing:

  • Platelet activation, aggregation and consumption

  • Further PF4 release

  • Tissue factor expression on monocytes

  • Activation of endothelial cells

This combines to create a highly pro-coagulant state with thrombocytopenia and a high risk of thrombosis.

Additional notes:

The antibody primarily recognises a heparin-induced conformational change in platelet factor 4. The type of change is affected by the length of the heparin molecule and degree of sulphation --> different incidence of HIT depending on the preparation.

Thrombocytopenia is multi-factorial: aggregation, consumption, removal of immune complexed platelets by reticuloendothelial system

 

Incidence

 

Presence of Heparin-PF4 antibodies alone is much more common than HIT syndrome

Ranges from 0.1-7% of patients, depending on:

  • Type of heparin:

    • Bovine > Porcine heparin (all UK Heparin is porcine)

    • UFH > LMWH (2.6% vs 0.2% in orthopaedic prophylaxis)

  • Patient population:

    • Surgical > medical patients

      • 1% in cardiac surgery

      • 6% in ECMO patients

    • Treatment vs prophylactic dose (0.7% vs <0.2%)

    • Exceptionally low risk in obstetrics

 

Diagnosis

 

Assessing for HIT:

  • Timing:

    • Plt count falls 5-10 days after starting heparin

    • (more rapid if received heparin on a previous occasion in last 3 months)

  • Severity of thrombocytopenia

    • Plt count falls >30-50% from baseline

    • Nadir count usually <55, but <15 is unusual

  • Thrombosis

    • 25-50% develop associated thrombosis

    • Common – DVT, PE, Arterial thrombosis (ACS, stroke, peripheral artery thrombosis)

    • Other – skin lesions, venous gangrene, adrenal bleed, total global amnesia

  • Alternative explanations

    • Consider the many other, more common causes of thrombocytopenia

 

Assess the pre-test probability with 4T score:

  • If low risk, HIT excluded without need for further tests (exception: very high risk ITU patients, eg ECMO)

  • If non-low risk, switch to alternative anticoagulant whilst tests performed

4 T.jpeg

Monitoring

 

Case for monitoring: Severity of HIT (up to 50% risk of thrombosis at 30 days). Cheap and simple.

Case against monitoring: Risk of false positives leading to inappropriate anticoagulation

Recommended to Monitor:

  • All patients due to have heparin should have a baseline platelet count

  • UFH infusions: Minimum of alternate day FBC for days 4-14 or until heparin stopped.

  • Post-op cardiac bypass patients receiving LMWH: Minimum of alternate day FBC for days 4-14 or until heparin stopped.

  • Any post-op patient who has received heparins in the preceding 100 days: Check FBC 24 hours after starting heparin

 

Do Not Monitor:

  • Post-op patients other than cardiac bypass who receive LMWH

  • Medical and obstetric patients receiving LMWH

 

Screening tests – Antigen Assays

 

Screening test looks for H-PF4 antibodies. 15% of patients exposed to heparin will produce H-PF4 antibodies but only a small fraction will lead to clinically significant HIT. i.e. negative test more useful than positive.

 

Chemiluminescent assay (e.g. HemosiL AcuStar)

  • Currently the preferred screening method

  • Approx. 35 min turnaround time.

  • Excellent sensitivity. Neg pred value >95%.

  • Specificity superior to ELISA. Pos pred value 70%

  • Start with magnetic particles coated with PF4 complexed with polyvinyl

  • Source of Anti-PF4/Heparin antibodies (Control, Patient) is added

  • After incubation, the sample is washed and a tracer AHG antibody added

  • After 2nd incubation, a trigger for luminescent reaction is added

  • Luminescnce is instantaneous, producing a flash of light, detected by analyser.

hit 2.png

Lateral Flow Immunoassay (LFIA)

  • Qualitative results. Rapid result. Requires fresh samples.

  • Detects Heparin-PF4 complexes bound to gold nanoparticles as they move along a membrane

  • IgG complexes are immobilised onto the membrane to generate a visible line

Latex Immunoassay (LIA IgGAM)

  • Quantitative (weak/moderate/strong) results

  • Performed on ACL TOP analysers (widely available)

  • Patient’s (potential) Heparin-PF4 antibodies compete with latex beads coated in HIT-like antibodies

Enzyme Linked Immunoabsorbent Assays (ELISA)

  • Multiple methods available. Approx. 2-4 hour turn-around.

  • Excellent sensitivity - negative test essentially rules out HIT

  • Specificity improved by use of IgG-specific assays (IgM and IgA thought unlikely to be pathogenic)

  • The stronger the optical density (OD), the higher the likelihood of a positive functional assay

 

Confirmatory tests - Functional assays

 

Heparin induced platelet activation (HIPA)

  • Heparin-induced platelet aggregation assay.

  • Requires donors with known antibodies to contribute blood sample

  • A washed platelet assay that tests platelet aggregation in different concentrations of heparin

Light transmission aggregometry (LTA)

  • Standard LTA detects increased light transmission platelets aggregate in presence of heparin

  • Can also be performed using ATP release to measure platelet activation

Serotonin Release Assay (SRA)

  • Considered gold standard functional assay but not available in UK

  • Requires a fresh platelet sample, radioactive serotonin and a healthy control patient.

Flow Cytometry

  • Can be used to detect surface expression of antigens that are presented following platelet activation

 

Treatment

Principles

  • Switch to an alternative non-heparin anticoagulant as soon as the diagnosis is suspected and the pre-test probability of HIT is high

  • HIT without thrombosis: Rx-dose anticoagulation for 4 weeks or until plt >150, whichever is longer

  • HIT with thrombosis: Rx-dose anticoagulation for three months

  • Provide patient alert card

  • Avoid all future heparin exposure, including heparin flushes, unless essential

Choice of alternative anticoagulant (parenteral)

  • Subcutaneous administration: Fondaparinux or Danaparoid

  • Fondaparinux: 5, 7.5 and 10mg based on weight of <50, 50-100 or >100kg

  • Direct thrombin inhibitors, continuous infusion: Argatroban (liver clearance) or Bivalirudin (renal clearance)

Choice of alternative anticoagulant (oral)

  • Warfarin:

    • Can be used once clinically stable

    • Only introduce after plt count normalised and with 5 days overlap with parental anticoagulant

    • Argatroban affects the INR and this should be >4 for 2 days before stopping

  • DOACs

    • Can be used once clinically stable

    • Evidence based on observational studies

    • Do not use if there has been arterial thrombosis

IVIg +/- Plasma exchange?

  • Consider in severe case where alternative anticoagulation cannot be delivered

Management of bleeding

  • Bleeding is rare in HIT.

  • Platelet transfusion can be used safely if bleeding occurs, but should not be used prophylactically.

 

Essential re-exposure to heparin

  • E.g. cardiac bypass surgery

  • Ideally wait until >3 months since HIT as antibodies highly likely to have cleared by then

  • Test for persistent antibodies with a functional assay prior to procedure

  • If still present, use a non-heparin anticoagulant or consider IVIg/PLEX if heparin truly unavoidable

  • If antibody negative, proceed with intra-op UFH but use non-heparin alternatives pre- and post-op

N.B. Type I HIT

More common than Type II, affects 10-30% of patients on heparin

Non-immune response to heparin treatment, also called “heparin associated thrombocytopenia”

Occurs 2-3 days after starting heparin, results from direct interaction between platelets and heparin, leading to platelet clumping/sequestration.

Benign, mild thrombocytopenia and not associated with thrombosis

Self-resolves rapidly and spontaneously and heparin can continue to be given.

other hit disorders

Classical HIT is triggered by heparin but other related disorders of anti-PF4 antibodies can occur

Still involve PF4 antibodies, but the antigen site on the PF4 is different to that of classical HIT.

  • Autoimmune HIT (aHIT): Severe subtype of HIT with both heparin-dependent and heparin-independent platelet-activating antibodies.

  • Spontaneous HIT: Caused by non-heparin tiggers, e.g. knee replacement surgery, infection. Investigate with a platelet-activation assay.

  • Vaccine-Induced Thrombocytopenia and Thrombosis (VITT): Caused by exposure to adenovirus-based COVID-19 vaccines. A similar syndrome can also occur following adenovirus infections.