Heparanase Activation of the Coagulation System in a Mice Sepsis Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 378-378
Author(s):  
Israel Henig ◽  
Elena Axelman ◽  
Benjamin Brenner ◽  
Israel Vlodavsky ◽  
Yona Nadir
Keyword(s):  
Tumor Metastasis ◽  
Conflicts Of Interest ◽  
Factor Xa ◽  
Factor Vii ◽  
Coagulation System ◽  
Knock Out ◽  
Over Expression ◽  
Plasma Factor ◽  
Knock Out Mice ◽  
D Dimer

Abstract Abstract 378 Background: Heparanase that is abundant in platelets and neutrophils is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is directly involved in the regulation of the hemostatic system. Heparanase was shown to form a complex and enhance tissue factor (TF) activity, resulting in increased factor Xa production (Nadir et al, Haematologica, 2010). In the present study, the effect of heparanase on sepsis was investigated. Methods: ICR mice, heparanase knock-out mice and heparanase over-expression mice were studied. Sepsis was induced by intra-peritoneal injection of lipopolysaccharides (LPS). Four hours after injection, blood was obtained via temple plexus puncture followed by mice sacrificing. Levels of thrombin-antithrombin (TAT), D-Dimer and IL-6 were tested using ELISA. Plasma factor VII levels were evaluated using the Western blot analysis and fibrinogen levels in the lung, kidney and spleen were estimated by immunostaining. Results: Intra-peritoneal injection of heparanase (0.5μg/mg) compared to PBS injection, increased the TAT (p<0.05) and D-Dimer (p<0.05) levels, which were similar to the ones induced by LPS (5μg/mg), although the IL-6 levels did not rise and mice did not show signs of illness. Moreover, heparanase injection half an hour following LPS administration resulted in reduced levels of TAT, D-Dimer, fibrinogen and of factor VII (p<0.001), increased levels of IL-1 (p<0.001) and profuse blood leak from puncture, compatible with severe disseminated intravascular coagulation (DIC). Similarly, injection of LPS to heparanase knock-out mice led to lower levels of TAT (p<0.001), D-Dimer (p<0.001) and IL-6 (p<0.001) compared to control mice, while injection of LPS to heparanase over-expression mice resulted in DIC. Conclusions: Heparanase is found to induce activation of the coagulation system without inflammatory response. It also contributes to laboratory enhancement of sepsis resulting in DIC. Inhibitors of heparanase may potentially attenuate morbidity and mortality in sepsis. Disclosures: No relevant conflicts of interest to declare.

The Effect of Antithrombin III on the Activity of the Coagulation Factors VII, IX and X

1976 ◽  
Vol 35 (02) ◽  
pp. 295-304 ◽  
Author(s):  
B Østerud ◽  
M Miller-Andersson ◽  
U Abildgaard ◽  
H Prydz
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Disc Electrophoresis ◽  
Polyacrylamide Gel ◽  
Factor Vii ◽  
Native Form ◽  
Factor Ixa ◽  
Plasma Factor

SummaryAntithrombin III, purified to homogeneity according to Polyacrylamide gel disc electrophoresis and immunoelectrophoresis, inhibited the activity of purified factor IXa and Xa, whereas factor VII was not inhibited either in the active or in the native form.Antithrombin III is the single most important inhibitor of factor Xa in plasma. Factor Xa does not, however, reduce the activity of antithrombin III against thrombin.

scholarly journals The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 335-343 ◽  
Author(s):  
GJ Jr Broze ◽  
LA Warren ◽  
WF Novotny ◽  
DA Higuchi ◽  
JJ Girard ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Antithrombin Iii ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Factor Xa ◽  
Factor Vii ◽  
Diisopropyl Fluorophosphate ◽  
Plasma Factor ◽  
Coagulation Inhibitor ◽  
Catalytically Active

Abstract Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. Progressive inhibition of TF activity occurs upon its addition to plasma. This process is reversible and requires the presence of VII(a), catalytically active Xa, Ca2+, and another component that appears to be associated with the lipoproteins in plasma, a lipoprotein-associated coagulation inhibitor (LACI). A protein, LACI(HG2), possessing the same inhibitory properties as LACI, has recently been isolated from the conditioned media of cultured human liver cells (HepG2). Rabbit antisera raised against a synthetic peptide based on the N-terminal sequence of LACI(HG2) and purified IgG from a rabbit immunized with intact LACI(HG2) inhibit the LACI activity in human serum. In a reaction mixture containing VIIa, Xa, Ca2+, and purified LACI(HG2), the apparent half-life (t1/2) for TF activity was 20 seconds. The presence of heparin accelerated the initial rate of inhibition threefold. Antithrombin III alpha alone had no effect, but antithrombin III alpha with heparin abrogated the TF inhibition. LACI(HG2) also inhibited Xa with an apparent t1/2 of 50 seconds. Heparin enhanced the rate of Xa inhibition 2.5-fold, whereas phospholipids and Ca2+ slowed the reaction 2.5-fold. Xa inhibition was demonstrable with both chromogenic substrate (S-2222) and bioassays, but no complex between Xa and LACI(HG2) could be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Nondenaturing PAGE, however, showed that LACI(HG2) bound to Xa but not to X or Xa inactivated by diisopropyl fluorophosphate. Thus, LACI(HG2) appears to bind to Xa at or near its active site. Bovine factor Xa lacking its gamma-carboxyglutamic acid-containing domain, BXa(-GD), through treatment with alpha-chymotrypsin, was used to further investigate the Xa requirement for VIIa/TF inhibition by LACI(HG2). LACI(HG2) bound to BXa(-GD) and inhibited its catalytic activity against a small molecular substrate (Spectrozyme Xa), though at a rate approximately sevenfold slower than native BXa. Preincubation of LACI(HG2) with saturating concentrations of BXa(-GD) markedly retarded the subsequent inhibition of BXa. The VII(a)/TF complex was not inhibited by LACI(HG2) in the presence of BXa(-GD), and further, preincubation of LACI(HG2) with BXa(-GD) slowed the inhibition of VIIa/TF after the addition of native Xa. The results are consistent with the hypothesis that inhibition of VII(a)/TF involves the formation of a VIIa-TF-XA-LACI complex that requires the GD of XA.(ABSTRACT TRUNCATED AT 400 WORDS).

Contribution of Lipocalin-2 from Both Myeloid Cells and Epithelium/Liver Is Required for Optimal Resistance to K. Pneumonia Infection

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 883-883
Author(s):  
Elisabeth Præstekjær Cramer ◽  
Sara Louise Dahl ◽  
Björn Rozell ◽  
Kasper Jermiin Knudsen ◽  
Kim Thomsen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Epithelial Cells ◽  
Conflicts Of Interest ◽  
Neutrophil Migration ◽  
Myeloid Cells ◽  
Infection Model ◽  
Lipocalin 2 ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice

Abstract Introduction NGAL/lipocalin-2 is a siderophore-binding protein stored in high amounts in specific granules of neutrophils. In addition, expression and constitutive secretion of lipocalin-2 can be induced in macrophages and epithelial cells under inflammatory conditions. In mice, lipocalin-2 is furthermore an acute phase-protein. Siderophores are the strongest iron chelators known and are produced by certain microorganisms to retrieve soluble iron from the host. By preventing uptake of siderophore bound iron, lipocalin-2 is bacteriostatic to bacteria that are dependent on this mechanism for uptake of iron. In accordance, lipocalin-2 knock-out mice are susceptible to infection by such bacteria. It is, however, not known whether it is the induced production of lipocalin-2 in epithelial cells and liver or the delivery of lipocalin-2 from infiltrating myeloid cells (neutrophils and macrophages) that is most important for these mechanisms of host defense against invading pathogens. Methods To study the contributions of lipocalin-2 from epithelial cells and liver compared to infiltrating myeloid cells, we used a Klebsiella pneumoniae lung infection model in C57BL/6 mice with chimeric expression of lipocalin-2. Bone marrow transplantation of lethally irradiated mice generated wild type-mice with a lipocalin-2 knock-out bone marrow (WT/KO) expressing lipocalin-2 in epithelium and liver but not in myeloid cells, and conversely knock out-mice with wild-type bone marrow (KO/WT) expressing lipocalin-2 in myeloid cells and not in epithelium and liver. Wild-type mice transplanted with wild-type bone marrow (WT/WT) and knock-out mice transplanted with knock-out bone marrow (KO/KO) were also generated. After 7 weeks of reconstitution, mice were nasally challenged with K. pneumoniae for induction of pneumonia and potential dissemination of the infection. The mice were sacrificed twenty-four hours after inoculation and examined. Results Lipocalin-2 levels in broncho alveolar lavage (BAL) fluid were comparable between WT/KO and KO/WT mice. Consistent with this, no difference in bacterial counts (CFU) in BAL fluid was seen. No differences in spleen CFUs were evident between the two chimeric subgroups WT/KO and KO/WT despite a quantitatively larger mean lipocalin-2 plasma level in WT/KO mice (almost 50 times) derived from epithelium and liver compared to the contribution from myeloid cells in KO/WT mice. However, mean CFU in spleen homogenates from KO/KO mice were more than 870 times higher compared to WT/WT mice. Both the lipocalin-2 contribution from myeloid cells and from epithelium and liver appeared to be indispensable judged by the higher spleen CFUs in mice lacking lipocalin-2 from either of the two compartments. Lipocalin-2 mRNA in the liver was present in equal amounts in mice with wild-type background despite the presence or absence of lipocalin-2 in the myeloid cells. No differences in neutrophil influx to the lungs were seen between groups as determined by MPO ELISA on lung homogenates. We conclude that lipocalin-2 derived both from myeloid cells and from epithelium and liver is required for full resistance to a siderophore-producing pathogen. Despite the higher levels of plasma lipocalin-2 in WT/KO mice compared to KO/WT mice, their bacteriostatic capacity is equal. The induction of lipocalin-2 in the liver is not dependent on the presence of lipocalin-2 in the myeloid cells, just as the migration of neutrophils to the infected lung is not, thus refuting a recent report that lipocalin-2 affects neutrophil migration. Disclosures No relevant conflicts of interest to declare.

Lyso-Sulfatide Binds Factor Xa and Potently Inhibits Thrombin Generation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1130-1130
Author(s):  
Subramanian Yegneswaran ◽  
Yajnavalka Banerjee ◽  
Jose A. Fernandez ◽  
Hiroshi Deguchi ◽  
John H. Griffin
Keyword(s):  
Free Amino ◽  
Conflicts Of Interest ◽  
Factor Xa ◽  
Coagulation System ◽  
Amino Group ◽  
Thrombin Time ◽  
Binding Studies ◽  
Binding Interaction ◽  
Dependent Inhibition ◽  
Gla Domain

Abstract Abstract 1130 Although phospholipids are well-recognized for their effects on coagulation reactions, little is generally known about the effects of sphingolipids on clotting pathways. Negatively-charged sulfatides can potently initiate the intrinsic pathway of coagulation system by binding and autoactivating factor (f) XII. Sphingosine potently inhibits the ability of factor Xa (fXa) to generate thrombin (fIIa) in the prothrombinase complex (II-ase) (fXa/fVa/phospholipids) by interacting directly with fXa's Gla domain. Here we report that lyso-sulfatide (lyso-SF) (sulfogalactosyl sphingosine), a lipid of minor abundance in plasma that is primarily in HDL particles, exhibits potent anticoagulant activity. Lyso-SF dose-dependently prolonged clotting in fXa-1-stage but not thrombin-time clotting assays. Lyso-SF inhibited II-ase activity by > 90 % in purified reaction mixtures (fXa/fVa/II) in the presence of 6 or 30 μM phospholipids (PL). However, lyso-SF did not inhibit fIIa generation by fXa/fVa in the absence of PL, suggesting the absolute requirement of PL for lyso-SF-dependent inhibition of fIIa generation. Lyso-SF inhibited fIIa generation by fXa/PL in the absence of fVa. Additionally, lyso-SF inhibited fIIa generation by Gla-domainless (gd)-fXa in the presence but not in the absence of fVa and PL. Lyso-SF-dependent inhibition of fIIa generation was also observed for fXa/fVa/PL when gd-II was used as the substrate instead of II. However, no inhibition by lyso-SF was observed when using gd-fXa/PL and gd-II/PL in the presence or absence of fVa. Lyso-SF had no effect on fXa or fIIa amidolytic activity. These data plus other studies suggested that ≥ two components of the II-ase complex needed to be PL-bound for potent inhibition of fIIa generation by lyso-SF. PL surfaces bind and assemble each the II-ase protein components; however, PL's and lyso-SF may also alter the conformations of fXa, fVa and II. To gain mechanistic insights for lyso-SF inhibition of II-ase activity, Surface Plasmon Resonance (SPR) and fluorescence spectroscopy were used to define molecular interactions. Remarkably, SPR binding studies showed that lyso-SF binds to immobilized fXa (KD = 83 μM) and gd-fXa (KD = 36 μM). Controls using SPR showed no binding of lyso-SF to immobilized fVIIa or fIXa whereas SPR confirmed the ability of fXa, fVIIa and fIXa to bind PL's. Fluorescence binding assays confirmed SPR data showing that lyso-SF bound to and altered the dansyl fluorescence of dansyl-GluGlyArg-labeled fXa (DEGR-fXa) both in the presence (KD = 50 μM) and absence (KD = 75 μM) of PL and that this binding required calcium ions. Thus, lyso-SF binds fXa outside the Gla domain. Fluorescence monitoring of fVa binding to DEGR-fXa in the presence of PL showed that lyso-SF inhibited this binding interaction. To characterize structure-activity relationships for lyso-SF inhibition of II-ase, different analogs of lyso-SF were tested for their ability to inhibit fIIa generation by gd-fXa/fVa/PL. Psychosine (galactosyl sphingosine), glucosyl sphingosine and lyso-sphingomyelin each inhibited fIIa generation showing that the sulfate ester moiety and the sugar group in lyso-SF were not essential for the anticoagulant effects of lyso-SF. However, acetylation of the free amino group in lyso-SF ablated its inhibition of fIIa generation showing that the free amino group on carbon 2 is essential for the inhibitory activity of lyso-SF. In conclusion, these findings show that lyso-SF and several of its analogs are potent anticoagulant lipids and that the mechanism for inhibition of fXa by lyso-SF may involve its binding to fXa at sites outside fXa's Gla domain. This suggests that certain sphingolipids may exert allosteric downregulation of fXa activity without inhibiting the enzyme's active site or the binding of the Gla domain to PL surfaces. Disclosures: No relevant conflicts of interest to declare.

Transcriptional Regulation of Transferrin Receptor by Heme in Erythroid Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2049-2049
Author(s):  
Matthias Schranzhofer ◽  
Nam-Chun Lok ◽  
Manfred Schifrer ◽  
Ernst W Muellner ◽  
Prem Ponka
Keyword(s):  
Mrna Stability ◽  
Aminolevulinic Acid ◽  
Conflicts Of Interest ◽  
Erythroid Cells ◽  
Knock Out ◽  
Iron Regulatory Proteins ◽  
Iron Incorporation ◽  
Knock Out Mice ◽  
Feedback Regulator ◽  
In Erythroid Cells

Abstract Abstract 2049 Erythroid cells are the largest consumers of iron which is delivered to them by tansferrin (Tf) by its cognate receptor (TfR). In contrast to other cells, developing red blood cells (RBC) regulate TfR expression not only at the level of mRNA stability via the iron regulatory proteins (IRP) 1 and 2, but also by transcription (Lok & Ponka, J Biol Chem 275:24185-90, 2000). Here we provide evidence that TfR expression and cellular uptake of iron from Tf is stimulated by enhanced heme synthesis. Incubation of erythroid cells with 5-aminolevulinic acid (ALA) increased TfR expression accompanied by increased iron incorporation into heme. This effect of ALA can be completely prevented by the inhibitors of heme biosynthesis (succinylacetone [blocks ALA dehydratase] or N-methylprotoporphyrin [blocks ferrochelatase]), indicating that the effect of ALA requires its metabolism to heme. The induction of TfR mRNA expression by ALA is mainly a result of increased mRNA synthesis since the effect of ALA can be abolished by actinomycin D. Recently, IRP2 was proposed to play a role in maintaining TfR mRNA stability in developing RBC (Cooperman et al., Blood 106:1084-91; 2005; Galy et al., Blood 106:2580-9, 2005). Importantly, we have demonstrated that ALA added to cultures of erythroid cells derived from IRP2 knock out mice restores the expression of TfR to levels observed in cells obtained from wild type mice. In conclusion, our results indicate that in erythroid cells heme serves as a positive feedback regulator that maintains high TfR levels thus ensuring adequate iron availability for hemoglobin synthesis. Disclosures: No relevant conflicts of interest to declare.

Oncogenic Regulation of Tissue Factor Expression

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-16-SCI-16
Author(s):  
Janusz W. Rak ◽  
Nathalie Magnus ◽  
Delphine Garnier ◽  
Esterina D’Asti ◽  
Maryam Hashemi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tissue Factor ◽  
Conflicts Of Interest ◽  
Ectopic Expression ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Coagulation System ◽  
Signaling Proteins ◽  
Mesenchymal Transition ◽  
Oncogenic Mutations

Abstract Abstract SCI-16 Coagulation system plays a long-recognized role in cancer progression and in the related morbidity and mortality (1, 2). Once regarded as an unspecific epiphenomenon of the underlying disease, this involvement is now viewed as a direct consequence of oncogenic mutations and the resulting acquisition of the procoagulant phenotype by cancer cells followed by local and systemic vascular consequences (Trousseau syndrome) (3). Tissue factor (TF) represents an illuminating molecular paradigm of these changes, acting as both the central regulator of the coagulation system circuitry and an emerging regulatory target of several oncogenic lesions. Thus, oncogene-driven TF upregulation has been documented in a wide spectrum of human cancer cells, including: colorectal (CRC), lung, breast, and skin cancer, as well as glioblastoma (GBM), medulloblastoma (MB), and hematopoietic malignancies. This is linked to activation of several dominant acting oncogenes, such as: K-ras, epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), HER-2, MET, retinoid acid receptor (RAR), and several others (4). These effects are also enabled and amplified by losses of tumor suppressor genes, such as p53 and PTEN, and modulated by microRNA (miR) networks, as well as microenvironmental and regulatory factors, such as hypoxia, inflammation, differentiation, and epithelial-to-mesenchymal transition (EMT) (5). In addition, oncogenic mutations activate several mechanisms that may sensitize cancer cells to extracellular stimuli, including the exposure to circulating coagulation factors that may access cancer cells through leaky tumor blood vessels. For instance, the expression of EGFRvIII in human GBM cells leads not only to a dramatic increase in TF levels, but also to the ectopic expression of coagulation factor VII, the main TF ligand. Simultaneously, oncogenic events (e.g., EGFRvIII or K-ras) induce marked upregulation of protease activated receptors 1 and 2 (PAR1/2), which further enhance the transmission of intracellular signals from the TF/FVIIa complex (6). Furthermore, oncogenes provoke cellular vesiculation whereby TF and other signaling proteins (including oncoproteins themselves) are released into the extracellular space and to the systemic circulation. As a result, these signaling proteins may be transferred to other cells, and modify their properties locally, regionally, and systemically (4, 7). These changes are a part of the signaling network that affects tumor growth, invasion, and metastasis, and acts through generation of a procoagulant, proinflammatory, and pro-angiogenic microenvironment, which contain niches for tumor-initiating cells (TICs). TICs (cancer stem cells) are key targets for oncogenic transformation and essential drivers of the malignant process. Their responses to the coagulation system may be altered by changes in TF and PAR status. TF targeting through genetic and pharmacological approaches results in impaired tumor initiation and growth in various experimental settings, including in transgenic models of GBM. In some instances host cell-associated TF may also play a role in disease progression, while in other cases tumor stroma and inflammatory cells are modulated indirectly by TF-expressing cancer cells (7). Collectively, oncogene-dependent deregulation of TF and activation of the coagulation system circuitry represents a unique biological effector mechanism, which likely promotes progression of human cancers, and thereby may serve as a potential therapeutic target. Disclosures: No relevant conflicts of interest to declare.

Essential Role of the Transcription Factor ZBP-89 in Lymphopoiesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 277-277
Author(s):  
Andrew J. Woo ◽  
Hui Huang ◽  
Taylor Piers ◽  
Alan B Cantor
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Transcription Factor ◽  
Conflicts Of Interest ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Chimeric Mouse ◽  
Knock Out ◽  
Erythroid Maturation ◽  
Knock Out Mice

Abstract Abstract 277 We previously identified the Krüppel-type zinc finger transcription factor ZBP-89 (also called zfp148) as a novel GATA1 associated protein in erythroid and megakaryocytic cells. ZBP-89 also associates with other GATA family members such as GATA2 and GATA3, Friend of GATA (FOG) cofactors, and RUNX1. It is ubiquitously expressed, but has high-level expression in a subset of tissues including thymus, spleen, bone marrow, lung and brain. Our prior studies using morpholino knockdown in zebrafish, in vitro differentiation and chimeric mouse analysis of ZBP-89 genetrap embryonic stem cells, and lentiviral shRNA knock down in primary human CD34+ cells demonstrated a functional role for ZBP-89 in erythroid and megakaryocyte maturation. In this study, we generated conditional knock out mice to further examine the requirements for ZBP-89 in vivo. On a mixed strain background, full ZBP-89 knock out mice were born at close to Mendelian ratios. However, the ZBP-89−/− mice were severely runted and had increased mortality over the first 30 days of life. Surviving pups had significant growth failure, but eventually matched their wild type and heterozygous littermates by about 6 weeks of age. Analysis of erythroid maturation in bone marrow and spleen using flow cytometry for CD71 and Ter119 demonstrated impaired erythroid maturation in a ZBP-89 allele-dose dependent manner. On a pure C57BL/6 genetic background, nearly 100% of the ZBP-89−/− mice died within the first 10 days of life from unclear causes. ZBP-89fl/fl, Mx1-Cre mice developed lymphopenia and platelet abnormalities following activation of Cre by polyI-polyC injection. The lymphopenia was due to reduction in both B and T cells. Further delineation of the T-cell defect using ZBP-89fl/fl, Lck-Cre mice demonstrated impaired maturation of double negative (CD4−CD8−) T cells at the DN3 (CD25+ CD44−) to DN4 (CD25−CD44−) stages in thymi from 5–6 week old mice. These findings indicate that ZBP-89 plays functional roles in multiple hematopoietic lineages. Moreover, they identify ZBP-89 as a novel transcriptional regulator of lymphocyte development. We speculate that this latter role involves its known interactions with GATA3, FOG-1, and/or RUNX1, which are all similarly involved in lymphopoiesis. We also show that the ZBP-89 family member ZBP-99 is highly expressed in thymus and other hematopoietic tissues, and may therefore play partially overlapping roles with ZBP-89. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Longitudinal Study of the Relationships between Haemostatic, Lipid, and Oestradiol Changes during Normal Human Pregnancy

1999 ◽  
Vol 81 (01) ◽  
pp. 71-75 ◽  
Author(s):  
Ian Greer ◽  
Ann Rumley ◽  
Grace Stewart ◽  
James Shepherd ◽  
Chris Packard ◽  
...  
Keyword(s):  
Blood Lipids ◽  
Plasma Cholesterol ◽  
Normal Pregnancy ◽  
Factor Vii ◽  
Fasting Serum ◽  
Plasma Factor ◽  
Normal Human ◽  
Haemostatic Factors ◽  
D Dimer ◽  
Coagulation And Fibrinolysis

SummaryIncreased activation of both blood coagulation and fibrinolysis occurs during normal pregnancy. The responsible mechanisms are unclear, but may include increases in both oestradiol and blood lipids. We, therefore, studied the associations between fasting serum oestradiol, plasma cholesterol and triglyceride, and Factor VII activity, PAI activity, t-PA antigen, fibrin D-dimer, and vWF antigen in 10 women, each sampled on 6 occasions between 10 weeks and 35 weeks during normal pregnancy. Strong and similar individual correlations were observed between increases in FVII, PAI, t-PA and D-dimer (but not vWF) and increases in both oestradiol and triglyceride. Associations between increments in plasma cholesterol and haemostatic factors (except for FVII), were somewhat weaker. We, therefore, suggest that oestradiol-induced hypertriglyceridaemia may be a cause of elevations in plasma Factor VII activity, PAI and t-PA, and fibrin turnover (D-dimer) during normal pregnancy, but is poorly related to the increase in vWF antigen.

scholarly journals TGF-B Inhibition Rescues Hematopoietic Defects in Fanconi Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-29-SCI-29
Author(s):  
Joel S Greenberger
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Conflicts Of Interest ◽  
Radiation Sensitivity ◽  
Mouse Strains ◽  
Knock Out ◽  
Bone Marrow Cultures ◽  
Knock Out Mice ◽  
The Individual

Abstract Four different combinations of double knock-out mouse strains have been created (SMAD3-/- Fancd2-/-) consisting of combinations of the individual knock-out strains on either the C57BL/6 or 129/Sv background. Sets of breeding experiments were carried out and the frequency of detection of double knock-out mice was significantly below the expected frequency of detecting DKO mice by breeding double heterozygotes (1 out of 16 or 6.25%). In fact, DKO mice were detected at a frequency ranging from 3.4% to 0.54%. Mice of all four DKO genotypes showed resistance of bone marrow hematopoietic progenitor cells to canonical TGF-β signaling, consistent with the SMAD3-/- parent. However, the predominant phenotype was that of the Fancd2-/- parent including reduced duration of hematopoiesis in long-term bone marrow cultures, reduced marrow stem cell competitive repopulation capacity, and retained mitomycin C and radiation sensitivity of bone marrow stromal cells. These mice should be a valuable resource for elucidating the bypass pathways involved in the reduced, but successful gestation of SMAD3-/- Fancd2-/- mice, and the interactions of the FA and TGF-β signaling pathways. Supported by the NIAID/NIH U19-A168021 and the Fanconi Anemia Research Fund. Disclosures No relevant conflicts of interest to declare.

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