Antonia Miñano

University of Murcia, Murcia, Murcia, Spain

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Publications (39)175.69 Total impact

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    ABSTRACT: Background: Severe deficiency but also moderate reduction of antithrombin (AT), a key endogenous anticoagulant, increase thrombotic risk. Mutations in SERPINC1, the gene encoding AT, are responsible for most of the severe congenital deficiencies. We aimed to identify new elements involved in the regulation of AT. Methods: We selected 19 patients with thrombosis and reduction of AT (50-90%) from 149 patients with potential AT deficiency, be-cause no mutation in the 7 exons of SERPINC1 was identified. The 5’ region (1500 bp) as well as intron1 and 2 of SERPINC1 were sequenced. In silico prediction of potential vitamin D receptor elements (RXRA/VDR) in SERPINC1 was done with JASPAR software. Luciferase reporter assays using two hepatic cell lines (PLC-PRF-5 and HepG2) were also used. Genotyping and AT activity was determined in 307 healthy subjects. Results: We identified 3 polymorphisms and 2 new point alterations in the 5’ region: g.1091 C>T was a low prevalent polymorphism, while g.2043 C>G was not detected in healthy sub-jects. The 4 polymorphisms found in the 5’ region of these patients did not affect AT levels in healthy subjects. In contrast, g.2143 C>G associated with low AT levels in family studies. The functional effects of this mutation were validated by reporter assays, as the mutated allele reduced 30-50% the Luciferase activity in two hepatic cell lines. This alteration affected a vitamin D receptor element (RXRA/VDR), potentially involved in transcriptional regulation. Accordingly, we searched for additional RXRA/VDR elements in SERPINC1. We identified three elements, two in intron 1 and one in intron 2. Therefore, we sequenced these introns in the remaining 18 patients. Interestingly, one patient carried an insertion of 4 repeated nucleo-tides that fully disturbed the RXRA/VDR with the highest score, which was located at intron 1 (IVS1+1179insTTGA). This insertion was a low prevalent polymorphism (2%) with functional effects, as it significantly associated with lower levels of anti-FXa activity (88% in carriers vs. 96% in non-carriers; p = 0.02). Conclusions: We have identified the first two regulatory alterations in SERPINC1 that reduce AT levels. Both alterations disrupt two potential RXRA/VDR elements. These results suggest that the vitamin D/vitamin A pathway could contribute to regulate this potent anticoagulant with potential pathological relevance and sustain the inclusion of these regions in molecular studies to characterize the AT deficiency.
    23rd Biennial International Congress on Thrombosis and MLTD Congress 2014 Spain, Valencia, Spain; 05/2014
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    ABSTRACT: IDENTIFICATION OF RXRA/VDR ELEMENTS INVOLVED IN THE REGULATION OF ANTITHROMBIN LEVELS. RELEVANCE IN ANTITHROMBIN DEFICIENCY ME de la Morena-Barrio1, M Toderici1, A Miñano1, J Padilla1, AI Antón1, N García-Barbera1, TMC Binder2, JC Souto3, V Vicente1, J Corral1 1 Centro Regional de Hemodonacion. Servicio de Hematologia y Oncologia Medica. Hospital Universi-tario Morales Meseguer. Universidad de Murcia, Murcia, Spain, 2 Universitätsklinikum Hamburg-Eppendorf, Germany, 3 Hospital Santa Creu y Sant Pau. Barcelona, Spain Background: Severe deficiency but also moderate reduction of antithrombin (AT), a key endogenous anticoagulant, increase thrombotic risk. Mutations in SERPINC1, the gene en-coding AT, are responsible for most of the severe congenital deficiencies. We aimed to identi-fy new elements involved in the regulation of AT. Methods: We selected 19 patients with thrombosis and reduction of AT (50-90%) from 149 patients with potential AT deficiency, be-cause no mutation in the 7 exons of SERPINC1 was identified. The 5× region (1500 bp) as well as intron1 and 2 of SERPINC1 were sequenced. In silico prediction of potential vitamin D receptor elements (RXRA/VDR) in SERPINC1 was done with JASPAR software. Luciferase reporter assays using two hepatic cell lines (PLC-PRF-5 and HepG2) were also used. Geno-typing and AT activity was determined in 307 healthy subjects. Results: We identified 3 polymorphisms and 2 new point alterations in the 5× region: g.1091 C>T was a low prevalent polymorphism, while g.2043 C>G was not detected in healthy sub-jects. The 4 polymorphisms found in the 5× region of these patients did not affect AT levels in healthy subjects. In contrast, g.2143 C>G associated with low AT levels in family studies. The functional effects of this mutation were validated by reporter assays, as the mutated allele reduced 30-50% the Luciferase activity in two hepatic cell lines. This alteration affected a vit-amin D receptor element (RXRA/VDR), potentially involved in transcriptional regulation. Ac-cordingly, we searched for additional RXRA/VDR elements in SERPINC1. We identified three elements, two in intron 1 and one in intron 2. Therefore, we sequenced these introns in the remaining 18 patients. Interestingly, one patient carried an insertion of 4 repeated nucleotides that fully disturbed the RXRA/VDR with the highest score, which was located at intron 1 (IVS1+1179insTTGA). This insertion was a low prevalent polymorphism (2%) with functional effects, as it significantly associated with lower levels of anti-FXa activity (88% in carriers vs. 96% in non-carriers; p = 0.02). Conclusions: We have identified the first two regulatory alterations in SERPINC1 that re-duce AT levels. Both alterations disrupt two potential RXRA/VDR elements. These results suggest that the vitamin D/vitamin A pathway could contribute to regulate this potent antico-agulant with potential pathological relevance and sustain the inclusion of these regions in mo-lecular studies to characterize the AT deficiency.
    Thrombosis Research 05/2014; 133:S10. DOI:10.1016/S0049-3848(14)50060-6 · 2.43 Impact Factor
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    ABSTRACT: Mutations in PMM2 impair phosphomannomutase-2 activity and cause the most frequent congenital disorder of glycosylation, PMM2-CDG. Mannose-1-phosphate, that is deficient in this disorder, is also implicated in the biosynthesis of glycosylphosphatidyl inositol (GPI) anchors. To evaluate whether GPI-anchor and GPI-anchored proteins are defective in PMM2-CDG patients.Methods The expression of GPI-anchor and seven GPI-anchored proteins was evaluated by flow cytometry in different cell types from twelve PMM2-CDG patients. Additionally, neutrophil CD16 and plasma hepatic proteins were studied by Western blot. Transferrin glycoforms were evaluated by HPLC. Patients and controls had similar surface expression of GPI-anchor and most GPI-anchored proteins. Nevertheless, patients displayed a significantly diminished binding of two anti-CD16 antibodies (3G8 and KD1) to neutrophils and also of anti-CD14 (61D3) to monocytes. Interestingly, CD16 immunostaining and asialotransferrin levels significantly correlated with patients' age. Analysis by flow cytometry of CD14 with MPhiP9, and CD16 expression in neutrophils by Western blot using H-80 ruled out deficiencies of these antigens. PMM2 mutations do not impair GPI-anchor or GPI-anchored protein expression. However, the glycosylation anomalies caused by PMM2 mutations might affect the immunoreactivity of monoclonal antibodies and lead to incorrect conclusions about the expression of different proteins, including GPI-anchored proteins. Neutrophils and monocytes are sensitive to PMM2 mutations, leading to abnormal glycosylation in immune receptors, which might potentially affect their affinity to their ligands, and contribute to infection. This study also confirms less severe hypoglycosylation defects in older PMM2-CDG patients.
    Orphanet Journal of Rare Diseases 10/2013; 8(1):170. DOI:10.1186/1750-1172-8-170 · 3.96 Impact Factor
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    ABSTRACT: The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 individuals from 21 Spanish families). Despite no SNP reaching the genome wide significance threshold, we verified milder positive associations in 307 blood donors from a different cohort. This validation study suggested LARGE, a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides, as a potential modulator of antithrombin based on the significant association of one SNPs, rs762057, with anti-FXa activity, particularly after adjustment for age, sex and SERPINC1 rs2227589 genotype, all factors influencing antithrombin levels (p = 0.02). Additional results sustained this association. LARGE silencing inHepG2 and HEK-EBNA cells did not affect SERPINC1 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention. Milder effects were observed on α1-antitrypsin, prothrombin and transferrin. Our study suggests LARGE as the first known modifier of plasma antithrombin, and proposes a new role for LARGE in modulating extracellular secretion of certain glycoproteins.
    PLoS ONE 05/2013; 8(5):e64998. DOI:10.1371/journal.pone.0064998 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Developmental haemostatic studies may help identifying new elements involved in the control of key haemostatic proteins like antithrombin, the most relevant endogenous anticoagulant. RESULTS: In this study, we showed a significant reduction of sialic acid content in neonatal antithrombin compared with adult antithrombin in mice. mRNA levels of St3gal3 and St3gal4, two sialyltransferases potentially involved in antithrombin sialylation, were 85% lower in neonates in comparison with adults. In silico analysis of miRNAs overexpressed in neonates revealed that mir-200a might target these sialyltransferases. Moreover, in vitro studies in murine primary hepatocytes sustain this potential control. CONCLUSIONS: These data suggest that in addition to the direct protein regulation, microRNAs may also modulate qualitative traits of selected proteins by an indirect control of post-translational processes.
    Journal of Biomedical Science 05/2013; 20(1):29. DOI:10.1186/1423-0127-20-29 · 2.74 Impact Factor
  • Thrombosis and Haemostasis 01/2013; 109(3). DOI:10.1160/TH12-09-0707 · 5.76 Impact Factor
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    ABSTRACT: Antithrombin deficiency was the first congenital thrombophilic factor identified [1]. Since then, protein C and protein S deficiencies, as well as specific mutations in the factor V and prothrombin genes, have joined antithrombin deficiency as genetic defects predisposing patients to venous thrombosis. However, it is unlikely that new common polymorphisms could play a key role in venous thrombosis [2]. © 2012 International Society on Thrombosis and Haemostasis.
    Journal of Thrombosis and Haemostasis 10/2012; DOI:10.1111/jth.12031 · 5.55 Impact Factor
  • Thrombosis Research 10/2012; 130:S117. DOI:10.1016/j.thromres.2012.08.046 · 2.43 Impact Factor
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    ABSTRACT: The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparin-binding domain. We speculated that the natural β-glycoform of antithrombin might compensate for the effect of heparin-binding mutations. We purified α- and β-antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the α-L99F glycoform (K(D), 107.9 ± 3nM) was restored in the β-L99F glycoform (K(D), 53.9 ± 5nM) to values close to the activity of α-wild type (K(D), 43.9 ± 0.4nM). Accordingly, the β-L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional β-glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombin mutations.
    Blood 04/2012; 120(4):900-4. DOI:10.1182/blood-2012-01-406207 · 9.78 Impact Factor
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    ABSTRACT: Mutations affecting mobile domains of antithrombin induce conformational instability resulting in protein polymerization that associates with a severe clinical phenotype, probably by an unknown gain of function. By homology with other conformational diseases, we speculated that these variants might infect wild-type (WT) monomers reducing the anticoagulant capacity. Infective polymerization of WT polymers and different P1 mutants (p.R425del, p.R425C and p.R425H) were evaluated by using native gels and radiolabeled WT monomers and functional assays. Human embryonic kidney cells expressing the Epstein-Barr nuclear antigen 1 (HEK-EBNA) cells expressing inducible (p.R425del) or two novel constitutive (p.F271S and p.M370T) conformational variants were used to evaluate intracellular and secreted antithrombin under mild stress (pH 6.5 and 39°C for 5 h). We demonstrated the conformational sensitivity of antithrombin London (p.R425del) to form polymers under mild heating. Under these conditions purified antithrombin London recruited WT monomers into growing polymers, reducing the anticoagulant activity. This process was also observed in the plasma of patients with p.R425del, p.R425C and p.R425H mutations. Under moderate stress, coexpression of WT and conformational variants in HEK-EBNA cells increased the intracellular retention of antithrombin and the formation of disulfide-linked polymers, which correlated with impaired secretion and reduction of anticoagulant activity in the medium. Therefore, mutations inducing conformational instability in antithrombin allow its polymerization with the subsequent loss of function, which under stress could sequestrate WT monomers, resulting in a new prothrombotic gain of function, particularly relevant for intracellular antithrombin. The in vitro results suggest a temporal and severe plasma antithrombin deficiency that may contribute to the development of the thrombotic event and to the clinical severity of these mutations.
    Molecular Medicine 03/2012; 18(1):762-70. DOI:10.2119/molmed.2012.00017 · 4.82 Impact Factor
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    ABSTRACT: Antithrombin is the main endogenous anticoagulant. Impaired function or deficiency of this molecule significantly increases the risk of thrombosis. We studied the genetic variability of SERPINC1 , the gene encoding antithrombin, to identify mutations affecting regulatory regions with functional effect on its levels. We sequenced 15,375 bp of this gene, including the potential promoter region, in three groups of subjects: five healthy subjects with antithrombin levels in the lowest (75%) and highest (115%) ranges of our population, 14 patients with venous thrombosis and a moderate antithrombin deficiency as the single thrombophilic defect, and two families with type I antithrombin deficiency who had neither mutations affecting exons or flanking regions, nor gross gene deletions. Our study confirmed the low genetic variability of SERPINC1 , particularly in the coding region, and its minor influence in the heterogeneity of antithrombin levels. Interestingly, in one family, we identified a g.2143 C>G transversion, located 170 bp upstream from the translation initiation codon. This mutation affected one of the four regions located in the minimal promoter that have potential regulatory activity according to previous DNase footprinting protection assays. Genotype-phenotype analysis in the affected family and reporter analysis in different hepatic cell lines demonstrated that this mutation significantly impaired, although it did not abolish, the downstream transcription. Therefore, this is the first mutation affecting a regulatory region of the SERPINC1 gene associated with antithrombin deficiency. Our results strongly sustain the inclusion of the promoter region of SERPINC1 in the molecular analysis of patients with antithrombin deficiency.
    Thrombosis and Haemostasis 03/2012; 107(3):430-7. DOI:10.1160/TH11-10-0701 · 5.76 Impact Factor
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    ABSTRACT: Factor VIIa (FVIIa), a trypsin-like serine protease, plays an essential role in haemostasis by initiating the coagulation in complex with its cofactor, tissue factor (TF). The TF pathway inhibitor is the main physiological inhibitor of FVIIa-TF complex, but FVIIa can also be inhibited by antithrombin, although little is known about this process. Functional analyses by second order kinetic determination and identification of FVIIa-antithrombin complex by electrophoresis, evaluating the effect of different cofactors: pentasaccharide, low molecular weight heparin (LMWH) and unfractionated heparin (UFH), confirmed that any activation of antithrombin significantly enhanced the inhibition of FVIIa. The analysis of the binding of FVIIa to heparin by surface plasmon resonance identified a high affinity interaction under physiologic conditions (K(D)=3.38 μM, with 0.15M of ionic strength) strongly dependent on Ca(2+) and ionic strength. This interaction was verified in cell models, indicating that FVIIa also binds to the surface of endothelial cells with similar requirements. Structural modeling suggests the presence of a potential exosite II in FVIIa. However, the binding of heparin did not display significant changes on both the intrinsic fluorescence and the associated functional consequences of FVIIa. These results indicate that FVIIa binds to exposed glycosaminglycans of the endothelium through an exosite II, structurally similar to that reported for thrombin and suggested for FIXa. This binding may favor its inhibition by antithrombin in the absence of TF, contributing to the physiological control of this protease. This process may also play an important role in the clearance of recombinant FVIIa administered to patients.
    Thrombosis Research 02/2011; 127(2):154-60. DOI:10.1016/j.thromres.2010.11.008 · 2.43 Impact Factor
  • JOURNAL OF THROMBOSIS AND HAEMOSTASIS; 01/2011
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    ABSTRACT: Citrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 ± 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 ± 237.6 ng/ml and 36.8 ± 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma.
    Thrombosis and Haemostasis 12/2010; 104(6):1143-9. DOI:10.1160/TH10-05-0297 · 5.76 Impact Factor
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    ABSTRACT: Antithrombin is an anticoagulant serpin with conformational sensitivity. Mutations and environmental factors may induce its polymerization by a mechanism involving domain swapping, which still requires verification. We have evaluated the functional and conformational effects on antithrombin of citrullination, a post-translational modification catalyzed by peptidylarginine deiminase (PAD), which changes arginine to citrulline. Purified antithrombin (native and latent forms) and plasma were incubated with PAD in the presence and absence of heparin. Citrullines were identified by proteomic analysis. Anti-activated factor X activity determination, IEF, SDS/PAGE and native PAGE were performed. The cleavage pattern with the metalloprotease AspN was studied, and its target residues were identified by Edman sequencing. We confirmed that citrullination of antithrombin abolished its activity; this abolition of activity was accelerated by heparin, which facilitated the early citrullination of Arg393 (P1 residue). Proteomic analyses revealed nine additional citrullines that caused a significant decrease in its electrostatic potential (from 5.95 to 5.06). It was demonstrated that citrullination of antithrombin caused its polymerization. The observation that these polymers, like heat-generated polymers, are cleaved by AspN in helix I is compatible with their linkage by domain swapping from strand 5 to strand 4 of beta-sheet A.
    FEBS Journal 10/2009; 276(22):6763-72. DOI:10.1111/j.1742-4658.2009.07391.x · 3.99 Impact Factor
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    ABSTRACT: We studied the effect of acrolein, an alpha,beta-unsaturated aldehyde that causes adduct-modification of lysine, cysteine, and histidine residues, on antithrombin, a key anticoagulant serpin. Intrinsic fluorescence, functionality (anti-FXa and anti-IIa activity), heparin affinity and conformational features of plasma and purified antithrombin were evaluated. In vivo experiments were carried out in mice. Intrinsic fluorescence showed a two-step conformational change. Acrolein, even at low dose, impaired the anticoagulant function of purified antithrombin by affecting its heparin affinity. However, higher concentrations of acrolein and long incubations are required to cause mild functional effects on plasma antithrombin and mice.
    FEBS letters 10/2009; 583(19):3165-70. DOI:10.1016/j.febslet.2009.07.062 · 3.34 Impact Factor
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    ABSTRACT: Recent data support that diabetes might be a conformational disease. Certainly, hyperglycaemia causes a broad range of deleterious effects that might facilitate protein aggregation. We have evaluated the effects of hyperglycaemia on antithrombin, a conformationally sensitive serpin with a potent anticoagulant role. Moreover, these studies might also help to understand the thrombotic risk associated to diabetes. We incubated in vitro plasma and purified antithrombin and human hepatoma cells (HepG2) with methyl-glyoxal and glucose. Moreover, a mouse model of acute diabetes was generated with streptozotocin. Antigen, anti-FXa activity, heparin affinity and conformational features of antithrombin were analysed. Histological and intracellular features and distribution of antithrombin in HepG2 and livers of mice were also evaluated. Hyperglycaemia in vitro induced a transition of antithrombin to a form with low heparin affinity that explained the loss of anticoagulant activity, without generation of abnormal conformers (polymers or latent antithrombin). However, these effects were not observed on circulating antithrombin from diabetic mice. In contrast, hyperglycaemia in vivo had significant effects on intracellular antithrombin, which was retained, forming microaggregates within the lumen of dilated cisterns of the endoplasmic reticulum. These effects explained the moderate type I deficiency observed in diabetic mice. Similar intracellular consequences were observed for another hepatic serpin, alpha1-antitrypsin. Our data further support that diabetes has conformational effects on structurally sensitive proteins. These effects on antithrombin, the main natural anticoagulant, might contribute to the hypercoagulable status of diabetic patients.
    Thrombosis Research 08/2009; 124(4):483-9. DOI:10.1016/j.thromres.2009.05.020 · 2.43 Impact Factor
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    ISTH 2009; 07/2009
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    ABSTRACT: L-asparaginase (L-ASP) treatment of patients with acute lymphoblastic leukemia causes a severe antithrombin deficiency by intracellular retention of this serpin within the endoplasmic reticulum (ER) of hepatic cells, and a subsequent risk of thrombosis. Interestingly, co-administration of dexamethasone with L-ASP seems to reduce the risk of thrombosis. We have investigated the effect of two corticoids, dexamethasone and prednisone, on the conformational consequences of L-ASP treatment on antithrombin. Levels, activity, conformation and immunohistological features of antithrombin were studied in patients, cell and mice models. Because of the importance of the steroid receptor-heat stress response (HSR) axis, and the role of unfolded protein response (UPR) in conformational diseases, we also evaluated Hsp27, Hsp70, Hsp90, HSF-1 and ER chaperons (Grp78 and Grp94). In all models, L-ASP alone or in combination with prednisone caused the intracellular retention of antithrombin associated with a severe deficiency. In contrast, the combination of L-ASP with dexamethasone ameliorated both the deficiency and intracellular retention of the serpin, which is associated with increased expression of heat shock proteins and ER-chaperons. These results suggest a protective effect of dexamethasone on the conformational consequences of L-ASP on antithrombin as a result of exacerbated HSR and UPR that help to explain the reduced risk of thrombosis reported in patients that follow this scheme of treatment.
    Journal of Thrombosis and Haemostasis 05/2009; 7(7):1128-33. DOI:10.1111/j.1538-7836.2009.03449.x · 5.55 Impact Factor
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    ABSTRACT: Although the control of thrombin in the microvasculature at the endothelial cell surface is crucial to prevent atherothrombosis, the role of antithrombin in arterial thrombosis is unclear. It is widely considered that antithrombin deficiency is unlikely to contribute to arterial thrombosis, but no convincing epidemiological study has been performed because of the low frequency of this deficiency. In this study we evaluated the role in myocardial infarction (MI) of a relatively common mutation affecting antithrombin gene (A384S: Antithrombin Cambridge II) that has functional features that may impair the right control of thrombogenic events caused by injury to the vascular wall. Moreover, this deficiency, which is not detected using common methods to diagnose antithrombin deficiency, also increases the risk of venous thrombosis. We included 1,224 patients with MI (691 consecutive patients and 533 survivors of a premature event), and 1,649 controls. The mutation was identified in 0.3% of controls, but 0.8% of MI patients. After adjusting for sex and other cardiovascular risk factors, the antithrombin Cambridge II significantly increased 5.66-fold the risk of MI (95% CI: 1.53-20.88; p = 0.009). Interestingly, young patients had the highest risk of MI associated with the mutation (OR: 9.98; 95%CI: 1.60-62.24; p = 0.009). This is the first epidemiological study that supports a role for antithrombin deficiency in arterial thrombosis. These results suggest that deficiency of antithrombin may be an independent risk factor for MI that has been underestimated, but larger studies are needed to confirm the relevance of inhibitors of thrombin in arterial thrombosis.
    Thrombosis and Haemostasis 04/2009; 101(3):483-6. DOI:10.1160/TH08-09-0583 · 5.76 Impact Factor

Publication Stats

328 Citations
175.69 Total Impact Points

Institutions

  • 2003–2013
    • University of Murcia
      • Faculty of Medicine
      Murcia, Murcia, Spain
  • 2012
    • Hospital General Universitario Gregorio Marañón
      Madrid, Madrid, Spain
  • 2005
    • Hospital Universitario Virgen de la Arrixaca
      • Departamento de Cirugía
      Murcia, Murcia, Spain