HIT

HIT

BCSH guideline recommendations

1.      Platelet count on day 1

2.      Platelet count on day 2 if received heparin in the last 100 days

3.      UFH platelet counts on alternate days from days 4-14

4.      LMW heparin platelet counts every 2-4 days from days 4-14

5.      Obstetric patients receiving prophylactic dose are at low risk and do not need platelet monitoring

6.      If platelet count falls by >50%, new thrombosis or skin allergy need a clinical assessment for HIT

7.      If high pretest probability heparin should be stopped and alternative anticoagulation commenced whilst laboratory tests performed

8.      Platelet activation assays have a higher sensitivity than platelet aggregation assays (but are technically demanding and should be restricted to labs with experience)

9.      Antigen assays for IgG should be measured.  Useful information is gained by reporting the optical density, inhibition by heparin and cut-off for a positive test (rather than simply +ve/-ve)

10.  Should be treated with lepirudin or danaparoid until the platelet count has recovered then switched to warfarin

11.  Platelets should be avoided for prophylaxis

12.  Lepirudin adjusted to a ratio of 1.5-2.5 reduces the risk of thrombosis / limb amputation / death (but can cause anaphylaxis esp if previously exposed)

13.  Danaparoid at high doses is equivalent to lepirudin (prophylactic dose is not recommended)

14.  Patients with previous HIT who are antibody negative (after 100 days) who require cardiac surgery should have UFH intraoperatively rather than anything else but should be anticoagulated with an alternative to UFH or LMWH postop.

15.  Patients requiring surgery should be delayed until the patient is antibody negative if possible

16.  Diagnosis should be documented clearly

Pathology

§   Development of IgG antibodies that recognise heparin – PF4 complexes

§   The antibodies recognise a heparin induced conformational change in PF4

§   The ability to induce the conformational change depends on the chain length and degree of sulphation of the glycosaminoglycan – explaining the differences in incidence of HIT associated with different heparins.

§   HIT-IgG/PF4/Heparin complexes form on the surface of platelets.  The IgG Fc regions bind and cross link the platelet FcyIIa receptors resulting in platelet activation and prothrombotic microparticles.

§   Also hypothesised that HIT antibody may lead to endothelial injury since PF4 can bind endothelial heparin sulphate.

§   Median time to disappearance of 50-80 days

Clinical features

§   Prevalence prophylactic sc UFH heparin 5% in orthopaedic patients cf 0.5% with LMW heparin

§   Lower in medical patients – 0.7% with UFH

§   Very low in medical and obstetric patients with LMW heparin – one case in 1,167 pregnancies in three studies

§   Bovine > porcine (UK, all heparins are pocine)

§   Platelet count typically falls 5-10 days after exposure but can be more rapid if the patient has had exposure in the previous 100 days.

§   Rare to develop HIT after 15 days

§   Median nadir 55 (rare for count to fall <15)

§   50% have associated thrombosis

§   10-20% develop skin lesions at injection site

6-8 High probability                 4-5 Intermediate probability              0-3 Low probability

Laboratory tests

Platelet activation assays

§   Platelet aggregometer can be used to detect aggregation of normal platelets in the presence of patient plasma and heparin

§   85% sensitivity (more specific than antigen assays)

§   Donor platelet responsiveness to HIT antibodies varies

§   HIT antibodies produce activation of platelets at 0.1 – 0.3 IU/mL that is no longer seen at 100 U/mL

§   Sensitivity can be increased using washed platelets but this is technically demanding.

Antigen assays

§   High sensitivity (80-100%) but low specificity

§   ELISA assays and rapid gel particle agglutination methods.

§   Some of the ELISA assays (GTI-PF4) can be repeated with high dose heparin (100 u/mL) and a 50% reduction in optical density is characteristic of HIT.

§   Strongly positive result indicates a much greater likelihood of HIT.

§   ELISA optical density results significantly correlate with the risk of thrombosis.

§   Also detect IgM and IgA antibodies which worsen the specificity.

Treatment

§   LMW heparin not an alternative (50%) cross reactivity in vivo

§   Fondaparinux (Xa inhibitor) may bind PF4 but its length is shorter than the 10 to 12 saccharides reported to be required for binding of HIT antibodies to PF4.  Thus expected to be non immunogenic and unable to causes HIT.

§   Warfarin should be delayed until the platelet count has normalised since is might increase the risk of microvascular thrombosis in HIT.

§   Platelet transfusions could theoretically contribute to thrombotic risk and are relatively contraindicated.

§   Major bleeding commonly complicates the treatment of HIT.

Lepirudin

§   Recombinant 65 amino-acid peptide

§   Direct irreversible thrombin inhibitor binding both free and clot bound thrombin

§   Half life of 60-90 minutes with renal excretion.

§   Best data from a meta-analysis of 3 studies HAT 1-3, comparing patients treated with lepirudin with historical controls 75 (danaparoid n=24, coumarins n=21, other treatments n=30).

§   HITT 113 patients treated with target APTT 1.5-2.5 – lower incidence of new thombosis (10% v 27) and non significant trends towards reduced mortality (9 v 18%) and limb amputation (7 v 10%).

§   HIT 91 patients compared to 47 historical controls who were not anticoagulated

§   Significant decrease in new thrombosis (4 v 15%) non significant reduction in mortality (14 v 20%) and limb amputation (3 v 0%).

§   Bleeding higher in lepirudin treated patients in HITT meta-analysis (42% v 24%) / major bleeding, requiring transfusion (18% v 7%).

§        Risk directly related to APTT, lepirudin levels and creatinine

§   Lepirudin foreign protein which can induce antibodies resulting in anaphylaxis (risk 0.015% on first exposure / 0.16% on re-exposure).  May also bind the protein preventing excretion and increasing the risk of bleeding.

§   Target APTT 1.5-2.5 should be compared to plasma concentration of approximately 0.6 to 1.4 mg/L

Other DTI = agartroban (used in US) – liver clearance so may be better in renal impairment, bivaluridin (under development)

Danaparoid

§   Heparinoid composed of heparin sulphate, dermatan sulphate and chondroitin sulphate

§   Inhibits Xa and to a much lesser extent thrombin

§   20% of cases exhibit cross reactivity to HIT antibodies in vitro but in vivo reactivity is rare although well described

§   Long half life 100% bioavailability

§   Xa levels can be used to monitor but not clear whether they provide any clinically useful information (expert opinion suggests are of value in severe renal failure and extremes of body weight).

§   Better safety profile cf. with lepirudin in bleeding risk, renal failure, anaphylaxis

Anticoagulation in patients with HIT

§   Reasonable to avoid UFH / LMW heparin

§   Haemodialysis – can use danaparoid and lepirudin

§   Cardiac surgery – probably best to use UFH as there is the greatest experience with this other protocols have been suggested (eg lepiruding / danaparoid) but limited experience and lack of antidote.  In addition they are unlikely to develop rapid onset HIT if they have not had recent heparin exposure.

§   High dose regime is equivalent to lepirudin

§   Prophylactic dose is not recommended

HIT should be clearly documented in the patient’s notes

Potential new treatment options

§   Oral Xa inhibitors and direct thrombin inhibitors

§        Rivaroxaban, apixaban, dabigatran

§        R-thrombomodulin

§        Sc, under development for DIC thrombosis

§        Defibrotide

§        Used to treat VOD

§        Suledoxide

§        Oral, under development for diabetic nephropathy