Publications
68 results found
Santamaria S, Crawley JTB, Yamamoto K, et al., 2017, A comparison of COMP (TSP5) proteolysis by ADAMTS7 and ADAMTS4, Autumn Meeting of the British-Society-for-Matrix-Biology (BSMB), Publisher: WILEY, Pages: A3-A4, ISSN: 0959-9673
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- Citations: 2
Santamaria S, Reglińska-Matveyev N, Gierula M, et al., 2017, Factor V anticoagulant cofactor activity that targets the early phase of coagulation, Journal of Biological Chemistry, Vol: 292, Pages: 9335-9344, ISSN: 0021-9258
Tissue factor pathway inhibitor (TFPI), the main inhibitor of initiation of coagulation, exerts an important anticoagulant role through the factor Xa (FXa)-dependent inhibition of tissue factor/factor VIIa (FVIIa). Protein S is a TFPI cofactor, enhancing the efficiency of FXa inhibition. TFPI can also inhibit prothrombinase assembly by directly interacting with coagulation factor V (FV) which has been activated by FXa. Since full-length TFPI associates with FV in plasma, we hypothesized that FV may influence TFPI inhibitory function. Using pure component FXa inhibition assays, we found that while FV alone did not influence TFPI-mediated FXa inhibition, it further enhanced TFPI in the presence of protein S, resulting in an ~8-fold reduction in Ki compared with TFPI alone. A FV variant (R709Q/R1018Q/R1545Q, FVΔIIa) that cannot be cleaved/activated by thrombin or FXa, also enhanced TFPI-mediated inhibition of FXa ~12-fold in the presence of protein S. In contrast, neither activated FV (FVa) nor recombinant B-domain-deleted FV could enhance TFPI-mediated inhibition of FXa in the presence of protein S, suggesting a functional contribution of the B domain. Using TFPI and protein S variants we show further that the enhancement of TFPI-mediated FXa inhibition by protein S and FV depends on a direct protein S/TFPI interaction and that the TFPI C-terminal tail is not essential for this enhancement. In FXa-catalyzed prothrombin activation assays, both FV and FVΔIIa (but not FVa) enhanced TFPI function in the presence of protein S. These results demonstrate a new anticoagulant (cofactor) function of FV that targets the early phase of coagulation before prothrombinase assembly.
Khan E, Ambrose N, Ahnstrom J, et al., 2016, A low balance between microparticles expressing tissue factor pathway inhibitor and tissue factor is associated with thrombosis in Behçet’s Syndrome, Clinical and Experimental Rheumatology, Vol: 6, ISSN: 1593-098X
Thrombosis is common in Behçet’s Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th−). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001). Amongst BS patients, the Th+ group had increased total and TF positive MP numbers (both p ≤ 0.0002) compared to the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05). Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th− BS patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.
Khan E, Ambrose N, Ahnstrom J, et al., 2016, A LOW BALANCE BETWEEN MICROPARTICLES EXPRESSING TISSUE FACTOR PATHWAY INHIBITOR AND TISSUE FACTOR IS ASSOCIATED WITH THROMBOSIS IN BEHCET'S SYNDROME, Publisher: CLINICAL & EXPER RHEUMATOLOGY, Pages: S143-S143, ISSN: 0392-856X
Ogbechi J, Ruf M-T, Hall BS, et al., 2015, Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
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- Citations: 31
Gierula M, Salles-Crawley II, Crawley JTB, et al., 2015, Factor VA in synergy with protein s enhances activated protein C binding to phospholipids, Publisher: WILEY-BLACKWELL, Pages: 313-313, ISSN: 1538-7933
Reglinska-Matveyev N, Crawley JT, Camire R, et al., 2015, FV enhances protein S cofactor function for TFPI in the inhibition of FXa, Publisher: WILEY-BLACKWELL, Pages: 54-54, ISSN: 1538-7933
Somajo S, Ahnstroem J, Fernandez-Recio J, et al., 2015, Amino acid residues in the laminin G domains of protein S involved in tissue factor pathway inhibitor interaction, THROMBOSIS AND HAEMOSTASIS, Vol: 113, Pages: 976-987, ISSN: 0340-6245
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- Citations: 10
Somajo S, Ahnstroem J, Gierula M, et al., 2015, Amino acid residues in the laminin G domains of protein S involved in tissue factor pathway inhibitor interaction, Journal of Thrombosis and Haemostasis, Vol: 113, Pages: 976-987, ISSN: 1538-7933
Protein S functions as a cofactor for tissue factor pathway inhibitor (TFPI) and activated protein C (APC). The sex hormone binding globulin (SHBG)-like region of protein S, consisting of two laminin G-like domains (LG1 and LG2), contains the binding site for C4b-binding protein (C4BP) and TFPI. Furthermore, the LG-domains are essential for the TFPI-cofactor function and for expression of full APC-cofactor function. The aim of the current study was to localise functionally important interaction sites in the protein S LG-domains using amino acid substitutions. Four protein S variants were created in which clusters of surface-exposed amino acid residues within the LG-domains were substituted. All variants bound normally to C4BP and were fully functional as cofactors for APC in plasma and in pure component assays. Two variants, SHBG2 (E612A, I614A, F265A, V393A, H453A), involving residues from both LG-domains, and SHBG3 (K317A, I330A, V336A, D365A) where residues in LG1 were substituted, showed 50-60 % reduction in enhancement of TFPI in FXa inhibition assays. For SHBG3 the decreased TFPI cofactor function was confirmed in plasma based thrombin generation assays. Both SHBG variants bound to TFPI with decreased affinity in surface plasmon resonance experiments. The TFPI Kunitz 3 domain is known to contain the interaction site for protein S. Using in silico analysis and protein docking exercises, preliminary models of the protein S SHBG/TFPI Kunitz domain 3 complex were created. Based on a combination of experimental and in silico data we propose a binding site for TFPI on protein S, involving both LG-domains.
Reglinska-Matveyev N, Andersson HM, Rezende SM, et al., 2014, TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain, Blood, Vol: 123, Pages: 3979-3987, ISSN: 0006-4971
Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest–specific 6 chimeras, with either the whole sex hormone–binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest–specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane.
Salles-Crawley II, Monkman JH, Ahnstroem J, et al., 2014, Vessel wall BAMBI contributes to hemostasis and thrombus stability., Blood, Vol: 123, Pages: 2873-2881, ISSN: 0006-4971
Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-β superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi−/− and Bambi+/− mice exhibit mildly prolonged bleeding times compared with Bambi+/+ littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi+/+ mice. No defects in thrombin generation in Bambi−/− mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi−/− mice, Bambi−/− transplanted with Bambi+/+ bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi+/+ mice receiving Bambi−/− bone marrow transplants. Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability.
Reglinska NB, Andersson HMH, Rezende SM, et al., 2013, The search for functionally important residues in protein S required for its enhancement of TFPI, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 328-328, ISSN: 1538-7933
Salles I, Monkman JH, Ahnstroem J, et al., 2013, BMP and activin membrane bound inhibitor (BAMBI): A novel regulator of thrombus formation, Publisher: WILEY-BLACKWELL, Pages: 274-275, ISSN: 1538-7933
Ahnstroem J, Andersson HM, Hockey V, et al., 2012, Identification of functionally important residues in TFPI Kunitz domain 3 required for the enhancement of its activity by protein S, BLOOD, Vol: 120, Pages: 5059-5062, ISSN: 0006-4971
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- Citations: 40
Elsoe S, Ahnstrom J, Christoffersen C, et al., 2012, Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL, ATHEROSCLEROSIS, Vol: 221, Pages: 91-97, ISSN: 0021-9150
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- Citations: 86
Ahnstrom J, Andersson HM, Canis K, et al., 2011, Activated protein S cofactor function of protein S: a novel function for a γ-carboxyglutamic acid residue, Publisher: WILEY-BLACKWELL, Pages: 14-14, ISSN: 1538-7933
Ahnstroem J, Andersson HM, Canis K, et al., 2011, Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue, BLOOD, Vol: 117, Pages: 6685-6693, ISSN: 0006-4971
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- Citations: 31
Christoffersen C, Obinata H, Kumaraswamy SB, et al., 2011, Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 9613-9618, ISSN: 0027-8424
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- Citations: 443
Nielsen SE, Ahnstrom J, Christoffersen C, et al., 2011, APOLIPOPROTEIN M BINDS OXIDIZED PHOSPHOLIPIDS AND INCREASES THE ANTIOXIDANT EFFECT OF HDL, 79th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: 52-52, ISSN: 1567-5688
Sevvana M, Kassler K, Ahnstrom J, et al., 2010, Mouse ApoM Displays an Unprecedented Seven-Stranded Lipocalin Fold: Folding Decoy or Alternative Native Fold?, JOURNAL OF MOLECULAR BIOLOGY, Vol: 404, Pages: 363-371, ISSN: 0022-2836
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- Citations: 8
Kappelle PJWH, Ahnstrom J, Dikkeschei BD, et al., 2010, Plasma apolipoprotein M responses to statin and fibrate administration in type 2 diabetes mellitus, ATHEROSCLEROSIS, Vol: 213, Pages: 247-250, ISSN: 0021-9150
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- Citations: 11
Ahnstrom J, Lindqvist PG, Walle U, et al., 2010, Plasma levels of apolipoprotein M in normal and complicated pregnancy, ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA, Vol: 89, Pages: 1214-1217, ISSN: 0001-6349
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- Citations: 4
Ahnstrom J, Gottsater A, Lindblad B, et al., 2010, Plasma concentrations of apolipoproteins A-I, B, and M in patients with critical limb ischemia, CLINICAL BIOCHEMISTRY, Vol: 43, Pages: 599-603, ISSN: 0009-9120
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- Citations: 12
Ahnstrom J, Gottsater A, Lindblad B, et al., 2010, Plasma concentrations of apolipoproteins A-I, B and M in patients with abdominal aortic aneurysms, CLINICAL BIOCHEMISTRY, Vol: 43, Pages: 407-410, ISSN: 0009-9120
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- Citations: 19
Ahnstrom J, Axler O, Dahlback B, 2010, HDL Stimulates apoM Secretion, PROTEIN AND PEPTIDE LETTERS, Vol: 17, Pages: 1285-1289, ISSN: 0929-8665
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- Citations: 7
Sevvana M, Ahnstrom J, Egerer-Sieber C, et al., 2009, Serendipitous Fatty Acid Binding Reveals the Structural Determinants for Ligand Recognition in Apolipoprotein M, JOURNAL OF MOLECULAR BIOLOGY, Vol: 393, Pages: 920-936, ISSN: 0022-2836
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- Citations: 57
Ahnstrom J, Axler O, Dahlback B, 2009, RECOMBINANT APOLIPOPROTEIN M SECRETION STIMULATED BY HDL, ATHEROSCLEROSIS SUPPLEMENTS, Vol: 10, ISSN: 1567-5688
Ahnstrom J, Axler O, Dahlback B, 2009, RECOMBINANT APOLIPOPROTEIN M SECRETION STIMULATED BY HDL, ATHEROSCLEROSIS SUPPLEMENTS, Vol: 10, ISSN: 1567-5688
Nielsen LB, Christoffersen C, Ahnstrom J, et al., 2009, ApoM: gene regulation and effects on HDL metabolism, TRENDS IN ENDOCRINOLOGY AND METABOLISM, Vol: 20, Pages: 66-71, ISSN: 1043-2760
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- Citations: 28
Dahlback B, Ahnstrom J, Christoffersen C, et al., 2008, Apolipoprotein M: structure and function, FUTURE LIPIDOLOGY, Vol: 3, Pages: 495-503, ISSN: 1746-0875
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- Citations: 4
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