Blood cell progenitors were scanned for the presence of the coagulation starter protein tissue factor (TF) by immunoelectron microscopy. Thereby, substantial TF expression was observed in the precursor cells of eosinophils. TF levels were lower in basophil precursors and barely detectable in neutrophil progenitors. In peripheral blood immediately processed to avoid activation of the TF gene, mature eosinophils were found to considerably express TF, unique among the granulocyte and monocyte fractions. TF was preferentially located in the specific granules in resting eosinophils. Platelet-activating factor (PAF), and more pronounced, granulocyte-macrophage colony-stimulating factor (GM-CSF) plus PAF, caused translocation of preformed TF to the eosinophil cell membrane. GM-CSF/PAF also increased the TF transcript levels. The activated eosinophils exhibited procoagulant activity that was abrogated by TF inhibition. Targeting the extracellular domain of TF with specific antibodies markedly suppressed the initial phase of the eosinophil passage across the IL-4-activated endothelium. Eosinophil rolling and firm adhesion remained unaffected. This suggests that TF specifically facilitates the early transendothelial migration of the eosinophils. In summary, eosinophils maintain a high TF expression during maturation, providing a main source of preformed TF in blood, which might be relevant for the thrombogenesis promoted by hypereosinophilic conditions. IntroductionTissue factor (TF), the crucial starter protein of hemostasis and a major determinant of its pathologic sequelae, 1 is basically expressed in the plasma membrane of cells located in the adventitial and medial layers of the vascular wall. TF binds the serine protease factor VIIa with high affinity, thereby enhancing its proteolytic activity by several orders of magnitude, whereby coagulation is initiated. A series of new findings suggests that preformed TF is present in intravascular compartments in humans, at variance with its designation. For a deeper understanding of the start process of intravascular coagulation, it is essential to know where TF is located and how its expression is regulated. Recently, circulating microvesicles (or microparticles) were revealed as source for preexisting TF in blood, which are apparently derived from leukocytes and platelets. 2-5 They most likely represent the earlier described TF pool in acellular plasma 6-9 because the selective removal of microvesicles strongly decreases the plasma TF contents. 3 Microvesicles are rapidly recruited to the site of vascular injury in vivo, where they elicit the coagulation start in a TF-dependent way. 10 Moreover, TF has been reported to appear on the cell surface and on microvesicles secreted from activated platelets. [11][12][13] In other work, TF was not detectable on platelets. 14 In addition, TF has been proposed to be present in neutrophils (summarized by Nakamura et al 15 ), although this has been called into question. 16 Notably, the functional competence of TF is not restricted to ...
While the adenosine 5-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagenadhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y 12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y 12 and P2Y 1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectronmicroscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y 1 -deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus. (Blood.
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