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FIGURE 2 Schematic representation of the effect of the molar ratio of PF4 and heparin on the formation of complexes. Abbreviation: PF4, platelet factor 4.

individuals are reported to vary greatly in their platelet content of PF4 (O'Brien et al., 1984; Rauova et al., 2005).

In most clinical settings, free heparin is in considerable molar excess over PF4. Therapeutic concentrations of heparin (0.2-0.4 U/mL) correspond to about 100-200 nmol/L heparin. When heparin is given to normal individuals, plasma concentrations of PF4 from endothelial reservoirs only reach approximately 8 nM (Dawes et al., 1982). For PF4 concentrations to approach 100-200 nmol/L, marked activation of circulating platelets is necessary. Complete activation of platelets in a concentration of 250 X 109/L will generate a plasma PF4 concentration of about 200 nM (Horne, 1993). Therefore, a molar excess of PF4 over therapeutic concentrations of heparin would be highly unlikely outside extreme clinical circumstances, although in the immediate environment of an activated platelet, the concentration of PF4 could rise much higher. On the other hand, prophylactic doses of heparin (e.g., 5000 U every 8-12 h by subcutaneous injection) administered in a setting associated with a degree of platelet activation (e.g., after surgery) might well produce molar ratios of heparin and PF4 that would favor platelet binding of heparin-PF4 complexes, and—if an immune response has occurred—platelet binding of heparin-PF4-IgG complexes. Indeed, such scenarios are the ones in which HIT is reported most frequently (Boshkov et al., 1993; Warkentin et al., 1995, 2000) (see Chapter 3).

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