Heparin-induced thrombocytopenia (HIT)

Definition

Heparin-induced thrombocytopenia (HIT) is an immune-mediated, drug-induced thrombocytopenia that, paradoxically, is associated not with bleeding but with a high risk of venous and arterial thrombosis. The term today always refers to what was formerly called HIT type II.

It is distinguished from the former HIT type I: a non-immunological, mild and self-limiting fall in platelets during the first days without bleeding or thrombotic risk, which is no longer regarded as a disease.

Classification

Forms by timing

• Typical onset: antibodies form after about 4 days; platelet fall and/or thrombosis typically between day 5 and 10 (up to about day 14) after the start of exposure
• Rapid onset: fall within 24 hours if antibodies are already present from an exposure within the previous 100 days
• Delayed onset: thrombocytopenia and thrombosis only days to weeks after exposure has ended
• Autoimmune or spontaneous form: HIT picture without prior exposure, mainly after orthopedic surgery; other polyanions (e.g. chondroitin sulphate, polyphosphates, nucleic acids, bacterial components) act as triggers

Occurrence & epidemiology

HIT occurs in about 1–2 % of people exposed to the unfractionated form (up to 2.4 % in studies); it is much rarer with the low-molecular-weight form, which is about ten times less immunogenic. Even very small amounts, such as those used to flush catheters, can be sufficient. Women have about twice the risk of men; HIT is rare under the age of 40. The risk is high after orthopedic surgery with high PF4 release.

Aetiopathogenesis

Platelet factor 4 (PF4) released from platelets binds to the negatively charged polysaccharide and changes its conformation, creating a new epitope. The body forms IgG antibodies against it. The immune complexes of PF4, polysaccharide and IgG bind to platelets and monocytes via Fcγ-IIA receptors and activate them. The consequences are platelet aggregation, release of procoagulant microparticles, tissue factor expression and massive thrombin generation.

Platelets are consumed in the process – hence the thrombocytopenia – while thromboses form at the same time. Thrombocytopenia without thrombosis (“isolated HIT”) carries a risk of up to 50 % of later thrombosis.

Clinical features

• Platelet fall of more than 50 % of the baseline value in about 95 % of patients; the nadir is usually between 20 and 150 G/l (mean about 55 G/l), so rarely in the range of bleeding risk
• Bleeding is rare
• Venous thrombosis: deep vein thrombosis, pulmonary embolism, also at unusual sites
• Arterial thrombosis: limb artery occlusion with threatened amputation, stroke, myocardial infarction
• Skin necrosis and erythematous skin lesions
• Acute systemic reaction shortly after a bolus exposure

Diagnosis

4Ts score (pretest probability)

0–2 points per criterion, maximum 8:

• Thrombocytopenia: fall above 50 % and nadir of 20 G/l or more = 2; fall of 30–50 % or nadir 10–19 G/l = 1; fall below 30 % or nadir below 10 G/l = 0
• Timing: fall on day 5–10 or within 1 day with exposure in the last 30 days = 2; consistent with day 5–10 but unclear, onset after day 10 or within 1 day with exposure 31–100 days ago = 1; fall before day 4 without recent exposure = 0
• Thrombosis or sequelae: proven new thrombosis, skin necrosis or acute systemic reaction after a bolus = 2; progressive or recurrent thrombosis, non-necrotic skin lesion or suspected thrombosis = 1; none = 0
• Other causes of thrombocytopenia: none apparent = 2; possible = 1; definite = 0

0–3 points: low, 4–5 points: intermediate, 6–8 points: high probability.

Laboratory tests

• Platelet count course: relative to the baseline before the start of exposure; exclusion of pseudothrombocytopenia
• Immunoassay for anti-PF4/polyanion antibodies (e.g. ELISA, chemiluminescence or particle gel assay) as the first laboratory test with intermediate or high pretest probability: high sensitivity, so a negative result largely excludes HIT; lower specificity, IgG-specific assays are more specific
• Functional platelet activation assay as the gold standard for confirmation after a positive immunoassay: heparin-induced platelet aggregation test (HIPA) or serotonin release assay (SRA) with washed donor platelets; laborious and available only in specialised laboratories
• Compression ultrasound of the leg veins or other imaging to look for thrombosis

Keep learning in the app

Further reading (open access)

1. Glob Cardiol Sci Pract 2018 (PMC6062760): Heparin-induced thrombocytopenia (HIT) – identification
2. J Clin Med 2021 (PMC7916628): Heparin-Induced Thrombocytopenia – New Concepts in Pathogenesis and Diagnosis
3. MSD Manual Professional: Thrombocytopenia – Other Causes
4. Onkopedia-Leitlinie (DGHO): Thrombozytopenien

Cross-references