The Interaction of Soluble Phospholipids with Coagulation Factor VIIa

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4421-4421
Author(s):  
Tanusree Sengupta ◽  
Rinku Majumder ◽  
Barry R. Lentz
Keyword(s):  
Conflicts Of Interest ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Current Data ◽  
Single Site ◽  
Coagulation Cascade ◽  
Site Model ◽  
Weak Site ◽  
Vitro Model

Abstract Abstract 4421 Factor VIIa (fVIIa) is one of the key proteins in the blood coagulation cascade. It activates factors IX and × on a negatively charged phospholipid surface in either a TF-dependent or TF-independent fashion (Silverberg et al, 1977; Bom et al, 1990). Monroe et al (1997) demonstrated that fVIIa binds to activated platelets independent of TF and partially restores thrombin generation in an in vitro model of hemophilia. Thus, it appears that interaction of fVIIa with platelet phospholipids plays an important role. We report that binding of 1,2-dihexanoyl-sn-glycero-3-phospholipids -L-serine (C6PS) and 1,2-dihexanoyl-sn-glycero-3-phosphoethanolamine (C6PE) to fVIIa causes changes in its activity as well as structure. Titration with C6PS led to changes in intrinsic fluorescence indicative of two or more binding sites for this lipid. Similar titrations with C6PE indicated that it probably binds to a single site on the protein. Experiments are underway to test this initial conclusion. Both lipids bind with comparable affinity (kd ~ 165 and 160 μ M) when data were analyzed using a single site model. We also examined the effect of the soluble lipids on the activity of fVIIa. Both C6PS and C6PE binding increased fVIIa proteolytic and amidolytic activity, with the effect of C6PS being more pronounced. Based on current data, it appears that both lipids bind to a single weak site, but that binding of either to this site promotes binding of C6PS to a second, tighter, and C6PS-specific site, which seems to be crucial in regulating activity. Further experiments are underway to test this hypothesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The relationship between tissue factor and cancer progression: insights from bench and bedside

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Yascha W. van den Berg ◽  
Susanne Osanto ◽  
Pieter H. Reitsma ◽  
Henri H. Versteeg
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Cancer Subtypes ◽  
Tumor Cell Behavior

Abstract It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.

scholarly journals Inhibition of human coagulation factor VIII by monoclonal antibodies. Mapping of functional epitopes with the use of recombinant factor VIII fragments

1989 ◽  
Vol 263 (1) ◽  
pp. 187-194 ◽  
Author(s):  
A Leyte ◽  
K Mertens ◽  
B Distel ◽  
R F Evers ◽  
M J M De Keyzer-Nellen ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Factor Viii ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Procoagulant Activity ◽  
Coagulation Factor Viii ◽  
Coagulation Cascade ◽  
Restriction Enzyme Digestion ◽  
Proteolytic Activation

The epitopes of four monoclonal antibodies against coagulation Factor VIII were mapped with the use of recombinant DNA techniques. Full-length Factor VIII cDNA and parts thereof were inserted into the vector pSP64, permitting transcription in vitro with the use of a promoter specific for SP6 RNA polymerase. Factor VIII DNA inserts were truncated from their 3′-ends by selective restriction-enzyme digestion and used as templates for ‘run-off’ mRNA synthesis. Translation in vitro with rabbit reticulocyte lysate provided defined radiolabelled Factor VIII fragments for immunoprecipitation studies. Two antibodies are shown to be directed against epitopes on the 90 kDa chain of Factor VIII, between residues 712 and 741. The 80 kDa chain appeared to contain the epitopes of the other two antibodies, within the sequences 1649-1778 and 1779-1840 respectively. The effect of antibody binding to these sequences was evaluated at two distinct levels within the coagulation cascade. Both Factor VIII procoagulant activity and Factor VIII cofactor function in Factor Xa generation were neutralized upon binding to the region 1779-1840. The antibodies recognizing the region 713-740 or 1649-1778, though interfering with Factor VIII procoagulant activity, did not inhibit in Factor Xa generation. These findings demonstrate that antibodies that virtually inhibit Factor VIII in coagulation in vitro are not necessarily directed against epitopes involved in Factor VIII cofactor function. Inhibition of procoagulant activity rather than of cofactor function itself may be explained by interference in proteolytic activation of Factor VIII. This hypothesis is in agreement with the localization of the epitopes in the proximity of thrombin-cleavage or Factor Xa-cleavage sites.

scholarly journals Management of the Bleeding Patient Receiving New Oral Anticoagulants: A Role for Prothrombin Complex Concentrates

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Lisa M. Baumann Kreuziger ◽  
Joseph C. Keenan ◽  
Colleen T. Morton ◽  
David J. Dries
Keyword(s):  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Oral Anticoagulants ◽  
New Oral Anticoagulants ◽  
Coagulation Cascade ◽  
Clotting Factors ◽  
Prothrombin Complex Concentrates ◽  
Clotting System ◽  
Clinical Trial Evidence

Ease of dosing and simplicity of monitoring make new oral anticoagulants an attractive therapy in a growing range of clinical conditions. However, newer oral anticoagulants interact with the coagulation cascade in different ways than traditional warfarin therapy. Replacement of clotting factors will not reverse the effects of dabigatran, rivaroxaban, or apixaban. Currently, antidotes for these drugs are not widely available. Fortunately, withholding the anticoagulant and dialysis are freqnently effective treatments, particularly with rivaroxaban and dabigatran. Emergent bleeding, however, requires utilization of Prothrombin Complex Concentrates (PCCs). PCCs, in addition to recombinant factor VIIa, are used to activate the clotting system to reverse the effects of the new oral anticoagulants. In cases of refractory or emergent bleeding, the recommended factor concentrate in our protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer an activated PCC (aPCC) [FELBA] due to reported benefit in human in vitro studies. Based on human clinical trial evidence, the 4-factor PCC (Kcentra) is suggested for patients with refractory rivaroxaban- or apixaban-associated hemorrhage. If bleeding continues, recombinant factor VIIa may be employed. With all of these new procoagulant agents, the risk of thrombosis associated with administration of factor concentrates must be weighed against the relative risk of hemorrhage.

scholarly journals A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

2007 ◽  
Vol 27 (3) ◽  
pp. 683-689 ◽  
Author(s):  
Geoffrey A. Allen ◽  
Egon Persson ◽  
Robert A. Campbell ◽  
Mirella Ezban ◽  
Ulla Hedner ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Vitro Model

Reversion of the Experimental Hemodilutional Coagulopathy Induced by Crystalloids and Colloids Using Different Coagulation Factor Concentrates

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4349-4349
Author(s):  
Carolina Caballo ◽  
Ana M Galan ◽  
Maribel Diaz-Ricart ◽  
Irene Lopez-Vilchez ◽  
Miguel Lozano ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Human Albumin ◽  
Massive Bleeding ◽  
Trauma Patients ◽  
Beneficial Effects ◽  
Ringer’S Lactate ◽  
The Impact

Abstract Abstract 4349 BACKGROUND: Massive bleeding and subsequent coagulopathy are responsible for 35% of deaths in trauma patients. Hemodilution during resuscitation may worsen the coagulopathy and perpetuate bleeding. STUDY DESIGN AND METHODS: Blood samples from healthy donors were diluted (30–60%) using crystalloids (saline, Ringer’s lactate, Plasmalyte™) or colloids (6%hydroxyethylstarch (HES130/0.4), 5% human albumin, and gelatin). The impact of hemodilution on platelet adhesion, thrombin generation (TG), and clot viscoelastic properties by thromboelastometry (TEM) was analyzed. Effects of fibrinogen (Fbn), prothrombin complex concentrates (PCCs), rFVIIa, or cryoprecipates (cryo) on hemodilution were also assessed. RESULTS: Hemodilution caused a significant decrease in platelet interaction that was not improved by the addition of any of the plasma derivatives. A decrease in TG and important alterations of TEM were also observed. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCCs and their combination with Fbn whereas rFVIIa only slightly accelerated it. Fbn restored the alterations of TEM caused by hemodilution including those more deeply altered by HES 130/0.4. The combination of Fbn with PCC or rFVIIa did not have an additional effect in TEM. Cryo significantly improved the alterations caused by hemodilution on TG and TEM parameters. Effects of cryo on TG disappeared after ultracentrifugation, suggesting that contaminating microvesicular material could account for this effect. CONCLUSION: Hemostatic alterations caused by hemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 seemed to exert a more deleterious effect on hemostasis. None of the concentrates improved platelet-mediated hemostasis, although they always showed variable beneficial effects on coagulation parameters. Our data indicate that PCC, rFVIIa and cryo enhance or accelerate thrombin generation. Fbn concentrates could be useful to preserve blood clotting abilities during fluid resuscitation of critically ill patients without exposing them to enhanced thrombin generation. Grants: PET(2008_0231), FIS(CP04-00112, PS09/00664), SAF2009-10365, RD06/0009 Disclosures: No relevant conflicts of interest to declare.

scholarly journals Augmented intrinsic activity of Factor VIIa by replacement of residues 305, 314, 337 and 374: evidence of two unique mutational mechanisms of activity enhancement

2004 ◽  
Vol 379 (2) ◽  
pp. 497-503 ◽  
Author(s):  
Egon PERSSON ◽  
Helle BAK ◽  
Anette ØSTERGAARD ◽  
Ole H. OLSEN
Keyword(s):  
Factor Viia ◽  
Coagulation Factor ◽  
Catalytic Efficiency ◽  
Peptide Bond ◽  
Intrinsic Activity ◽  
Factor X ◽  
In Vitro Characterization ◽  
Km Value ◽  
Structural Mechanisms

Coagulation Factor VIIa (FVIIa) lacks the ability to spontaneously complete the conversion to a fully active enzyme after specific cleavage of an internal peptide bond (Arg152–Ile153) in the zymogen. Recently, several variants of FVIIa with enhanced intrinsic activity have been constructed. The in vitro characterization of these variants has shed light on molecular determinants that put restrictions on FVIIa in favour of a zymogen-like conformation and warrants continued efforts. Here we describe a new FVIIa variant with high intrinsic activity containing the mutations Leu305→Val, Ser314→Glu, Lys337→Ala, and Phe374→Tyr. The variant, called FVIIaVEAY, processes a tripeptidyl substrate very efficiently because of an unprecedented, 5.5-fold lowering of the Km value. Together with a 4-fold higher substrate turnover rate this gives the variant a catalytic efficiency 22 times that of wild-type FVIIa, which is reflected in a considerably enhanced susceptibility to inhibition by antithrombin and other inhibitors. For instance, the affinity of FVIIaVEAY for the S1 probe and inhibitor p-aminobenzamidine is represented by an 8-fold lower Ki value compared with that of FVIIa. Activation of Factor X in solution occurs about 10 times faster with FVIIaVEAY than with FVIIa, due virtually exclusively to an increased kcat value. The high activity of FVIIaVEAY is not accompanied by an increased burial of the N-terminus of the protease domain. A comparison of the kinetic parameters and molecular properties of FVIIaVEAY with those of the previously described mutant V158D/E296V/M298Q-FVIIa (FVIIaIIa), and the locations of the substitutions in the two variants, reveals what appear to be two profoundly different structural mechanisms dictating improvements in enzymic performance.

scholarly journals An in Vitro Model of Differentiation of Memory B Cells Into Plasmablasts and Plasma Cells Including Detailed Phenotypic and Molecular Characterization.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1636-1636
Author(s):  
Michel Jourdan ◽  
Anouk Caraux ◽  
John De Vos ◽  
Geneviève Fiol ◽  
Marion Larroque ◽  
...  
Keyword(s):  
B Cells ◽  
In Vitro Model ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Memory B Cells ◽  
Vitro Model ◽  
Intermediate Cells

Abstract Abstract 1636 Poster Board I-662 Human plasma cells (PCs) and their precursors play an essential role in humoral immune response, but are rare and difficult to harvest. We report here i) the generation of human syndecan-1+ and immunoglobulin secreting PCs starting from memory B cells (MBCs) in a 3-step- and 10-day (D) culture, including a 6-fold cell amplification. ii) We report the detailed phenotypic and Affymetrix gene expression profiles of these in vitro PCs as well as of intermediate cells - activated B cells (actBCs) and plasmablasts (PBs) - compared to MBCs and bone marrow PCs, which is accessible through an open web ATLAS (http://amazonia.transcriptome.eu/). iii) We show this B cell to PC differentiation to involve IRF4 and AICDA expression in D4 actBCs, decrease of PAX5 and BCL6 expressions and increase in PRDM1 and XBP1 expressions in D7 PBs and D10 PCs. It involves downregulation of genes controlled by Pax5, induction of genes controlled by Blimp-1 and XBP1 (unfold protein response). iv) The phenotype of D10 PCs resembles that of peripheral blood PCs detected after immunization of healthy donors. This in vitro model will facilitate further studies in PC biology. It will likewise be helpful to study plasma-cell dyscrasias, including Multiple Myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Modulating the Antithrombin-Mediated in Vivo Clearance of Coagulation Factor VIIa

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4233-4233 ◽  
Author(s):  
Henrik Østergaard ◽  
Lene Hansen ◽  
Hermann Pelzer ◽  
Henrik Agersø ◽  
Anette A. Pedersen ◽  
...  
Keyword(s):  
Complex Formation ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Site Directed Mutagenesis ◽  
Wild Type ◽  
Sprague Dawley ◽  
Resistant Variant ◽  
Opposite Behavior

Abstract The short half-life of coagulation factor VIIa (FVIIa) in circulation is the result of elimination through multiple pathways of which inactivation by the plasma inhibitor antithrombin (AT) accounts for as much as 65% of the total clearance in humans. Remarkably, the rate of inhibition in vivo is about 30 times greater than the uncatalyzed rate of inhibition in vitro suggesting the presence of rate enhancing components in vivo (Agersø et al. (2011) J Thromb Haemost, 9:333-338). Prime candidates include endogenous heparin-like glycosaminoglycans (GAGs) potentiating the reactivity of antithrombin, or tissue factor (TF) which upon binding to FVIIa increases its susceptibility to inhibition. In the present study site-directed mutagenesis of FVIIa was undertaken to identify variants with altered AT reactivity in order to explore the relationship between the reactivity of FVIIa with AT in vitro and in vivo as well as the nature of endogenous rate enhancing components. The pharmacokinetic properties of FVIIa variants were determined in Sprague Dawley rats as this model recapitulates the aspects of AT-mediated FVIIa clearance observed in humans and allows for interaction of human FVIIa with endogenous rat TF. Similar to the human situation, inactivation of wild-type FVIIa in rat is evident as an accumulation of circulating FVIIa-AT complexes and a progressive divergence of the pharmacokinetic profiles representing FVIIa clot activity and total FVIIa antigen. Initially, the ability to modulate the in vivo complex formation with AT was investigated using two FVIIa variants exhibiting enhanced (>200%) or reduced (<10%) in vitro reactivity with AT, respectively, regardless of the type of cofactor present. Reflecting the in vitro reactivity, clot activity and antigen PK profiles in rats were found to coincide for the AT resistant variant along with essentially no detectable AT complex formation, whereas exacerbated AT complex formation and clot activity:antigen discrepancy was observed for the variant exhibiting enhanced in vitro reactivity. Interestingly, among the generated FVIIa variants with altered AT reactivity, two subsets were identified that displayed differential in vitro reactivity with AT depending on the type cofactor present. Accordingly, one group exhibited a greater susceptibility to inhibition relative to wild-type FVIIa in the presence of heparin but not in the presence of TF, while the other group demonstrated the opposite behavior. Endowed with the ability to report on the cofactor identity from the rate of inhibition relative to wild-type FVIIa, variants from each group were tested for their tendency to accumulate as complexes with AT following intravenous administration to rats. Supporting a contribution from endogenous GAGs to the in vivo inactivation of FVIIa, the measured in vivo peak levels of accumulated FVIIa-AT complexes were found to directly correlate with the in vitro rate constants determined for the variants in the presence of heparin, but not when the cofactor was TF or the combination of TF and heparin. Altogether, these results 1) demonstrate a direct relationship between the in vitro reactivity of FVIIa with AT in the presence of heparin and the clearance of FVIIa through this pathway in vivo, and 2) identify heparin-like GAGs as the likely rate enhancing component of FVIIa inhibition in vivo. Disclosures Østergaard: Novo Nordisk A/S: Employment. Hansen:Novo Nordisk A/S: Employment. Pelzer:Novo Nordisk A/S: Employment. Agersø:Novo Nordisk A/S: Employment. Pedersen:Novo Nordisk A/S: Employment. Glue:Novo Nordisk A/S: Employment. Johnsen:Novo Nordisk A/S: Employment. Andersen:Novo Nordisk A/S: Employment. Bjelke:Novo Nordisk A/S: Employment. Breinholt:Novo Nordisk A/S: Employment. Stennicke:Novo Nordisk A/S: Employment. Gandhi:Novo Nordisk A/S: Employment. Olsen:Novo Nordisk A/S: Employment. Hermit:Novo Nordisk A/S: Employment.

scholarly journals Bacteremia, Not Coagulation Proteases Contribute to In Vivo Complement Activation in Sepsis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 275-275
Author(s):  
Ravi Shankar Keshari ◽  
Robert Silasi-Mansat ◽  
Cristina Lupu ◽  
Fletcher B. Taylor ◽  
Florea Lupu
Keyword(s):  
Complement Activation ◽  
Time Course ◽  
Conflicts Of Interest ◽  
Coagulation Cascade ◽  
Activation Markers ◽  
E Coli ◽  
Complement Proteins ◽  
Direct Activation

Abstract Bacterial sepsis induces strong activation of coagulation, complement and fibrinolytic systems that contribute to disseminated intravascular coagulation, organ damage and death. While the contact of the blood with pathogens or pathogen-associated molecular patterns (PAMPs) can trigger the activation of both systems, a bidirectional complement-coagulation crosstalk is believed to occur. Although the role of complement activation products as positive regulators of coagulation is documented, direct activation of the complement proteins by thrombin or other hemostatic proteases was alluded but not demonstrated in vivo. Here we aimed to: (i) determine if in vivo generation of thrombin and other hemostatic proteases can activate the complement proteins and (ii) discriminate between the direct effect of the pathogen/PAMPs vs. hemostatic proteases on complement activation in a clinically relevant model of sepsis. We have compared the time-course of complement activation markers (C3b, C5a and C5b-9 terminal complex) in plasma of baboons exposed to 1010 cfu/kg (LD100) E. coli vs. intravenous infusion of factor Xa/PC:PS, a potent procoagulant stimulus. In baboons challenged with LD100 E. coli, complement activation markers C3b, C5a and C5b-9 reached maximum levels after 2 hrs (see figure). Complement activation coincided with the peak of bacteremia and LPS, but not with markers of thrombin generation (TAT and fibrinogen consumption; see figure) or fibrinolysis (FDP, D-dimers), which reached peak levels after 6 hours. Differently, infusion of FXa/PC:PS (36.6 pmol/L FXa and 56.3 nmol/L PC/PS per kg body weight) induced a rapid burst of thrombin and almost full consumption of fibrinogen during the first 10 min post-infusion, with no increase of complement activation markers. Based on these data we conclude that in vivo activation of the coagulation cascade does not support complement activation as was postulated by previous in vitro studies. Therefore, we conclude that pathogens and PAMPs are the main activators of the complement during sepsis while direct activation by hemostatic proteases is minor or absent. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Infantile Hemangioma: A Tumor Involving Hemogenic Endothelium with Erythropoetic Potential

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4305-4305
Author(s):  
Tinte Itinteang ◽  
Anasuya Vishvanath ◽  
Helen D Brasch ◽  
Darren J Day ◽  
Swee T Tan
Keyword(s):  
Conflicts Of Interest ◽  
Infantile Hemangioma ◽  
Erythropoietin Receptor ◽  
Specific Cell ◽  
Hemogenic Endothelium ◽  
Qrt Pcr ◽  
Associated Proteins ◽  
Mesodermal Origin ◽  
Vitro Model

Abstract Abstract 4305 Background Infantile hemangioma (IH) is a tumor of the microvasculature predominantly composed of proliferating endothelial cells, but also contains progenitor cells of mesenchymal and hematopoietic lineages. We have previously shown that IH has a primitive mesodermal origin. Here we investigated expression of hematopoietic associated proteins (Tal-1, GATA-2, CD133 & CD34) as well as the erythropoietin receptor (EPOR) and the embryonically-associated hemoglobin zeta chain (HBZ) by both the cells of the endothelium and the cells emanating from proliferating IH explants. Additionally we investigated if the cells emanating from the explants generate erythrocytes in vitro. Purpose To investigate the expression of hematopoietic associated proteins and the primitive erythropoietic capacity of proliferating IH. Methods Proliferating IH biopsies from 5 patients were (i) processed for IHC staining for Tal-1, GATA-2, CD133, CD34, HBZ and EPOR; (ii) used to determine the relative expression of Tal-1, GATA-2, CD133, CD34, HBZ & EPOR transcripts by qRT-PCR; (ii) cultured as explants using our in vitro model and differentiated the cells down the erythropoietic lineage. Results IHC showed that the cells that line the endothelium forming the capillaries of proliferating IH expressed Tal-1, GATA-2, CD133, CD34, HBZ and EPOR. qRT-PCR confirmed the IHC data as abundant expression mRNA transcripts for the same proteins was detected in both the tissue and the cells emanating from the cultured explants. Following 5 months in culture morphological biconcave cells were visible, and were confirmed to be erythrocytes by immunoreactivity to the erythrocyte-specific cell surface marker glycophorin A. Conclusion The mRNA and protein expression of hematopoietic associated proteins in proliferating IH supports our previous studies showing this tumor expressing markers of primitive mesoderm and confirms a hemogenic endothelium phenotype. The expression of the primitive erythropoiesis-associated proteins HBZ and EPOR by proliferating IH and its functional ability of proliferating IH explants to form erythrocytes in vitro confirms the erythropoietic potential. Proliferating IH thus represents an extra-medullary site of tumor-associated erythropoiesis. Disclosures: No relevant conflicts of interest to declare.

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