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2026 Part XII: Hemostasis and Thrombosis Chapter 118: Heparin-induced Thrombocytopenia 2027

TABLE 118–1. Heparin-Induced Thrombocytopenia Risk exists as a tetramer. Crystal structure analysis shows that this tetramer
is encircled by a ring of positive charge (Fig. 118–2), and heparin
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Factors
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is thought to bind to this region. There are two closely spaced HIT
Patient-Specific Factors Heparin-Specific Factors antibody recognition domains (Fig. 118–2). These domains are dis-
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Patient population (surgical > Type of heparin (unfractionated tinct from the heparin-binding domain. About half of patients have
medical > obstetric > pediatric) heparin > low-molecular- antibodies that react with one or the other HIT antigenic domain
weight heparin) and one-third of patients do not have antibodies that react to either
Major trauma > minor trauma Duration of heparin (~5 days domain, suggesting that there are other HIT antigenic sites on PF4.
> shorter courses) Studies of antihuman PF4 monoclonal antibodies suggest that unlike
nonpathogenic anti-PF4 antibodies, HIT antibodies markedly increase
Sex (female > male)
their binding affinity for PF4 maintained in a tetrameric as opposed
to dimeric state. Moreover, tetrameric PF4 and UFH need to be at
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approximately 1:1 molar ratio for optimal HIT antigenicity. 30,31 At this
bacterial wall (Fig. 118–1) and that antibodies against this complex may ratio, ultralarge complexes (>670 kDa) of PF4 and heparin form that
be an important antimicrobial defensive mechanism. These antigenic appear as visible colloidal complexes, and these are likely to be the anti-
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complexes, as well as circulating PF4–heparin complexes, are detected genic source in HIT. 32,33 At higher or lower ratios, PF4 predominantly
by splenic marginal B cells that subsequently produce pathogenic HIT forms smaller and less antigenic PF4–heparin complexes. Ultralarge
antibodies. 25 complexes are inefficiently formed with LMWH, offering a potential
The nature of the antigenic heparin–PF4 complex has been par- explanation as to why this class of agents is associated with a lower
tially defined. At the concentrations reached at sites of injury, PF4 incidence of HIT compared with UFH. Fondaparinux does not form

Hypothesized initial Initial
exposure IgM response
Microbes
V H

V L

Atherosclerotic plaque
Targeted activation of
Endothelial cells Heparin vascular cells
PF4 tetramer

Macrophages
A
Heparin Surface protein
exposure with GAG
Postheparin IgG side chains bound
Heparin response to PF4
infusion

Heparin Activated platelet
Marginal PF4 tetramer
pre-B cells
Circulating
PF4
B
Figure 118–1. Proposed etiology of the immune response in heparin-induced thrombocytopenia (HIT). A. Proposed first exposure to HIT antigenic
complex either during microbial invasion or within growing atherosclerotic plaques, which are known to contain both platelet factor 4 (PF4) and
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immune-responsive cells. In both cases, soluble PF4 and negatively charged molecules must be presented to B cells and result in an initial immu-
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noglobulin M—perhaps low affinity—response. B. On exposure to heparin, especially unfractionated heparin, complexes form with free PF4 and
are presented to splenic marginal B cells, which subsequently produce pathogenic HIT antibodies that bind with high affinity to PF4 complexed
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to surface GAG complexes. The concentrated binding of HIT antibodies to surface PF4–GAG complexes may enhance FcγRIIA aggregation and
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subsequent platelet activation.

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