Heparin-Induced Thrombocytopenia (BSH 2012)

 

Type II HIT Pathophysiology

 

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

Danaparoid is a heparinoid also produced from pigs but a different fraction.

 

Exposure to heparin may --> Heparin-platelet factor 4 antibodies.

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 --> different incidence of HIT depending on the preparation.

 

IgG-Heparin-PF4 complexes activate platelets and thrombin --> prothrombotic state.

 

Incidence

 

Bovine > Porcine heparin (all UK Heparin is porcine)

Surgical > medical patients

UFH > LMWH (5% vs 0.5% in orthopaedic prophylaxis)

Risk with prophylactic LMWH 0.2-0.9% depending on the study

 

Diagnosis

 

Typically:

- Plt count falls 5-10 days after starting heparin

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

- Plt count falls >50%, nadir count <55 (<15 is unusual)

- 50% have associated thrombosis

 

Assess the re-test probability with 4T score.

- If low risk, HIT excluded without need for further tests

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

4 T.jpeg

Monitoring

 

Monitor:

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

- Post-op patients, inc obstetric, receiving UFH should have plt count every 2-3 days from days 4-14 or until heparin stopped.

- Post-op cardiac bypass patients receiving LMWH should have plt count every 2-3 days from days 4-14 or until heparin stopped.

 

Do Not Monitor:

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

- Medical and obstetric patients receiving heparin

 

Clinical Manifestations of HIT

 

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

 

Other – skin lesions, venous gangrene, adrenal bleed, total global amnesia, rigors, acute collapse and death, warfarin-induced skin necrosis.

 

Screening tests – Antigen Assays (2 methods):

 

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 (HemosiL AcuStar) used at Addenbrookes.

-       Neg pred value >95%.

-       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

 

 

 

ELISA

-       Used at Bristol.

-       Similarly good neg pred value, weak positive pred value

 

Confirmatory tests:

 

HIPA - Heparin-induced platelet aggregation assay. Processed in Germany.

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

 

SRA - Serotonin-release assay is a commercial test. Requires a fresh platelet sample, radioactive serotonin and a healthy control patient.

 

Treatment

 

Licensed – argatroban & danaparoid

Unlincensed but used – fondaparinux & bivalirudin

 

Basic principle is stop heparin and start alternative anticoagulation

Initial anticoagulant dose should be the same whether or not there is already thrombosis at the time of diagnosis.

Warfarin should be introduced once plt count is in the normal range.

- It should be overlapped with original AC by 5 days using low-dose dosing.

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

 

Bleeding is rare in HIT.

- Platelet transfusion can be used safely if bleeding occurs, but should be used prophylactically.

 

Danaparoid

- Heparinoid that indirectly inhibits Xa and thrombin

- Predictable dose response and long half-life (24 hours)

- Monitor with a specific anti-Xa assay if wt >90kg or renal impairment

- Given as bolus dose followed by reducing dose infusion regimen.

 

Argatroban

- Direct thrombin inhibitor

- Metabolised by liver

- 2.0 ug/kg/min to achieve APTT ratio of 1.5-3.0 (start at 0.5ug/kg/min if unwell)

 

Fondaparinux

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

 

UFH and LMWH should be avoided in the future (but recurrence is rare)

Exception for cardiac surgery if >100 days since HIT and antibody test now neg.

 

N.B. Type I HIT

 

Occurs 2 days after starting heparin, results from direct effect of platelet activation by heparin. Will resolve rapidly and spontaneously whilst heparin continues to be given.