Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia by Lubica Rauova, Mortimer Poncz, Steven E.

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Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia by Lubica Rauova, Mortimer Poncz, Steven E. McKenzie, Michael P. Reilly, Gowthami Arepally, John W. Weisel, Chandrasekaran Nagaswami, Douglas B. Cines, and Bruce S. Sachais Blood Volume 105(1):131-138 January 1, 2005 ©2005 by American Society of Hematology

Formation of PF4-heparin complexes. Formation of PF4-heparin complexes. SEC-HPLC of PF4-heparin complexes formed at varying PF4-heparin ratios (PHRs). In the absence of heparin, PF4 migrates as a single peak at 23 minutes. In the presence of heparin, 2 populations of complexes are observed: ULCs and smaller complexes (SCs). A portion of the PF4 does not form complexes with heparin and elutes at 23 minutes. Data are expressed as the percentage of total counts of each experiment and represent the mean ± SEM of 3 independent experiments. (A) PF4; (B) PHR1.7:1; (C) PHR1.1:1; (D) PHR0.8:1; (E) PHR0.07:1; (F) PHR0.06:1. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Stability of PF4-heparin complexes. Stability of PF4-heparin complexes. SEC-HPLC of PF4-heparin complexes as in Figure 1. (A) Chromatograph of PF4-heparin complexes at a PHR of 1:1. (B) Rechromatograph of SC from (A) after 24 hours of incubation at 37°C. (C) Rechromatograph of ULCs from panel A after 1 or 24 hours of incubation at 37°C. (D) Rechromatograph of ULCs from panel A after incubation with excess heparin as described in “Results.” Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Transmission electron microscopy of rotary shadowed PF4-heparin complexes. Transmission electron microscopy of rotary shadowed PF4-heparin complexes. Fields demonstrating the appearance of PF4-heparin complexes at the optimal PF4-heparin ratio. Triangles (▸) indicate representative ULCs; arrows point to representative SCs. The coating of metal from the shadowing technique makes the extended structure of the IgG appear artificially larger in comparison to that of compact structure of the PF4-heparin complexes. Magnification bar = 50 nm. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Disruption of PF4 tetramers. Disruption of PF4 tetramers. (A) Cartoon based on the crystal structure of PF4, illustrating the salt bridges that may be important in tetramer formation. (B) SDS-PAGE demonstrating the equilibrium of PF4 monomer (M), dimers (D), and tetramers (T) in WT PF4 and PF4 with induced mutations after BS3 crosslinking. This gel is representative of 3 independent experiments. (C-D) Chromatographs from SEC-HPLC of PF4-K50E (C) and PF4-E28R-K50E (D), as in Figure 1. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Recognition of complexes by KKO Recognition of complexes by KKO. Equal amounts of PF4 (□), ULCs (▪), or SCs (▦) were captured on immobilized KKO, RTO, or polyclonal antibody. Recognition of complexes by KKO. Equal amounts of PF4 (□), ULCs (▪), or SCs (▦) were captured on immobilized KKO, RTO, or polyclonal antibody. The amount captured was measured with a secondary anti-PF4 antibody. Data are the mean ± SD of 3 independent experiments performed in triplicate. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Transmission electron microscopy of rotary shadowed PF4-heparin complexes with KKO antibody bound. Transmission electron microscopy of rotary shadowed PF4-heparin complexes with KKO antibody bound. Galleries showing the appearance of PF4-heparin complexes with KKO antibody bound. IgG molecules have a typical 3-lobed structure, but their appearance can vary widely because they are quite flexible molecules. (A) Examples of PF4-heparin complexes with a single KKO bound. (B) Examples of PF4-heparin complexes with multiple KKO antibodies bound to each. Below each frame is very high contrast image to highlight the shadowed molecules and eliminate the background. Arrows point to the antibodies. Magnification bar = 50 nm. Adobe Photoshop 7.0 (Adobe, San Jose, CA) was used to produce high-contrast images. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology

Activation of human platelets by KKO and PF4-heparin complexes. Activation of human platelets by KKO and PF4-heparin complexes. Platelet activation as measured by flow cytometry examining P-selectin expression, PAC-1 binding, and annexin V binding. Platelet agonists, ADP and PMA, were included as positive controls. Data are presented as the percentage of activated platelets after each treatment and are the mean ± SD of 3 independent experiments. Lubica Rauova et al. Blood 2005;105:131-138 ©2005 by American Society of Hematology