scholarly journals bFGF blockade reduces intraplaque angiogenesis and macrophage infiltration in atherosclerotic vein graft lesions in ApoE3*Leiden mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Parma ◽  
Hendrika A. B. Peters ◽  
Thijs J. Sluiter ◽  
Karin H. Simons ◽  
Paolo Lazzari ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Tube Formation ◽  
Macrophage Infiltration ◽  
Intraplaque Hemorrhage ◽  
Vein Grafts ◽  
Matrigel Plug

Abstract Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction. Basic Fibroblast Growth Factor (bFGF) plays a key role in angiogenesis and inflammation and is involved in the pathogenesis of atherosclerosis. Therefore, we aim to test K5, a small molecule bFGF-inhibitor, on remodelling of accelerated atherosclerotic vein grafts lesions in ApoE3*Leiden mice. K5-mediated bFGF-signalling blockade strongly decreased intraplaque angiogenesis and intraplaque hemorrhage. Moreover, it reduced macrophage infiltration in the lesions by modulating CCL2 and VCAM1 expression. Therefore, K5 increases plaque stability. To study the isolated effect of K5 on angiogenesis and SMCs-mediated intimal hyperplasia formation, we used an in vivo Matrigel-plug mouse model that reveals the effects on in vivo angiogenesis and femoral artery cuff model to exclusively looks at SMCs. K5 drastically reduced in vivo angiogenesis in the matrigel plug model while no effect on SMCs migration nor proliferation could be seen in the femoral artery cuff model. Moreover, in vitro K5 impaired endothelial cells functions, decreasing migration, proliferation and tube formation. Our data show that K5-mediated bFGF signalling blockade in hypercholesterolemic ApoE3*Leiden mice reduces intraplaque angiogenesis, haemorrhage and inflammation. Therefore, K5 is a promising candidate to stabilize advanced atherosclerotic plaques.

scholarly journals miRNA-126-3p carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein grafts neointimal formation in vivo

2020 ◽  
Author(s):  
Qingxi Qu ◽  
Limei Wang ◽  
Weidong Bing ◽  
Yanwen Bi ◽  
Chunmei Zhang ◽  
...  
Keyword(s):  
Vein Graft ◽  
Target Genes ◽  
Vascular Endothelial Cells ◽  
Fluorescent Microscopy ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Neointimal Formation ◽  
Vein Grafts

Abstract Background: The aim of this study was to determine whether the combination of MSC implantation with miRNA-126-3p overexpression would further improve the surgical results after vein grafting.Methods: hucMSCs and HUVECs were isolated from human umbilical cords and characterized by a series of experiments. Lentivirus vector encoding miRNA-126-3p was transfected into hucMSCs and verified by PCR. We analyzed the miRNA-126-3p-hucMSC function in vascular endothelial cells by using a series of co-culture experiments. miRNA-126-3p-hucMSCs-exosomes were separated from cell culture supernatants and identified by WB and TEM. We validated the role of miRNA-126-3p-hucMSCs-exosomes on HUVECs proliferative and migratory and angiogenic activities by using a series of function experiments. We further performed co-culture experiments to detect downstream target genes and signaling pathways of miRNA-126-3p-hucMSCs in HUVECs. We established a rat vein grafting model, CM-Dil-labeled hucMSCs were injected intravenously into rats and the transplanted cells homing to the vein grafts were detected by fluorescent microscopy. We performed historical and immunohistochemical experiments to exam miRNA-126-3p-hucMSC transplantation on vein grafts neointimal formation and reendothelialization in vitro. Results: We successfully isolated and identified primary hucMSCs and HUVECs. Primary hucMSCs were transfected with lentiviral vectors carrying miRNA-126-3p at a MOI 75. Co-culture studies indicated that overexpression of miRNA-126-3p in hucMSCs enhanced HUVECs proliferation, migration and tube formation in vivo. We successfully separated hucMSCs-exosomes and found that miRNA-126-3p-hucMSCs-exosomes can strengthen the proliferative, migratory, and tube formation capacities of HUVECs. Further PCR and WB analysis indicated that, SPRED-1/PIK3R2/AKT/ ERK1/2 pathways are involved in this process. In the rat vein arterialization model, reendothelialization analysis showed that transplantation with hucMSCs modified with miRNA-126-3p had a higher reendothelialization of the vein grafts. The subsequent historical and immunohistochemical examination revealed that delivery with miRNA-126-3p overexpressed hucMSCs significantly reduced vein graft intimal hyperplasia in rats.Conclusion: These results suggest hucMSC-based miRNA-126-3p gene therapy may be a novel option for the treatment of vein graft disease after CABG.

scholarly journals A novel family of RGD-containing disintegrins (Tablysin-15) from the salivary gland of the horsefly Tabanus yao targets αIIbβ3 or αVβ3 and inhibits platelet aggregation and angiogenesis

2011 ◽  
Vol 105 (06) ◽  
pp. 1032-1045 ◽  
Author(s):  
Huan Liu ◽  
Xuening Yang ◽  
John Andersen ◽  
Yipeng Wang ◽  
Fuyuki Tokumasu ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Endothelial Cell ◽  
Platelet Adhesion ◽  
Solid Phase ◽  
Thrombus Formation ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Rgd Motif

SummaryA novel family of RGD-containing molecules (Tablysin-15) has been molecularly characterised from the salivary gland of the haematophagous horsefly Tabanus yao. Tablysin-15 does not share primary sequence homology to any disintegrin discovered so far, and displays an RGD motif in the N-terminus of the molecule. It is also distinct from disintegrins from Viperidae since its mature form is not released from a metalloproteinase precursor. Tablysin-15 exhibits high affinity binding for platelet αIIbβ3 and endothelial cell αVβ3 integrins, but not for α5β1 or α2β1. Accordingly, it blocks endothelial cell adhesion to vitronectin (IC50 ~1 nM) and marginally to fibronectin (IC50 ~1 μM), but not to collagen. It also inhibits fibroblast growth factor (FGF)-induced endothelial cell proliferation, and attenuates tube formation in vitro. In platelets, Tablysin-15 inhibits aggregation induced by collagen, ADP and convulxin, and prevents static platelet adhesion to immobilised fibrinogen. In addition, solid-phase assays and flow cytometry demonstrates that αIIbβ3 binds to Tablysin-15. Moreover, immobilised Tablysin-15 supports platelet adhesion by a mechanism which was blocked by anti-integrin αIIbβ3 monoclonal antibody (e.g. abciximab) or by EDTA. Furthermore, Tablysin-15 dose-dependently attenuates thrombus formation to collagen under flow. Consistent with these findings, Tablysin-15 displays antithrombotic properties in vivo suggesting that it is a useful tool to block αIIbβ3, or as a prototype to develop antithrombotics. The RGD motif in the unique sequence of Tablysin-15 represents a novel template for studying the structure-function relationship of the disintegrin family of inhibitors.

scholarly journals miRNA-126-3p carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein graft neointimal formation in vivo

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qingxi Qu ◽  
Limei Wang ◽  
Weidong Bing ◽  
Yanwen Bi ◽  
Chunmei Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Cord ◽  
Vein Graft ◽  
Fluorescent Microscopy ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Neointimal Formation ◽  
Vein Grafts

Abstract Background The aim of this study was to determine whether the combination of MSC implantation with miRNA-126-3p overexpression would further improve the surgical results after vein grafting. Methods human umbilical cord MSCs (hucMSCs) and human umbilical vein endothelial cells (HUVECs) were isolated from human umbilical cords and characterized by a series of experiments. Lentivirus vector encoding miRNA-126-3p was transfected into hucMSCs and verified by PCR. We analyzed the miRNA-126-3p-hucMSC function in vascular endothelial cells by using a series of co-culture experiments. miRNA-126-3p-hucMSCs-exosomes were separated from cell culture supernatants and identified by WB and TEM. We validated the role of miRNA-126-3p-hucMSCs-exosomes on HUVECs proliferative and migratory and angiogenic activities by using a series of function experiments. We further performed co-culture experiments to detect downstream target genes and signaling pathways of miRNA-126-3p-hucMSCs in HUVECs. We established a rat vein grafting model, CM-Dil-labeled hucMSCs were injected intravenously into rats, and the transplanted cells homing to the vein grafts were detected by fluorescent microscopy. We performed historical and immunohistochemical experiments to exam miRNA-126-3p-hucMSC transplantation on vein graft neointimal formation and reendothelialization in vitro. Results We successfully isolated and identified primary hucMSCs and HUVECs. Primary hucMSCs were transfected with lentiviral vectors carrying miRNA-126-3p at a MOI 75. Co-culture studies indicated that overexpression of miRNA-126-3p in hucMSCs enhanced HUVECs proliferation, migration, and tube formation in vivo. We successfully separated hucMSCs-exosomes and found that miRNA-126-3p-hucMSCs-exosomes can strengthen the proliferative, migratory, and tube formation capacities of HUVECs. Further PCR and WB analysis indicated that, SPRED-1/PIK3R2/AKT/ERK1/2 pathways are involved in this process. In the rat vein arterialization model, reendothelialization analysis showed that transplantation with hucMSCs modified with miRNA-126-3p had a higher reendothelialization of the vein grafts. The subsequent historical and immunohistochemical examination revealed that delivery with miRNA-126-3p overexpressed hucMSCs significantly reduced vein graft intimal hyperplasia in rats. Conclusion These results suggest hucMSC-based miRNA-126-3p gene therapy may be a novel option for the treatment of vein graft disease after CABG.

Abstract 654: Loss of SPRR3 In ApoE -/- Mice Leads to Increased Atheroma Vulnerability and Evidence of Plaque Rupture and Cardiac Infarcts

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Amanda K Segedy ◽  
Bin Li ◽  
Caressa D Lietman ◽  
MacRae F Linton ◽  
Pampee P Young
Keyword(s):  
Myocardial Infarction ◽  
Plaque Rupture ◽  
Experimental Studies ◽  
Intraplaque Hemorrhage ◽  
Type I ◽  
Gelatinase Activity ◽  
Plaque Instability ◽  
Atherosclerosis Progression

Atheroma rupture is the leading cause of myocardial infarction. While studies have examined inflammatory cell-mediated effects on plaque vulnerability, less is known about the role of vascular smooth muscle cells (VSMCs) or specific molecular players in the maintenance of atheroma stability. We reported that loss of small proline-rich repeat protein 3 (SPRR3), enriched in atheroma VSMCs, leads to increased VSMC death and significantly accelerates atherosclerosis progression in ApoE -/- mice. Here, we show that loss of SPRR3 promotes features in plaques of brachiocephalic arteries common to unstable lesions, such as increased necrotic core size, reduced cap collagen content, and reduced VSMC content. Moreover, ApoE -/- mice lacking SPRR3 develop coronary artery lesions with advanced features, including intraplaque hemorrhage. In addition, Sprr3 -/- ApoE -/- mice fed a high-fat diet for 6 months develop spontaneous myocardial infarction. In vitro , SPRR3 deficient VSMCs show reduced expression of procollagen type I, an event associated with Akt activation. SPRR3-deficient VSMCs also show increased expression of MMP2 transcripts, and aortic root lesions of Sprr3 -/- ApoE -/- mice have increased gelatinase activity consistent with MMP2 activation. Our data demonstrate that SPRR3 loss in ApoE -/- mice decreases VSMC survival and collagen I synthesis while increasing MMP2 synthesis and activity, resulting in atheroma instability with evidence of downstream myocardial infarction. Taken together the results present the Sprr3 -/- ApoE -/- mouse as an experimental model of plaque rupture. This model will be used for additional experimental studies including in vivo genetic modulation of the Akt pathway as well as in vitro studies to determine phenotypic outcome, i.e. coronary arterial lesions, myocardial infarction, VSMC survival and collagen synthesis. We hope to establish a mechanistic link between altered Akt signaling and matrix integrity in the context of atheroma rupture, as well as potentially use SPRR3 as a molecular marker which could lead to detection of plaque instability as well as therapeutic intervention methodologies.

Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 566-576 ◽  
Author(s):  
Mhairi J. Maxwell ◽  
Erik Westein ◽  
Warwick S. Nesbitt ◽  
Simon Giuliano ◽  
Sacha M. Dopheide ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Imaging Techniques ◽  
Platelet Aggregates ◽  
Adhesive Interactions ◽  
Membrane Tethers ◽  
Atherosclerotic Plaque Rupture

Abstract Disturbances of blood flow at sites of atherosclerotic plaque rupture are one of the key pathogenic events promoting platelet activation and arterial thrombus formation. Shear effects of platelets have been extensively investigated in vitro; however, the mechanisms by which shear promotes platelet aggregation in vivo remain incompletely understood. By employing high-resolution imaging techniques to in vitro and in vivo thrombosis models, we demonstrate a unique mechanism initiating shear-dependent platelet aggregation involving aggregate formation between discoid platelets. These discoid platelet aggregates are initially unstable and result from the development of membrane tethers between coadhering platelets. Tether formation involves the adhesive function of GPIb/V/IX and integrin αIIbβ3, and conversion of discoid platelet aggregates into stable aggregates requires released ADP. The efficiency of this process is regulated by 3 independent variables, including the reactivity of the adhesive substrate, the level of shear flow, and the platelet density at the adhesive surface. These studies identify a new mechanism initiating platelet aggregation that is critically influenced by shear, physical proximity between translocating platelets, and membrane tether formation. Moreover, they provide a model to explain how the discoid morphology of platelets facilitates the maintenance of adhesive interactions with thrombogenic surfaces under high shear stress conditions.

scholarly journals miRNA-126-3p Carried by Human Umbilical Cord Mesenchymal Stem Cell Enhances Endothelial Function through Exosome-mediated Mechanisms in Vitro and Attenuates Vein Grafts Neointimal Formation in Vivo

2020 ◽  
Author(s):  
Qingxi Qu ◽  
Limei Wang ◽  
Weidong Bing ◽  
Yanwen Bi ◽  
Chunmei Zhang ◽  
...  
Keyword(s):  
Vein Graft ◽  
Target Genes ◽  
Vascular Endothelial Cells ◽  
Fluorescent Microscopy ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Neointimal Formation ◽  
Vein Grafts

Abstract Background: The aim of this study was to determine whether the combination of MSC implantation with miRNA-126-3p overexpression would further improve the surgical results after vein grafting. Methods: hucMSCs and HUVECs were isolated from human umbilical cords and characterized by a series of experiments. Lentivirus vector encoding miRNA-126-3p was transfected into hucMSCs and verified by PCR. We analyzed the miRNA-126-3p-hucMSC function in vascular endothelial cells by using a series of co-culture experiments. miRNA-126-3p-hucMSCs-exosomes were separated from cell culture supernatants and identified by WB and TEM. We validated the role of miRNA-126-3p-hucMSCs-exosomes on HUVECs proliferative and migratory and angiogenic activities by using a series of function experiments. We further performed co-culture experiments to detect downstream target genes and signaling pathways of miRNA-126-3p-hucMSCs in HUVECs. We established a rat vein grafting model, CM-Dil-labeled hucMSCs were injected intravenously into rats and the transplanted cells homing to the vein grafts were detected by fluorescent microscopy. We performed historical and immunohistochemical experiments to exam miRNA-126-3p-hucMSC transplantation on vein grafts neointimal formation and reendothelialization in vitro. Results: We successfully isolated and identified primary hucMSCs and HUVECs. Primary hucMSCs were transfected with lentiviral vectors carrying miRNA-126-3p at a MOI 75. Co-culture studies indicated that overexpression of miRNA-126-3p in hucMSCs enhanced HUVECs proliferation, migration and tube formation in vivo. We successfully separated hucMSCs-exosomes and found that miRNA-126-3p-hucMSCs-exosomes can strengthen the proliferative, migratory, and tube formation capacities of HUVECs. Further PCR and WB analysis indicated that, SPRED-1/PIK3R2/AKT/ ERK1/2 pathways are involved in this process. In the rat vein arterialization model, reendothelialization analysis showed that transplantation with hucMSCs modified with miRNA-126-3p had a higher reendothelialization of the vein grafts. The subsequent historical and immunohistochemical examination revealed that delivery with miRNA-126-3p overexpressed hucMSCs significantly reduced vein graft intimal hyperplasia in rats. Conclusion: These results suggest hucMSC-based miRNA-126-3p gene therapy may be a novel option for the treatment of vein graft disease after CABG.

scholarly journals IN VITRO AND IN VIVO ANTIANGIOGENIC EFFECT OF ARTOCARPUS HETEROPHYLLUS SEED EXTRACT

2018 ◽  
Vol 11 (9) ◽  
pp. 268
Author(s):  
Thiruselvi M ◽  
Brindha Durairaj
Keyword(s):  
Tumor Growth ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Seed Extract ◽  
Antiangiogenic Effect ◽  
Artocarpus Heterophyllus ◽  
Matrigel Plug ◽  
Hydroethanolic Extract

Objective: Angiogenesis the formation of new blood vessels from the pre-existing vasculature plays a major role in tumor growth, invasion, and metastasis of cancer diseases. The current research was designed for the inhibition of angiogenesis, which can provide a novel way to inhibit tumor growth and metastasis in cancer.Methods: The antiangiogenic properties of serial concentrations of the hydroethanolic extract of Artocarpus heterophyllus were examined in human umbilical vein endothelial cells (HUVECs) using a tube formation assay in vitro and in a Matrigel plug assay as in vivo model.Results: Hydroethanolic extract of A. heterophyllus significantly inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in the HUVECs in culture dose-dependently. Further, the new blood vessel formation was observed to be inhibited by the extract at 100 mg/kg p.o. in Matrigel plug model in C57BL/6 mice. However, the effect was enhanced in higher concentration (500 mg/kg p.o.) demonstrating the in vivo antiangiogenic activity of the extract.Conclusion: This study demonstrated that the hydroethanolic seed extract of A. heterophyllus strongly inhibited the angiogenesis in HUVECs. Moreover, the extract significantly inhibited the VEGF production in HUVECs, confirming their possible antiangiogenic mechanism.

scholarly journals Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 336 ◽  
Author(s):  
Laura Parma ◽  
Hendrika A. B. Peters ◽  
Fabiana Baganha ◽  
Judith C. Sluimer ◽  
Margreet R. de Vries ◽  
...  
Keyword(s):  
Dna Damage ◽  
Vein Graft ◽  
Thrombus Formation ◽  
Graft Patency ◽  
Intraplaque Hemorrhage ◽  
Long Term Effects ◽  
Atherosclerotic Lesions ◽  
Ros Accumulation

Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.

Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases

2010 ◽  
Vol 69 (12) ◽  
pp. 2204-2212 ◽  
Author(s):  
M Asif Amin ◽  
Bradley J Rabquer ◽  
Pamela J Mansfield ◽  
Jeffrey H Ruth ◽  
Hubert Marotte ◽  
...  
Keyword(s):  
Tube Formation ◽  
Scid Mice ◽  
Janus Kinase ◽  
Microvascular Endothelial Cell ◽  
Interleukin 18 ◽  
Matrigel Plug ◽  
Synovial Tissues

BackgroundInterleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA).ObjectiveTo examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved.MethodsHuman dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice.ResultsIL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1α did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo.ConclusionTargeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.

A Comparison of the in Vitro and in Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis (Wessler) and Non-Stasis Rabbit Models

1980 ◽  
Vol 44 (02) ◽  
pp. 081-086 ◽  
Author(s):  
C V Prowse ◽  
A E Williams
Keyword(s):  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Factor Ix ◽  
Coagulation System ◽  
In Vitro Tests ◽  
Clinical Use ◽  
Low Activity

SummaryThe thrombogenic effects of selected factor IX concentrates were evaluated in two rabbit models; the Wessler stasis model and a novel non-stasis model. Concentrates active in either the NAPTT or TGt50 in vitro tests of potential thrombogenicity, or both, caused thrombus formation in the Wessler technique and activation of the coagulation system in the non-stasis model. A concentrate with low activity in both in vitro tests did not have thrombogenic effects in vivo, at the chosen dose. Results in the non-stasis model suggested that the thrombogenic effects of factor IX concentrates may occur by at least two mechanisms. A concentrate prepared from platelet-rich plasma and a pyrogenic concentrate were also tested and found to have no thrombogenic effect in vivo.These studies justify the use of the NAPTT and TGt50 in vitro tests for the screening of factor IX concentrates prior to clinical use.

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