Implications

The identification of mutations of human PF4 that lead to loss of HIT antibody binding does not necessarily localize the epitopes at which antibodies attach because the actual binding site(s) could be elsewhere in the PF4 tetramer. Moreover, HIT antibodies appear to recognize multiple sites on PF4-heparin (Suh et al., 1998). Because the PF4 molecule is a nearly symmetrical tetramer (Ibel et al., 1986), the HIT epitope could be expressed four times on each PF4-heparin heterodimer, creating the potential for even a single antibody clone to react with four sites on a PF4 tetramer complexed with heparin. Studies from our group (Visentin et al., 1994, 1996) and others (Amiral et al., 1995; Arepally et al., 1995) have shown that although antibodies reactive with PF4-heparin complexes are nearly always present in patients with HIT, not all patients who form such antibodies experience thrombosis or even thrombocytopenia. Factors that could predispose antibody-formers to develop the HIT syndrome include the formation of unusually potent (high-titer) antibodies (Suh et al., 1997) and the presence of underlying conditions, congenital or acquired, that predispose one to thrombosis. It can be speculated that antibodies recognizing certain sites on PF4-heparin form ICs that are particularly effective in activating platelets. The same antibodies might be more likely to promote vessel injury when they bind to PF4 complexed with GAGs on ECs. Alternatively, patients who make antibodies that recognize multiple sites on PF4-heparin may be more likely to produce pathogenic ICs, leading to more severe symptomatology.

The recent finding that human PF4 reverts the anergic Tr cell phenotype and impairs their suppressive activity (Liu et al., 2005) suggests a previously unrecognized role of PF4 in the regulation of immune responsiveness.

On the basis of findings made by our group and many others, we propose the following model for HIT and associated thrombosis in patients mounting an immune response to PF4-heparin (Fig. 6): (1) Injected heparin recruits PF4 from EC GAGs and releases PF4 directly from circulating platelets (Zucker, 1975); (2) APCs, including B cells, process PF4-heparin, which binds to PF4 with high avidity, may alter the processing of PF4 in such a way that one or more peptides not ordinarily seen by the immune system ("neoantigens") are generated; thus "conventional" and "cryptic" PF4-derived peptides could be presented to T cells in the context of Class II HLA; (3) Released PF4 induces loss of suppressive activity of Tr cells (Liu et al., 2005), allowing PF4-specific T-cell clones engaged on APCs to expand, thus activating CD4+ effector T cells and B cells; (4) Activated B cells secrete antibodies reactive with PF4-heparin complexes formed on the platelet surface (Newman and Chong, 2000; Rauova et al., 2006) to produce ICs that engage platelet Fc receptors (Amiral et al., 1992; Visentin et al., 1994; Greinacher et al., 1994); Engagement of the Fc receptor by ICs leads to platelet activation (Visentin et al., 1994; Greinacher et al., 1994; Kelton et al., 1994) and initiation of a vicious cycle of platelet-derived procoagulant microparticle formation, PF4 release, platelet-derived CD154 (CD40 ligand) exposure/release (Henn et al., 1998), and formation of additional PF4-heparin complexes, triggering even more platelet activation and thrombocytopenia (Warkentin et al., 1994; Visentin, 1999); (6) Soluble CD40 ligand (sCD154) released from activated platelets induces tissue factor (TF)

^ CD40 p CD154 I Fc receptor £ TF '.•'. platelet microparticles

FIGURE 6 (See color insert) Proposed model of pathogenesis in HIT and thrombosis. PF4 is postulated to be both the target for the antibody (when complexed with heparin) and a modulator of T-cell responsiveness (see text for additional details). Abbreviations: APC, antigen-presenting cell; GAG, glycosaminoglycan; HIT, heparin-induced thrombocytopenia; MHC, major histocompatibility complex; PF4, platelet factor 4; TCR, T-cell receptor; Tr, T regulatory; TF, tissue factor.

^ CD40 p CD154 I Fc receptor £ TF '.•'. platelet microparticles

FIGURE 6 (See color insert) Proposed model of pathogenesis in HIT and thrombosis. PF4 is postulated to be both the target for the antibody (when complexed with heparin) and a modulator of T-cell responsiveness (see text for additional details). Abbreviations: APC, antigen-presenting cell; GAG, glycosaminoglycan; HIT, heparin-induced thrombocytopenia; MHC, major histocompatibility complex; PF4, platelet factor 4; TCR, T-cell receptor; Tr, T regulatory; TF, tissue factor.

expression on monocytes and ECs (Henn et al., 1998; Mach et al., 1997); (7) Following clearance of heparin, released PF4 reassociates with GAGs on ECs and PBMCs; (8) Antibodies bind to these newly formed targets to cause EC damage and/or activation (Visentin et al., 1994) and more TF expression (Arepally and Mayer, 2001; Pouplard et al., 2001), thus (9) enhancing—together with the released platelet-derived microparticles—thrombin generation with resulting thrombosis or disseminated intravascular coagulation (Warkentin et al., 1998; Visentin, 1999).

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