Heparin Induced Thrombocytopenia (HIT)
Dr Andrew Walden MRCP, PhD
SpR in ICU medicine, John Radcliffe hospital, Oxford
Focus on definition of HIT
HIT is an
adverse drug reaction in which there is thrombocytopaenia in the
presence of heparin administration. Traditionally HIT has been divided
into 2 types:
- Type I - non-immune mediated
- Type II - immune mediated
Type I seldom leads to a significant drop in the platelet count below 100,000 l-1 , has a classically earlier onset and is not associated with thrombosis.
II is clinically more important as it is associated with thrombosis. It
tends to occur later after exposure to heparin (see Table 1).
are many causes for coagulopathy and thrombocytopenia in the intensive
care unit but type II HIT is an essential diagnosis to exclude as it
can result in life-threatening arterial and venous thromboses.
of cases of Type II HIT occur between 5-14 days post heparin exposure
and this is known as 'typical HIT'. However, type II HIT may occur as
rapid onset within hours (30%) or in a delayed form that manifests days
to weeks after heparin has been stopped (5%).
Focus on Pathogenesis of HIT
acts on the antithrombin III system of the coagulation pathway. In HIT,
heparin causes the release of Platelet Factor-4 (PF-4) from alpha
granules within the platelets. PF-4 neutralises the heparin effect and
the subsequent complex of PF-4 and heparin leads to the stimulation of
IgG antibodies. The antibody-PF-4-heparin complexes then bind to the Fc
receptors on the platelet cell surface leading to platelet activation
and aggregation. This effect, coupled with concomitant cytokine
release, results in thrombocytopaenia and thrombus formation (see
fig.1). Thrombosis is further augmented by stimulation of monocytes,
tissue factor production and activation of the extrinsic coagulation
pathway. This process can lead to unchecked arterial and venous
Focus on the Incidence of HIT
true incidence of HIT remains open to debate but is estimated at 1%
with low molecular weight heparins (LMWH) but may be as high as 5% with
unfractionated heparins (UFH). HIT has been described with every route
of heparin administration and with doses ranging from full
anticoagulation with intravenous heparin, to the use of heparin coated
Focus on the Diagnosis of HIT
of HIT requires a low threshold for suspecting it. The rule of the 4T’s
is a simple and effective method of identifying those patients with
suspected HIT (see table 2). Skin lesions can be full blown skin
necrosis at subcutaneous sites of heparin injection or smaller
erythematous patches or nodules. These areas are generally painful and
pruritic and should be considered a marker of HIT even in the presence
of a normal platelet count.
Other features include a systemic response to heparin injection and overt disseminated intravascular coagulopathy.
HIT is a clinicopathological syndrome, the interpretation of blood
tests must be performed with a clear pre-test probability as to the
likelihood of the syndrome. Two types of tests can be employed –
functional washed platelet assays and antigen assays. Antigen tests
tend to have a high sensitivity and therefore a negative test is useful
whereas the functional platelet assays are more specific but need a
higher level of expertise and are generally more time-consuming. It is
essential that treatment is not delayed awaiting tests results where
there is an intermediate to high suspicion of HIT.
Focus on the treatment of HIT
the clinical suspicion of HIT is intermediate to high, it is essential
to stop UFH or LMWH. There should be no delay in commencing
anticoagulation with alternative agents while awaiting confirmatory
tests as the risk of thrombosis remains as high as 50% even after
The commonest anticoagulant used in the UK is the recombinant form of the leech-derived anticoagulant hirudin – Lepirudin.
This can be monitored in a similar way to UFH with activated partial
thromboplastin time (APTT) initially checked every 6 hours and the dose
adjusted such that the APTT ratio is 2.5-3 times normal. Excretion is
renal so dose adjustments have to be made in cases of renal impairment.
Agatrobin is a arginine
derivative that is most commonly used in patients with HIT who are
undergoing percutaneous coronary intervention. Metabolism is mainly in
the liver and its effects on the INR make concomitant dosing of
warfarin difficult to assess.
Fondipareux and Bilavirudin are 2 drugs that are not licensed but can be used in HIT.
is the drug of choice for the long term treatment of HIT however its
use should be avoided in the acute phase as it can lead to significant
Key Learning points
- HIT is a serious and not uncommon complication of treatment with both unfractionated and low molecular weight heparins
- It is important to use the 4T’s to determine the pre-test probability of HIT before sending confirmatory tests
HIT is suspected, it is essential to withdraw heparin and commence
treatment with an alternative anticoagulant to prevent thrombotic
Heparin-Induced Thrombocytopaenia: Diagnosis and Management.
Circulation 2004; 110:454-458
Napolitano LM, Warkentin TE, Almahameed A, Nasraway SA.
Heparin-induced thrombocytopenia in the critical care setting: diagnosis and management.
Crit Care Med 2006 34: (12):2898-911
Greinacher A, Janssens U, Berg G et al.
Lepirudin (recombinant Hirudin) for parenteral anticoagulation in patients with Heparin-induced thrombocytopaenia.
Circulation 1999; 100:587-93