Nonidiosyncratic Heparininduced Platelet Activation

The functional consequence of heparin binding to platelets is subtle cell stimulation. Antibody-independent activation of platelets by heparin in vitro has been reported from many laboratories. However, the results of these studies have varied, presumably because of differences in experimental conditions. In plasma, for example, heparin alone causes slight platelet aggregation, whereas platelets suspended in laboratory buffers are reported to aggregate either briskly or not at all in response to heparin (Eika, 1972; Salzman et al., 1980; Westwick et al., 1986; Chong and Ismail, 1989). In citrate-anticoagulated plasma, heparin also potentiates platelet activation by agonists such as ADP and collagen (Holmer et al., 1980; Chen and Sylven, 1992; Xiao and Theroux, 1998; Aggarwal et al., 2002; Klein et al., 2002), and this effect is more pronounced in patients with acute illness, arterial disease, and anorexia nervosa (Mikhailidis et al., 1985; Reininger et al., 1996; Burgess and Chong, 1997).

The platelet proaggregatory effect of heparin does not appear to be an artifact of low ionized calcium concentration due to citrate anticoagulant: Chen and colleagues (1992) observed that heparin enhanced collagen-induced platelet aggregation in a dose-dependent fashion even in whole blood anticoagulated with hirudin (i.e., physiological calcium concentrations). On the other hand, the responsiveness of washed platelets to agonists when resuspended in buffers containing physiological calcium has been reported to be both increased and decreased by heparin (Saba et al., 1984; Westwick et al., 1986). Although the data are not always consistent, this much seems clear: direct heparin-induced platelet aggregation requires metabolic energy and is mediated by fibrinogen; therefore, it depends on platelet fibrinogen receptors (platelet glycoprotein IIb/IIIa) and divalent cations (Chong and Ismail, 1989). There is also evidence that heparin can antagonize platelet inhibition by prostacyclin (Saba et al., 1979; Eldor and Weksler, 1979; Fortini et al., 1985; Berglund and Wallentin, 1991).

The properties of heparin that influence its platelet binding also influence its stimulating effect on platelets: heparin of a high molecular weight is more active than low molecular weight heparin (LMWH), and heparin with low affinity for antithrombin and fibronectin is more active (because it is more available) than heparin with high affinity for these plasma proteins (Salzman et al., 1980; Holmer et al., 1980; Westwick et al., 1986; Chong and Ismail, 1989; Brace and Fareed, 1990; Xiao and Theroux, 1998; Aggarwal et al., 2002; Klein et al., 2002). The latter observation implies that the anticoagulant (antithrombin-dependent) activity of heparin is distinct from its platelet stimulatory effects. Furthermore, nonheparin polysaccharides can mimic the effect of heparin on platelets if they are sufficiently large and charged (Tiffany and Penner, 1981). In contrast, heparan sulfate (the predominant anticoagulant GAG in danaparoid) has negligible platelet-activating properties, as it has a relatively low degree of sulfation, despite sharing a carbohydrate backbone similar to that of heparin (Lindahl and Kjellen, 1991; Burgess and Chong, 1997).

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