FRCA Notes

Heparin - Induced Thrombocytopaenia

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Heparin tends to cause two different thrombocytopaenic reactions:

Non-immune, type I thrombocytopaenia within 4 days of anticoagulant doses of heparin

Rarely of clinical significance
Platelet numbers recover without stopping the heparin

Severe, immune-mediated, type II thrombocytopaenia (HIT)

Type I reaction occurs in up to 10% of patients receiving heparin therapy

Type 2 HIT typically occurs 4 - 14 days after IV or SC heparin (either UH or LMWH)
Can occur up to 90 days following initial exposure to heparin if there is subsequent re-exposure

Incidence in patients being treated with:

Unfractionated heparin: 3 - 5%
LMWH: 0.1 - 1%
Fondaparinux: carries a lower incidence of HIT than UH/LMWH

Risk Factors

Cumulative dose >32,000 IU
Continuous infusions
CPB within 100 days
IV administration (rather than SC)
It is more common in:

Surgical patients (vs. medical patients)
Female patients (2x)
Patients who receive bovine-sourced heparin vs. porcine-sourced heparin

Platelet factor 4 is a chemokine released from the alpha granules of activated platelets
It binds endogenous heparan sulfate on endothelial cells, inhibiting anti-thrombin and performing a haemostatic role

In HIT, heparin complexes with the platelet factor 4
This complex is bound by IgG
Consequent widespread immune activation causes a consumptive coagulopathy
There is platelet aggregation and massive generation of diffuse clots, leading to thrombosis
Platelet activation also causes further platelet factor 4 release, causing a positive feedback loop

Thrombocytopaenia (95%) - platelet count typically falls by ≥50%
Venous thrombosis (50%) - mortality (mainly from PE) is high
Arterial thrombosis (20%) - can cause CVA and limb ischaemia
Skin necrosis/lesions (10 - 20%)

4T score

Clinical diagnosis is based on the 4T score

Variable	2 points	1 point	0 points
Acute thrombocytopaenia	Plt decrease by ≥50% AND nadir ≥20x10⁹/L	Plt decrease by 30-50% OR nadir 10-20x10⁹/L	Plt decrease by <30% OR nadir <10x10⁹/L
Timing of onset	Day 5-10 OR D1 if recent heparin exposure	Day >10 OR unclear exposure	≤Day 4 with no recent exposure
Thrombosis	New thrombosis or anaphylactoid reaction	Progressive or recurrent thrombosis	None
Other cause for thrombocytopaenia	None	Possible	Definite

A score <4 has a NPV of 97 - 99%
A score 4 - 5 indicates intermediate probability of HIT
A score 6 - 8 indicates high probability of HIT
A score >8 is associated with HIT 100% of the time

Laboratory tests

Functional platelet activation assay

Measures the ability of patient serum to activate test platelets in the presence of heparin
Gold standard, but lengthy and expensive

Detection of anti-platelet factor 4 antibodies

Antibodies present in many individuals; only up to 15% of those with antibodies go on to develop Type 2 HIT

Cessation of heparin and/or LMWH
Consider platelet tranfusion, especially if invasive procedure is required
Consider plasmapheresis or IVIg
Use an alternative agent for thromboprophylaxis

Antiplatelet agents

Tirofiban
Iloprost
Cangrelor

Hirudin derivaties

Lepirudin and bivalirudin are hirudin derivatives made as a recombinant protein in yeast
Are direct thrombin inhibitors whose main use is in HIT
Are administered as infusions owing to their short half-life
Monitored with APTTr, ACT or ECT
Cleared by enzymatic proteolysis (80%) or renal excretion (20%)
Lepirudin is no longer available in the UK due to manufacturing cessation (as opposed to safety concerns)

Danaparoid

A heparinoid factor Xa inhibitor
Long half-life so caution in renal failure
There is some HIT cross-reactivity
Monitored using anti-Xa levels

Argatroban

A non-peptide arginine derivative
A direct thrombin inhibitor
No cross-reactivity
Administered as an infusion starting at 2μg/kg/minute
Monitored using ECT
Hepatic metabolism so safe(r) in renal failure than the other agents, which all rely on a degree of renal excretion