Platelet‐ and erythrocyte‐derived microparticles trigger thrombin generation via factor XIIa

Abstract

SwedenTo cite this article: van der Meijden PEJ, van Schilfgaarde M, van Oerle R, Renné T, ten Cate H, Spronk HMH. Platelet-and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10: 1355-62.See also Shapiro S, Laffan M. Making contact with microparticles. This issue, pp 1352-4.Summary. Background: The procoagulant properties of microparticles (MPs) are due to the of the presence of phosphatidylserine (PS) and tissue factor (TF) on their surface. The latter has been demonstrated especially on MPs derived from monocytes. Objectives: To investigate the relative contribution of TF and factor (F)XII in initiating coagulation on MPs derived from monocytes, platelets and erythrocytes. Methods: Microparticles were isolated from calcium ionophore-stimulated platelets, erythrocytes and monocytic THP-1 cells. MPs were quantified, characterized for cellspecific antigens and analyzed for TF, PS exposure and their thrombin-generating potential. Results: The MP number was not proportional to PS exposure and the majority of the MPs exposed PS. TF activity was undetectable on platelet-and erythrocyte-derived MPs (< 1 fM nM )1 PS), whereas monocyte-derived MPs exposed TF (32 fM nM )1 PS). Platelet-, erythrocyte-and monocyte-derived MPs, but not purified phospholipids, initiated thrombin generation in normal plasma in the absence of an external trigger (lag time < 11 min). Deficiency or inhibition of FVII had no effect on thrombin generation induced by platelet-and erythrocyte-derived MPs, but interfered with monocyte MP-triggered coagulation. Platelet-and erythrocyte-derived MPs completely failed to induce thrombin generation in FXII-deficient plasma. In contrast, monocyte-derived MPs induced similar thrombin generation in normal vs. FXII-deficient plasma. Conclusion: MPs from platelets and erythrocytes not only propagate coagulation by exposing PS but also initiate thrombin generation independently of TF in a FXII-dependent manner. In contrast, monocyte-derived MPs trigger coagulation predominantly via TF.

Is a decrease of microparticles related to improvement of hemostasis after FVIII injection in hemophilia A patients treated on demand?

“…Microparticles have been shown to provide a negatively charged surface (PS exposure) for the aggregation and subsequent activation of coagulation factors, as well as promoting coagulation via the expression of coagulation proteins such as TF and adhesion molecules such as P-selectin on their surface [8,21]. A decrease in circulating MPs, as seen in our study, may imply that MPs are incorporated in the hemostatic plug formed after FVIII injection, at the site of injury.…”

“…Microparticles can carry phosphatidylserine (PS), which may contribute to their procoagulant nature, and they also express various activation markers such as P-selectin (CD62P) and tissue factor (TF, CD142) [6]. Exposure of PS on MPs offers coagulation factors a binding site during both initiation and propagation of coagulation, which could accelerate thrombin formation [7,8]. The presence of TF on MPs also increases their procoagulant activity, while the main source of circulating TFpositive MPs is thought to be monocytes [4].…”

Excess of heme induces tissue factor-dependent activation of coagulation in mice

“…30 Platelet-and erythrocyte-derived MPs, which are TF negative, contribute to thrombin generation in a FXII/FXI-dependent manner, whereas thrombin generation induced by TF-positive leukocyte-derived MPs requires FVII but not FXII. 32,33 In our dose titration and time course experiment, we did not observe any increase in the total number of PS-positive MPs at 1, 3 or 6 h after heme treatment (data not shown), which may explain the lack of FXI contribution to the heme-induced activation of coagulation. Furthermore, it is unlikely that increased levels of free heme can lead to the activation of FXII because treatment of heme-injected mice with 14E11 antibody (an inhibitor of FXIIa-mediated activation of FXI), had no effect on plasma TAT levels.…”

The polyphosphate–factor XII pathway drives coagulation in prostate cancer-associated thrombosis

“…These findings extend earlier studies showing that MPs derived from platelets of healthy individuals initiate coagulation via FXII activation. 44 Vice versa platelet-stimulated fibrin formation is defective in the absence of FXII. [45][46][47] Supporting a function for the polyP/FXII coagulation pathway in cancer-associated thrombosis, zymogen FXII plasma levels are low in samples from patients with advanced gastrointestinal 48 and nonmetastatic colorectal cancer 49 compared with healthy controls.…”