A novel biological effect of platelet factor 4 (PF4): enhancement of LPS-induced tissue factor activity in monocytes

Engstad, Charlotte Sissener; Lia, Karin; Rekdal, Øystein; Olsen, Jan Ole; Østerud, Bjarne

doi:10.1002/jlb.58.5.575

Cited by 73 publications

(50 citation statements)

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“…Thus, although P-selectin-expressing platelets may not induce tissue factor (TF) expression on monocytes (Weyrich et al, 1996), as suggested by others (Celi et al, 1994), a P-selectin-and PF4-dependent interaction among activated platelets, granulocytes and monocytes augments lipopolysaccharide-induced TF expression on monocytes (Engstad et al, 1995). Consequently, in an inflammatory event, TF expression on monocytes may be disproportionately expressed in MPD patients, resulting in activation of the coagulation protease cascades via TF binding to factor VII/VIIa.…”

Section: Discussionmentioning

confidence: 98%

Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders

Jensen¹,

Brown²,

Lund

et al. 2000

Br J Haematol

110

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Summary. Chronic myeloproliferative disorders (MPDs) are characterized by a high incidence of thrombohaemorrhagic complications, possibly caused by platelet dysfunction. In an attempt to define platelet functional abnormalities, we assessed the expression of activation-dependent membrane proteins in unstimulated and agonist [ADP and thrombin receptor-activating peptide (TRAP)]-stimulated platelets using quantitative whole blood flow cytometry in samples from 50 MPD patients and 30 controls. The receptor densities of activation markers and glycoproteins (GPs) were quantified using standardized fluorescent beads. Compared with controls, the mean percentage of P-selectin-positive (15´3% vs. 7´2%; P , 0´001) and thrombospondin (TSP)-positive (6´6% vs. 3´7%; P 0´003) platelets was increased in unstimulated platelets from patients. Patients having experienced a thrombotic event had a higher mean percentage of TSP-positive non-stimulated platelets than patients without a history of thrombosis (9´0% vs. 4´6%; P 0´02) and a higher GPIV molecules of equivalent fluorochrome (MEF) value (33113 vs. 24471 MEF; P 0´02). Mean MEF values of monoclonal antibodies (mAbs) against GPIb (34055 vs. 38945 MEF; P , 0´001) and GPIIb/IIIa (1416 vs. 1648 MEF; P , 0´001) were significantly reduced among patients, whereas surface expression of GPIV was increased in patients (28273 vs. 16258 MEF; P , 0´001). In TRAP (10 mmol/l) stimulated whole blood, the MEF of P-selectin (9611 vs. 13293 MEF; P 0´004) and CD63 (2385 vs. 5177 MEF; P , 0´001) and the ratio of PAC-1/GPIIb/IIIa MEF (0´98 vs. 2´00; P , 0´001) was reduced in patients, indicating either a reduced granule GP content or an intrinsic cellular defect in receptor-mediated granule secretion and activation of the GPIIb/IIIa complex. Expressed as the relative change of MEF compared with unstimulated platelets, TRAP induced decrease of GPIb (7´8% vs. 45%; P , 0´001) and increase of GPIIb/IIIa (49´1% vs. 95´7%; P , 0´001) and GPIV expression (17´8% vs. 55´2%; P , 0´001) was attenuated in patients.

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Section: Discussionmentioning

confidence: 98%

Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders

Jensen¹,

Brown²,

Lund

et al. 2000

Br J Haematol

110

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“…Unlike PBP and other chemokines, PF4 appears to bind mostly to large, negatively charged molecules such as heparin, and though many biologic functions have been attributed to PF4, its true role in vivo is unknown. [6][7][8][9] Although the biologic roles of these chemokines need further investigation, their genes offer an opportunity to understand megakaryocyte-specific expression. Like many other genes encoding chemokines, both the PBP and PF4 genes are encoded by 3 exons, and are preceded by a TATA box in the immediate 5Ј-flanking region.…”

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confidence: 99%

Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus

Zhang

Thornton

Kowalska

et al. 2001

Blood

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The genes for the related human (h) chemokines, PBP (platelet basic protein) and PF4 (platelet factor 4), are within 5.3 kilobases (kb) of each other and form a megakaryocyte-specific gene locus. The hypothesis was considered that the PBP and PF4 genes share a common distal regulatory region(s) that leads to their high-level megakaryocyte-specific expression in vivo. This study examined PBP and PF4 expression in transgenic mice using 4 distinct human PBP/PF4 gene locus constructs. These studies showed that within the region studied there was sufficient information to regulate tissue-specific expression of both hPBP and hPF4. Indeed this region contained sufficient DNA information to lead to expression levels of PBP and PF4 comparable to the homologous mouse genes in a position-independent, copy number-dependent fashion. These studies also indicated that the DNA domains that led to this expression were distinct for the 2 genes; hPBP expression is regulated by a region that is 1.5 to 4.4 kb upstream of that gene. Expression of hPF4 is regulated by a region that is either intergenic between the 2 genes or immediately downstream of the hPF4 IntroductionPlatelet basic protein (PBP) and platelet factor 4 (PF4) are related, platelet-specific chemokines that are expressed at high levels during megakaryopoiesis and stored in platelet ␣-granules. 1 They represent 3% to 5% of total protein releasate from platelets on a molar basis. PBP is N-terminally cleaved to ␤-thromboglobulin (␤-TG) and then to neutrophil-activating peptide-2 (NAP-2). [2][3][4] This final product binds and activates the chemokine receptor CXCR2 on neutrophils. 5 What role this chemokine has in thrombosis and inflammation is unclear. Unlike PBP and other chemokines, PF4 appears to bind mostly to large, negatively charged molecules such as heparin, and though many biologic functions have been attributed to PF4, its true role in vivo is unknown. [6][7][8][9] Although the biologic roles of these chemokines need further investigation, their genes offer an opportunity to understand megakaryocyte-specific expression. Like many other genes encoding chemokines, both the PBP and PF4 genes are encoded by 3 exons, and are preceded by a TATA box in the immediate 5Ј-flanking region. 10,11 Transient transcriptional studies with the immediate 5Ј-flanking region defined a PU.1-binding promoter region upstream of the PBP gene, 12 similar to a thrombopoietininduced enhancer domain upstream of the platelet-specific [alpha]IIb gene. 13 Several silencers and promoter domains have been similarly defined in the immediate 5Ј-flanking region of the PF4 gene, including one GATA-1 binding site. 14,15 Reporter gene constructs with 245 bp of the immediate 5Ј-flanking region of the hPF4 gene showed that this region contained sufficient information to drive tissue-specific expression of a LacZ reporter construct 16 and that 1.1 kb of rat PF4 promoter can drive vigorous tissue-specific expression. 17 However, neither of these constructs had sufficient information to drive positionind...

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“…The extrinsic pathway is initiated by tissue factor (TF). TF is a transmembrane glycoprotein constitutively expressed on extravascular cells (like fibroblasts and pericytes surrounding blood vessels), while inducible expressed upon blood vessel injury [41,42], as well as in monocytes upon stimulation with LPS or bacteria's [43][44][45]. TF is also exposed on circulating cell-derived microparticles (MPs) [46].…”

Section: Whole Blood Effector Systemsmentioning

confidence: 99%

Biocompatibility and Biotolerability Assessment of Microspheres Using a Whole Blood Model

Rokstad¹,

Strand²,

Espevik³

et al. 2013

MNS

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The whole blood model is a powerful method for determining the immediate inflammatory reactions towards foreign objects in general. This review focuses on the use of a lepirudin based whole blood model for evaluating microspheres relevant in cell transplantation applications. This whole blood model can be regarded as a holistic model with readouts from cross-talks between leukocytes, complement, most of the coagulation components and fibrinolysis. A major advantage is the possibility to evaluate a panel of different microspheres under identical conditions, and also the possibility of comparing the reaction patterns between species. This model is a valuable tool for gaining a mechanistic understanding by selected readouts (as complement and coagulation activation products, cytokines, cell-surface receptors, protein adsorption, cell-attachment), and by use of inflammatory blocking agents (inhibitors). The whole blood model is put in the context of today's knowledge about inflammatory systems, discussed according to biocompatibility and biotolerability terms and finally discussed according to its ability to predict the outcome of the transplanted microspheres in an in vivo situation.3

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A novel biological effect of platelet factor 4 (PF4): enhancement of LPS-induced tissue factor activity in monocytes

Cited by 73 publications

References 0 publications

Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders

Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders

Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus

Biocompatibility and Biotolerability Assessment of Microspheres Using a Whole Blood Model

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