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Chapter 133 Heparin-Induced Thrombocytopenia 1975

Endothelial
cell Heparan B-lymphocyte
sulfate Heparin
Resting
platelet

GpIIb/IIIa
HIT
antibody
PF4
tetramer

Fc receptor

Endothelial cell activation Monocyte Microparticles Fibrinogen

Thrombin Activated platelet

Tissue
factor
Fig. 133.1 PATHOGENESIS OF HEPARIN-INDUCED THROMBOCYTOPENIA. Heparin produces
mild platelet activation, resulting in release of platelet factor 4 (PF4) from platelet α-granules and the formation
of immunogenic PF4/heparin complexes. B lymphocytes generate immunoglobulins G (IgGs) that recognize
the PF4/heparin complexes; the Fc “tails” of the IgG bind to platelet FcγIIa receptors, resulting in Fc receptor
clustering and consequent “strong” platelet activation. Platelet-derived microparticles are generated that
accelerate thrombin generation. The heparin-induced thrombocytopenia (HIT) antibodies also recognize PF4
bound to endothelial heparan sulfate, leading to immunoinjury that causes endothelial activation. Recent
evidence suggests that HIT antibodies also activate monocytes. The greatly increased thrombin generation
observed in HIT helps to explain its association with venous and arterial thrombosis, as well as some of its
unusual clinical features (e.g., warfarin-induced venous limb gangrene, decompensated disseminated intravas-
cular coagulation), and also provides a rationale for treatments that control thrombin generation (e.g., with
indirect [antithrombin-dependent] or with direct thrombin inhibitors). (Reprinted with permission from Grein-
acher A, Warkentin TE: Treatment of heparin-induced thrombocytopenia: An overview. In Warkentin TE, Greinacher A,
editors: Heparin-induced thrombocytopenia, ed 4, New York, 2007, Informa Healthcare USA, p 287.)

on Thrombocytopenia, Timing (of onset of thrombocytopenia or It is uncertain whether one scoring system offers advantages over
thrombosis), Thrombosis (or other clinical sequelae of HIT), and no the other. In general, low scores in either system indicate a low
oTher explanation for thrombocytopenia, with each of the 4Ts probability of HIT, whereas high scores indicate approximately a
scoring as an integer of 0, 1, or 2 points, based upon the likelihood 50 : 50 chance of HIT. Thus laboratory testing is crucial to establish
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of HIT (thus the maximum score is 8 points) (Table 133.2). The a diagnosis of HIT.
presence of platelet-activating HIT antibodies is unlikely (<3%) with
a low score (≤3 points), but relatively probable (approximately 65%)
with a high score (≥6). An intermediate score (4 or 5) indicates a LABORATORY DIAGNOSIS
clinical profile compatible with HIT, but also with other disorders,
such as sepsis; here the frequency of platelet-activating HIT antibod- Assays for HIT antibodies can be classified as platelet “activation” (or
ies is still only approximately 10% to 20%. “functional”) and PF4-polyanion “antigen” assays (or immunoassays).
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A newer scoring system is called the HIT Expert Probability Activation assays that measure serotonin release from C-labeled,
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(HEP) score (Table 133.3). In the initial evaluation, a HEP score washed platelets (i.e., the serotonin-release assay [SRA]) are quite
of 4 points or higher indicated an approximately 50% probability of sensitive and specific for detecting clinically significant HIT antibod-
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HIT, whereas a score of 3 points or lower was associated with only a ies. Important quality control maneuvers include the selection of
3% probability of HIT. platelet donors whose platelets respond well to Fc receptor