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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

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.

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.