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

PF4: EAEEDGDLQCLCVKTTSQVRPRHITSLEVIKAGPHCPTAQLIATLKNGRKICLDLQAPLYKKIIKKLLES
Site 1
Site 2
Front Side Top

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9
7
D -D Antigenic P Antigenic
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Site 2 P Ant igenic Site 1
Site 2
Figure 118–2. Platelet factor 4 (PF4) tetramer structure. At the top is the linear sequence of PF4. The regions that are known to contribute to
heparin-induced thrombocytopenia (HIT) antigenicity when PF4 is complexed to heparin are boxed. Below are three views of the PF4 tetramer with
the positively charged residues shown in both light and dark blue. Sites at which HIT neoepitopes are exposed on the PF4 tetramer are indicated.
(Adapted with permission from Li ZQ, Liu W, Park KS, et al: Defining a second epitope for heparin-induced thrombocytopenia antibodies using KKO, a murine
HIT-like monoclonal antibody. Blood 99(4):1230–1236, 2002.)
large complexes with PF4, explaining the negligible incidence of HIT wherein a pathogenic HIT-like antibody is infused into mice expressing
with this agent and supporting its potential utility in the prevention or both human PF4 and FcγRIIA, heparin infusion is not needed to cause
treatment of HIT. thrombocytopenia and a prothrombotic state. The explanation for a
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A passive immunization murine model of HIT has been used to lack of need to infuse heparin in this model is as follows: One important
demonstrate the following components are necessary to induce both potential role of heparin in the pathogenesis of HIT is to form solu-
thrombocytopenia and a prothrombotic state in HIT: the presence of ble, circulating PF4–heparin complexes that induce anti-PF4–heparin
human PF4 in platelets, FcγRIIA on the surface of platelets and pos- antibody production by presentation of the complex to splenic mar-
sibly other vascular cells, and the presence of a pathogenic HIT-like ginal B cells (see Figs. 118–1 and 118–3). Passive immunization with
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antibody. Heparin has a more complex relationship to the pathogen- HIT antibodies in these mice obviates the need for delivery of soluble
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esis of HIT (Fig. 118–3). In the passive immunization model of HIT, antigenic complexes to the spleen. Another role for infused heparin is
Possible outcomes

PF4-coated
platelets
Infused
Quiescent platelet heparin
No HIT
Low levels of No activation
surface PF4

High levels of
surface PF4 HIT
Activated platelet

Quiescent platelet Activated platelet Heparin
Surface GAG Circulating PF4
protein tetramers HIT IgG

Figure 118–3. The role(s) of heparin in heparin-induced thrombocytopenia (HIT). On the left is depicted a quiescent platelet surface with GAG-
expressing proteins as well as individual FcγRIIA receptors. Platelet factor 4 (PF4) is normally released by platelets in the steady-state, especially in
individuals with underlying inflammation and/or atherosclerosis. Additionally, individuals have a wide range of platelet PF4 content, and this, too,
contributes to having individuals with different levels of surface PF4 binding. Heparin infusions leads to HIT immunoglobulin G formation (see Fig.
118-1B), but also removes surface-bound PF4. If the individual has little initial surface-bound PF4, the surface of the platelets will be wiped clean of
bound PF4 by the infused heparin and not be targeted by the HIT antibodies (right, top) so that HIT antibodies circulate but HIT does not develop.
If there is significant residual surface-bound PF4 after heparin infusion, HIT antibodies will attach to the cell surface and activate the platelets (right,
bottom), potentially leading to HIT.

Kaushansky_chapter 118_p2025-2034.indd 2027 9/18/15 5:43 PM