Platelet surface-associated activation and secretion-mediated inhibition of coagulation factor XII.

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 (ki/ka = 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.

Experimental study on the hemostatc activity of Pollen Typhae: a traditional folk medicine used by external and oral application.

Pollen Typhae is the traditional Chinese herbal medicine widely used to treat the hemorrhagic diseases both by external and oral application. The present study examines the hemostatic properties and its components of Pollen Typhae. Pollen extract significantly reduced prothrombin time (PT), activated partial prothrombin time (APTT) and recalcification time. Pollen extract directly activated factor XII in the coagulation cascade. Acidic polysaccharide in the pollen that adsorbed to the diethylaminoethyl (DEAE) column was the causative agent of factor XII activation. These results suggested that an electronegative charge attributed to an acidic polysaccharide in the pollen extract contributed to the hemostatic activity. We then examined the hemostatic activity of administered pollen extract in the mouse tail bleeding model. Tail bleeding was significantly decreased after oral administration of the pollen extract, whereas the acidic polysaccharide fraction did not affect the duration of tail bleeding. These results suggest that the oral anticoagulant effect of Pollen Typhae is attributed to compounds other than acidic polysaccharides. We concluded that the activation of the intrinsic coagulation pathway by the acidic polysaccharide contributes to the external hemostatic property of Pollen Typhae, and the action of components such as flavonoids that possess anticoagulant activity are causative agent when orally administered.

Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII.

The role of the intrinsic coagulation system on the risk of myocardial infarction is unclear. In the Study of Myocardial Infarctions Leiden (SMILE) that included 560 men younger than age 70 with a first myocardial infarction and 646 control subjects, we investigated the risk of myocardial infarction for levels of factor XI (factor XIc) and factor XII (factor XIIc). Furthermore, the risks for factor VIII activity (factor VIIIc) and factor IX activity (factor IXc) were assessed. Factor XIc was 113.0% in patients compared with 109.8% in control subjects (difference, 3.2%; 95% CI, 1.1%-5.4%). The risk of myocardial infarction adjusted for age for men in the highest quintile compared with those in the lowest quintile was 1.8-fold increased (ORadj, 1.8; 95% CI, 1.2-2.7). In contrast, factor XIIc among patients with myocardial infarction was lower than in control subjects, respectively, 93.0% and 98.6% (difference, 5.6%; 95% CI, 3.3%-7.9%). The odds ratio of myocardial infarction for men in the highest quintile versus those in the lowest quintile was 0.4 (ORadj, 0.4; 95% CI, 0.2-0.5). The highest risk was found among men with both high factor XIc and low factor XIIc (analyses in tertiles: ORadj, 6.4; 95% CI, 2.2-18.0). Factor VIIIc increased the risk of myocardial infarction although not dose dependently. Factor IXc increased the risk; odds ratio of myocardial infarction for men in the highest quintile versus those in the lowest quintile was 3.2 (ORadj, 3.2; 95% CI, 2.0-5.1). Thus, factors XIc and XIIc have opposite and synergistic effects on the risk of myocardial infarction in men; factor VIIIc and factor IXc increase the risk.