Abciximab inhibits procoagulant activity but not the release reaction upon collagen- or clot-adherent platelets.
In addition to inhibiting platelet (plt) aggregation abciximab, a glycoprotein (GP) IIb/IIIa antagonist, reduces coagulation in blood or platelet-rich plasma. We assessed the effects of abciximab (10 micro g mL(-1)) on adhesion-dependent procoagulant activity (PCA) of plt upon: (i) collagen to model initial adhesion; or (ii) plasma clot or fibrin to model a preformed thrombus with retained thrombin activity. In a two-stage assay gel-filtered plt (GFP) first adhered on collagen, plasma clot, or fibrin, and plt activation was traced with platelet factor 4 (PF 4) release. Second, PCA was measured on adherent plt (i) by soluble prothrombin fragments (F1 + 2); and (ii) chromogenically by adding defibrinated plasma and thromboplastin. Abciximab inhibited aggregation upon collagen-adherent plt both in the absence and presence of plasma. In contrast, without plasma abciximab enhanced plt deposition to fibrin surfaces depending on thrombin generation and fibrin polymerization. However, abciximab reduced PCA and generation of F1 + 2 on adherent plt surface-independently by 35%, whereas PF 4 release persisted. Also, a GP Ib inhibitor, mAb SZ2, attenuated PCA by 40% alone, and by 65% together with abciximab, leaving 35% of PCA unaltered. Abciximab decreased generation of new thrombin on both collagen- and clot-adherent plt. However, abciximab did not inhibit alpha-granule release, suggesting distinct pathways for PCA and release reaction. Deposition of isolated plt on clots in the presence of abciximab was dependent on thrombin and polymerizing plt-derived fibrin(ogen). Due to local consumption of natural anticoagulants adjacent to a preformed thrombus the antithrombotic effect of abciximab benefits from additional inhibition of thrombin.
Ilveskero
S
S
Wihuri Research Institute, Department of Internal Medicine, Helsinki, Finland.
Lassila
R
R
D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010978:Platelet Factor 4 / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012701:Serotonin; D010978:Platelet Factor 4; D005337:Fibrin; D003094:Collagen; D013917:Thrombin; D000077284:Abciximab