Abstract Number: PB0880
Meeting: ISTH 2021 Congress
Background: APAC is a heparin proteoglycan mimetic with dual AntiPlatelet and AntiCoagulation activities. It inhibits collagen- and thrombin-induced platelet aggregation and prolongs coagulation times. APAC targets to damaged vascular sites co-localizing with collagen and von Willebrand factor (VWF) and diminishes arterial occlusion in several thrombosis models. APAC also VWF-dependently reduces platelet and fibrin deposition on collagen and tissue factor surfaces.
Upon activation, platelets release procoagulant factors including platelet factor 4 (PF4), which neutralizes negatively charged heparin-like glycosaminoglycans. PF4 as a chemokine has also well-established role in inflammation and heparin-induced thrombocytopenia.
Aims: We assessed the effect of PF4-APAC interaction by coagulation and platelet aggregation in vitro and the structure-function relationship of APAC after dissociation of the heparin-protein complex.
Methods: APAC-spiked samples, ±PF4, were studied in human citrated-plasma and platelet rich-plasma for APTT and TT, and collagen-induced (0.5 µg/mL) aggregation, respectively. In addition, APAC was reduced with dithiothreitol (DTT) to release the heparin and to assess subsequent activity after dissociation.
Results: APAC and unfractionated heparin (UFH, 0.5-1.5 µg/mL; n=3-5) prolonged the clotting times by ≥1.8-fold and ≥1.2-fold, respectively. APAC was at least 1.3-fold (APTT) and 1.5-fold (TT) more potent anticoagulant than UFH. DTT-treatment decreased the anticoagulant potency of APAC to the level of UFH. PF4 (0.25-3.25 µg/mL) diminished the anticoagulant properties of both APAC and UFH. In collagen-induced platelet aggregation, APAC concentration-dependently (0.5-10 µg/mL; n=4) inhibited platelets unlike UFH. Again, PF4 (1.6-3.2 µg/mL) reduced anti-aggregatory effects of APAC.
Conclusions: We confirmed that APAC is more potent antiplatelet and anticoagulant agent than UFH in platelet aggregation and clotting time analysis. PF4 reversed APAC’s activity, demonstrating its avid binding to heparin conjugate. Interestingly, after dissociating the heparin chains of APAC, the anticoagulant potency matched with UFH. Overall, the spatial organization of heparin chains supports both the anticoagulant and antiplatelet effects of APAC.
To cite this abstract in AMA style:Nevzorov I, Jouppila A, Lassila R. A Novel Dual AntiPlatelet and AntiCoagulant APAC: Interaction Between Platelet Factor 4 (PF4) and APAC Decreases Functional Activity [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-dual-antiplatelet-and-anticoagulant-apac-interaction-between-platelet-factor-4-pf4-and-apac-decreases-functional-activity/. Accessed May 16, 2022.
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