The assembly of the factor X-activating complex on activated human platelets

Abstract

Summary. Platelet membranes provide procoagulant surfaces for the assembly and expression of the factor X-activating complex and promote the proteolytic activation and assembly of the prothrombinase complex resulting in normal hemostasis. Recent studies from our laboratory and others indicate that platelets possess specific, high-affinity, saturable, receptors for factors XI, XIa, IX, IXa, X, VIII, VIIIa, V, Va and Xa, prothrombin, and thrombin. Studies described in this review support the hypothesis that the factor X-activating complex on the platelet surface consists of three receptors (for the enzyme, factor IXa; the substrate, factor X; and the cofactor, factor VIIIa), the colocalization of which results in a 24 million-fold acceleration of the rate of factor X activation. Whether the procoagulant surface of platelets is defined exclusively by procoagulant phospholipids, or whether specific protein receptors exist for the coagulant factors and proteases, is currently unresolved. The interaction between coagulation proteins and platelets is critical to the maintenance of normal hemostasis and is pathogenetically important in human disease.

PAR-1-Stimulated Factor IXa Binding to a Small Platelet Subpopulation Requires a Pronounced and Sustained Increase of Cytoplasmic Calcium

“…*To whom correspondence should be addressed: Fredda London, Ph.D., Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, Tel: 215-707-4458; Fax: 215-707-3005; e-mail FVIIIa (4,6,11). The physiological relevance of these interactions is emphasized by the fact that occupancy of these binding sites on activated platelets is closely correlated with enhanced rates of FX activation leading to an increase in catalytic efficiency (kcat/K m ) of >2 × 10 7 -fold in the presence of the assembled complex (7), and the fact that severe, spontaneous and post-traumatic bleeding complications occur in patients with deficiencies of FIX (12), FVIII (13), FX (14) and platelet receptors for FVIIIa (15,16).Although platelets respond to many agonists with functional endpoints required for primary hemostasis including adhesion to subendothelial matrix, secretion of granule contents, aggregation and platelet plug formation to stop the flow of blood through breaches of the vasculature (17,18), exposure to strong agonists, such as collagen and thrombin, results as well in membrane surface changes allowing binding and complexation of the coagulation proteins responsible for physiologically relevant intrinsic FXa and thrombin generation (19)(20)(21). Little is known of the platelet signal transduction mechanisms resulting in these membrane surface changes.…”

The effect of bemiparin on neointimal hyperplasia and endothelial cell proliferation in a rabbit carotid artery model

“…[11][12][13][14][15] It is known as a secondgeneration LMWH due to its ultra-low molecular weight (3.600 Da). According to its low molecular weight, it has lower anti-factor IIa (thrombin) activity and an anti-Xa: anti-IIa activity ratio of 8:1 versus a ratio of 1:1 for UFHs and dalteparin 2-3:1.…”

“…In addition, LMWHs are successful in the prevention and treatment of thromboembolism. [6,[13][14][15][16][17][18][19][20][21][22][23][24][25] They are more effective than UFH in venous thromboembolism (VTE) and non-Q wave myocardial infarction. Routine heparin therapy in this setting is still under debate.…”

Effects of Bemiparin, Dalteparin, and Unfractionated Heparin on Platelet Interaction With Human Subendothelium Under Flow Conditions

“…Platelet activation leads to the release of factor 4, which partially inhibits the effect of unfractionated heparin (14). In addition, during the process of thrombogenesis factor Xa binds to the platelet membrane, where it helps to generate thrombin, which in turn further activates platelet function (15). Because LMWH has a greater affinity for factor Xa than unfractionated heparin, this may account for the greater effect we saw with LMWH in the flow system used for our assays, as well as for the tendency for bemiparin to have a greater effect than dalteparin, given that the former's affinity for anti-Xa is 2-fold to 3-fold greater than that of the latter (5).…”

“…Thrombin generation from platelet-membrane factor X activation is an important event in the pathogenesis of arterial thrombosis (15). For that reason, the greater inhibition of factor Xa caused by LMWH than UFH could support a theoretical preference for the use of LMWH in the prevention of arterial thrombosis.…”