Platelet factor 4 (PF4) and tissue factor pathway inhibitor (TFPI) are two proteins with high affinity for heparin. They are each stored in platelets, as well as on endothelial cell surfaces, from where both are displaced or released following an injection of heparin with a rapid and marked increase in serum levels. Prior work has demonstrated that the platelet count is one of the factors affecting the levels of heparin-releasable PF4. We therefore characterized the response to a dose of intravenous heparin previously demonstrated to completely displace PF4 from the non-platelet pool in subjects with normal or increased platelet counts. Seventeen patients with essential thrombocytosis (ET), 10 patients with polycythemia vera and high platelet counts (PV-H), 7 patients with polycythemia vera and normal platelet counts (PV-N) and 10 controls received an initial bolus of 40 I.U./kg of unfractionated heparin, followed 2 hours later by a 2nd bolus of a fixed dose of 1000 I.U. TFPI activity did not show any variation among the different groups, either before (TFPI) or after (HR-TFPI) the first bolus of heparin: ET, TFPI 92.6 ± 21.5%, HR-TFPI 298.3 ± 165.8; PV-H, TFPI 91.5 ± 32.0, HR-TFPI 210 ± 1.0; PV-N, TFPI 69.4 ± 24.0, HR-TFPI 203.0 ± 79.0; C, TFPI 109.5 ± 33.5, HR-TFPI 234.0 ± 60.4. TFPI activity returned to basal values prior to the 2nd injection of heparin, which again elicited a rise in TFPI, albeit smaller due to the lower level of heparin injected. In contrast to the lack of any difference between groups with respect to TFPI, the level of heparin-releasable PF4 (HR-PF4) was significantly higher in ET and PV-H patients compared to PV-N patients or controls. However when normalized for platelet count, both PV-H and PV-N had HR-PF4 levels after the 1st heparin injection that were significantly higher than observed in ET patients (PV-H 1.163 + 0.108, PV-N 1.411 + 0.019, ET 0.737 + 0.086 ng/10/3 platelets) supporting an increased platelet activation in PV. Thus, although platelets contain approximately 5-10% of the total amount of TFPI in plasma, they do not affect the major intravascular pool of TFPI mobilizable by heparin. However, since the concentration at the site of vessel wall injury is enhanced several-fold, TFPI could play a role in competing with PF4 to limit thrombus formation in patients with high platelet count.
Keywords: PF4; Tissue Factor Pathway Inhibitor (TFPI); heparin; thrombocytosis.