Abstract
Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from α-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto-inhibition mechanism (k i/k a = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface-associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface-associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis.
Highlights
Coagulation factor XII is a serine protease zymogen that can undergo auto-activation in the presence of foreign surfaces
To determine whether PS contributes to platelet-dependent fXIIa generation or whether it is merely concurrent with manifestation of an additional necessary factor, we examined the effect of annexin V on purified factor XII (fXII) activation
Several studies have examined the participation of activated platelets or platelet-derived material in fXII activation [9], [10], [13], [11], [12], the overall role of platelets in fXII activation remains disputed [15], [17]
Summary
Coagulation factor XII (fXII) is a serine protease zymogen that can undergo auto-activation in the presence of foreign surfaces. Interest in fXII recently increased due to the findings that fXII-deficient mice were protected from thrombosis [3], [4], [5] and that fXIIa inhibitors prevent arterial thrombosis without affecting haemostasis in mice [6] and primates [7]. These observations suggest that the role of fXIIa must be reconsidered, which has stimulated research on (patho)physiological fXII activation mechanisms. A mechanism for fXIIa involvement in thrombus formation has not been proposed to explain its dispensability in haemostasis; further, no study has analysed the potential roles for platelet subpopulations [18], [19], [20], which differentially bind other coagulation factors [21]
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