Interpretation of Platelet Activation by HIT Serum in the Absence of Added Heparin

With activation assays, it is not uncommon for HIT serum or plasma to cause platelet activation, even in the absence of added heparin (Warkentin and Kelton, 2001; Prechel et al., 2005). However, even greater platelet activation occurs in the presence of added heparin. When strong serum-dependent platelet activation occurs with buffer and at a 0.1-0.3 U/mL heparin concentration, it is important to ensure that the other reactions (at 100 U/mL heparin, and 0.1-0.3 U/mL heparin together with Fc receptor blockade) are as expected. This is because residual thrombin could produce strong platelet activation in both the absence and presence of low heparin concentration, thereby causing the potential for a false-positive result.

There are at least two potential explanations for strong platelet activation in the absence of added heparin. First, there may be residual heparin in the sample (White et al., 1992; Potzsch et al., 1996). However, this phenomenon can persist despite attempts to remove heparin using binding resins. Further, heparin-independent platelet activation can be a feature of serum obtained from patients with "delayed-onset HIT," in which the presence of residual heparin is unlikely because onset of thrombocytopenia and thrombosis begins several days after the patient's last exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2). A second explanation is that some HIT antibodies recognize platelet-bound PF4 in the absence of an exogenous source of heparin, perhaps by PF4 bound to platelet glycosaminoglycans such as chondroitin sulfate (Rauova et al., 2006). Alternatively, as HIT antibodies are heterogeneous, there may be pathogenic antibody subpopulations that bind relatively well to PF4 even in the absence of heparin or heparin-like molecules (Newman and Chong, 1999; Amiral et al., 2000). This phenomenon has implications for the interpretation of tests of cross-reactivity of LMWH and danaparoid, as discussed later.

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