TY  - JOUR
AU  - Cumbo, Marija
AU  - Dunjić-Manevski, Sofija
AU  - Gvozdenov, Maja
AU  - Mitić, Martina Mia
AU  - Đorđević, Valentina
AU  - Tomić, Branko
PY  - 2024
UR  - https://doiserbia.nb.rs/Article.aspx?ID=0354-46642400007C
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2358
AB  - Thrombotic disorders are some of the main comorbidities in cancer patients. So far, research has indicated that thrombin, a key regulator of hemostasis, contributes to cancer progression. However, data on its origin in tumor microenvironments remain elusive. Based on previous research, we analyzed the RNA and protein expression of prothrombin, a precursor of thrombin, in selected colorectal cancer (CRC) cell lines. Since the effect of prothrombin in cancer development has not been previously reported, we treated the cells for 24 h and 48 h with different prothrombin concentrations and assessed the effect on cell proliferation and migration. Our results show that the tested CRC cell lines expressed prothrombin and that prothrombin inhibited proliferation and migration. The presented results suggest that prothrombin may contribute to CRC etiopathology and could serve as a potential diagnostic biomarker and therapeutic target. The mechanisms underlying prothrombin expression in cancer cells, potential prothrombin activation, and the underlying processes driving the described effects warrant further investigation.
PB  - Serbian Biological Society, Institute for Biological Research "Siniša Stanković"
T2  - Archives of Biological Sciences
T2  - Archives of Biological Sciences
T1  - The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells
EP  - 120
IS  - 1
SP  - 111
VL  - 76
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2358
ER  - 

@article{
author = "Cumbo, Marija and Dunjić-Manevski, Sofija and Gvozdenov, Maja and Mitić, Martina Mia and Đorđević, Valentina and Tomić, Branko",
year = "2024",
abstract = "Thrombotic disorders are some of the main comorbidities in cancer patients. So far, research has indicated that thrombin, a key regulator of hemostasis, contributes to cancer progression. However, data on its origin in tumor microenvironments remain elusive. Based on previous research, we analyzed the RNA and protein expression of prothrombin, a precursor of thrombin, in selected colorectal cancer (CRC) cell lines. Since the effect of prothrombin in cancer development has not been previously reported, we treated the cells for 24 h and 48 h with different prothrombin concentrations and assessed the effect on cell proliferation and migration. Our results show that the tested CRC cell lines expressed prothrombin and that prothrombin inhibited proliferation and migration. The presented results suggest that prothrombin may contribute to CRC etiopathology and could serve as a potential diagnostic biomarker and therapeutic target. The mechanisms underlying prothrombin expression in cancer cells, potential prothrombin activation, and the underlying processes driving the described effects warrant further investigation.",
publisher = "Serbian Biological Society, Institute for Biological Research "Siniša Stanković"",
journal = "Archives of Biological Sciences, Archives of Biological Sciences",
title = "The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells",
pages = "120-111",
number = "1",
volume = "76",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2358"
}

Cumbo, M., Dunjić-Manevski, S., Gvozdenov, M., Mitić, M. M., Đorđević, V.,& Tomić, B.. (2024). The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells. in Archives of Biological Sciences
Serbian Biological Society, Institute for Biological Research "Siniša Stanković"., 76(1), 111-120.
https://hdl.handle.net/21.15107/rcub_imagine_2358

Cumbo M, Dunjić-Manevski S, Gvozdenov M, Mitić MM, Đorđević V, Tomić B. The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells. in Archives of Biological Sciences. 2024;76(1):111-120.
https://hdl.handle.net/21.15107/rcub_imagine_2358 .

Cumbo, Marija, Dunjić-Manevski, Sofija, Gvozdenov, Maja, Mitić, Martina Mia, Đorđević, Valentina, Tomić, Branko, "The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells" in Archives of Biological Sciences, 76, no. 1 (2024):111-120,
https://hdl.handle.net/21.15107/rcub_imagine_2358 .

TY  - JOUR
AU  - Dunjić Manevski, Sofija
AU  - Cumbo, Marija
AU  - Pruner, Iva
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Taxiarchis, Apostolos
AU  - Antović, Jovan
AU  - Đordjević, Valentina
PY  - 2023
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.14195
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2199
AB  - Introduction Prothrombin Belgrade mutation is the result of the c.1787G>A substitution in the prothrombin gene. It is located in the antithrombin and sodium binding site and leads to impaired inactivation of thrombin by antithrombin, resulting in antithrombin resistance and thrombotic disorders. However, it negatively affects sodium binding and may have hypocoagulant effects. Considering that prothrombin Belgrade mutation mechanism is still not fully elucidated and that sodium binding is important for thrombin affinity towards fibrinogen, our aim was to determine whether this mutation affects fibrin clot formation and lysis. Methods Using HEK293T cell line, recombinant wild type and mutated prothrombin were generated by transient transfection. Samples that correspond to plasma of a non-carrier, heterozygous and homozygous carriers were reconstituted using prothrombin deficient plasma and recombinant proteins. Reconstituted samples were used in OHP assay (Overall Hemostasis Potential) to determine kinetic profiles of coagulation and fibrinolysis. Clot turbidity assay was performed to observe kinetics of clot formation and lysis more closely. Fibrin clots formed in reconstituted plasma samples were analyzed by confocal microscopy to determine density of fibrin network. Fibrin clots were additionally observed using electron microscopy to determine thickness of individual fibrin fibers. Results No significant difference found in OHP, OCP, OFP, and fibrin network density between wild type, heterozygous, and homozygous carrier reconstituted plasma samples. There were significant differences between samples for slope and slope time parameters in kinetic profiles and fibrin fiber thickness. Conclusions Results indicate that prothrombin Belgrade mutation has no significant impact on fibrinolysis, however it may affect kinetics of clot formation and its architecture.
T2  - International Journal of Laboratory Hematology
T1  - Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties
VL  - n/a
DO  - 10.1111/ijlh.14195
ER  - 

@article{
author = "Dunjić Manevski, Sofija and Cumbo, Marija and Pruner, Iva and Gvozdenov, Maja and Tomić, Branko and Taxiarchis, Apostolos and Antović, Jovan and Đordjević, Valentina",
year = "2023",
abstract = "Introduction Prothrombin Belgrade mutation is the result of the c.1787G>A substitution in the prothrombin gene. It is located in the antithrombin and sodium binding site and leads to impaired inactivation of thrombin by antithrombin, resulting in antithrombin resistance and thrombotic disorders. However, it negatively affects sodium binding and may have hypocoagulant effects. Considering that prothrombin Belgrade mutation mechanism is still not fully elucidated and that sodium binding is important for thrombin affinity towards fibrinogen, our aim was to determine whether this mutation affects fibrin clot formation and lysis. Methods Using HEK293T cell line, recombinant wild type and mutated prothrombin were generated by transient transfection. Samples that correspond to plasma of a non-carrier, heterozygous and homozygous carriers were reconstituted using prothrombin deficient plasma and recombinant proteins. Reconstituted samples were used in OHP assay (Overall Hemostasis Potential) to determine kinetic profiles of coagulation and fibrinolysis. Clot turbidity assay was performed to observe kinetics of clot formation and lysis more closely. Fibrin clots formed in reconstituted plasma samples were analyzed by confocal microscopy to determine density of fibrin network. Fibrin clots were additionally observed using electron microscopy to determine thickness of individual fibrin fibers. Results No significant difference found in OHP, OCP, OFP, and fibrin network density between wild type, heterozygous, and homozygous carrier reconstituted plasma samples. There were significant differences between samples for slope and slope time parameters in kinetic profiles and fibrin fiber thickness. Conclusions Results indicate that prothrombin Belgrade mutation has no significant impact on fibrinolysis, however it may affect kinetics of clot formation and its architecture.",
journal = "International Journal of Laboratory Hematology",
title = "Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties",
volume = "n/a",
doi = "10.1111/ijlh.14195"
}

Dunjić Manevski, S., Cumbo, M., Pruner, I., Gvozdenov, M., Tomić, B., Taxiarchis, A., Antović, J.,& Đordjević, V.. (2023). Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties. in International Journal of Laboratory Hematology, n/a.
https://doi.org/10.1111/ijlh.14195

Dunjić Manevski S, Cumbo M, Pruner I, Gvozdenov M, Tomić B, Taxiarchis A, Antović J, Đordjević V. Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties. in International Journal of Laboratory Hematology. 2023;n/a.
doi:10.1111/ijlh.14195 .

Dunjić Manevski, Sofija, Cumbo, Marija, Pruner, Iva, Gvozdenov, Maja, Tomić, Branko, Taxiarchis, Apostolos, Antović, Jovan, Đordjević, Valentina, "Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties" in International Journal of Laboratory Hematology, n/a (2023),
https://doi.org/10.1111/ijlh.14195 . .

TY  - CONF
AU  - Dunjić Manevski, Sofija
AU  - Cumbo, Marija
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Ušjak, Dušan
AU  - Đorđević
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2126
AB  - Introduction: The prothrombin Belgrade variant (c.1787G>A, p.Arg596Gln) is a rare mutation found in
Serbia, Japan, China, America, India and leads to antithrombin resistance. Prothrombin Belgrade mutation influencesthrombin-antithrombin interactions and leadsto impaired inactivation of mutated thrombin. Also, it affectssodium binding site in thrombin, which isimportant forswitching from fast thrombin
configuration (coagulant properties) to slow configuration (anticoagulant properties). It has only been
found in a heterozygous state, which could mean that homozygous carriers are incompatible with life.
By using prothrombin (FII) deficient plasma, we could reconstitute plasma of wild type, heterozygous and
homozygous carrier, which could give more insight into the mechanism of this mutation.
Methods: Recombinant wild type and mutated prothrombin were generated by transient transfection
in HEK293T cell line. Western blot analysis was performed to test the efficiency of transfection. Human
Prothrombin ELISA (Nordic BioSite, Sweden) was used in order to measure recombinant prothrombin
concentration. Overall Hemostasis Potential (OHP) assay was performed to assess recombinant protein
activity. Recombinant wild type and mutated prothrombin were added to FII deficient plasma (Siemens,
Germany) in order to create reconstituted plasma, in the final concentration of 0.1 mg/mL, as it is approximately the level of prothrombin in human plasma.
Results: Reconstituted plasma samples that correspond to non-carrier, heterozygous carrier, and homozygous mutation carrier plasma were reconstructed. Recombinant proteinstested by OHP assay were
functional.
Conclusion: Reconstituted plasma samples allow us to examine the mechanism of prothrombin Belgrade mutation in various assays and in homozygous form as well.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins
EP  - 71
SP  - 71
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2126
ER  - 

@conference{
author = "Dunjić Manevski, Sofija and Cumbo, Marija and Gvozdenov, Maja and Tomić, Branko and Ušjak, Dušan and Đorđević",
year = "2023",
abstract = "Introduction: The prothrombin Belgrade variant (c.1787G>A, p.Arg596Gln) is a rare mutation found in
Serbia, Japan, China, America, India and leads to antithrombin resistance. Prothrombin Belgrade mutation influencesthrombin-antithrombin interactions and leadsto impaired inactivation of mutated thrombin. Also, it affectssodium binding site in thrombin, which isimportant forswitching from fast thrombin
configuration (coagulant properties) to slow configuration (anticoagulant properties). It has only been
found in a heterozygous state, which could mean that homozygous carriers are incompatible with life.
By using prothrombin (FII) deficient plasma, we could reconstitute plasma of wild type, heterozygous and
homozygous carrier, which could give more insight into the mechanism of this mutation.
Methods: Recombinant wild type and mutated prothrombin were generated by transient transfection
in HEK293T cell line. Western blot analysis was performed to test the efficiency of transfection. Human
Prothrombin ELISA (Nordic BioSite, Sweden) was used in order to measure recombinant prothrombin
concentration. Overall Hemostasis Potential (OHP) assay was performed to assess recombinant protein
activity. Recombinant wild type and mutated prothrombin were added to FII deficient plasma (Siemens,
Germany) in order to create reconstituted plasma, in the final concentration of 0.1 mg/mL, as it is approximately the level of prothrombin in human plasma.
Results: Reconstituted plasma samples that correspond to non-carrier, heterozygous carrier, and homozygous mutation carrier plasma were reconstructed. Recombinant proteinstested by OHP assay were
functional.
Conclusion: Reconstituted plasma samples allow us to examine the mechanism of prothrombin Belgrade mutation in various assays and in homozygous form as well.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins",
pages = "71-71",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2126"
}

Dunjić Manevski, S., Cumbo, M., Gvozdenov, M., Tomić, B., Ušjak, D.,& Đorđević. (2023). Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 71-71.
https://hdl.handle.net/21.15107/rcub_imagine_2126

Dunjić Manevski S, Cumbo M, Gvozdenov M, Tomić B, Ušjak D, Đorđević. Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:71-71.
https://hdl.handle.net/21.15107/rcub_imagine_2126 .

Dunjić Manevski, Sofija, Cumbo, Marija, Gvozdenov, Maja, Tomić, Branko, Ušjak, Dušan, Đorđević, "Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):71-71,
https://hdl.handle.net/21.15107/rcub_imagine_2126 .

TY  - CONF
AU  - Dunjić Manevski, Sofija
AU  - Cumbo, Marija
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Ušjak, Dušan
AU  - Đorđević, Valentina
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2123
AB  - Introduction: The prothrombin Belgrade variant (c.1787G>A, p.Arg596Gln) is a rare mutation found in
Serbia, Japan, China, America, India and leads to antithrombin resistance. Prothrombin Belgrade mutation influencesthrombin-antithrombin interactions and leadsto impaired inactivation of mutated thrombin. Also, it affectssodium binding site in thrombin, which isimportant forswitching from fast thrombin
configuration (coagulant properties) to slow configuration (anticoagulant properties). It has only been
found in a heterozygous state, which could mean that homozygous carriers are incompatible with life.
By using prothrombin (FII) deficient plasma, we could reconstitute plasma of wild type, heterozygous and
homozygous carrier, which could give more insight into the mechanism of this mutation.
Methods: Recombinant wild type and mutated prothrombin were generated by transient transfection
in HEK293T cell line. Western blot analysis was performed to test the efficiency of transfection. Human
Prothrombin ELISA (Nordic BioSite, Sweden) was used in order to measure recombinant prothrombin
concentration. Overall Hemostasis Potential (OHP) assay was performed to assess recombinant protein
activity. Recombinant wild type and mutated prothrombin were added to FII deficient plasma (Siemens,
Germany) in order to create reconstituted plasma, in the final concentration of 0.1 mg/mL, as it is approximately the level of prothrombin in human plasma.
Results: Reconstituted plasma samples that correspond to non-carrier, heterozygous carrier, and homozygous mutation carrier plasma were reconstructed. Recombinant proteinstested by OHP assay were
functional.
Conclusion: Reconstituted plasma samples allow us to examine the mechanism of prothrombin Belgrade mutation in various assays and in homozygous form as well.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins
EP  - 71
SP  - 71
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2123
ER  - 

@conference{
author = "Dunjić Manevski, Sofija and Cumbo, Marija and Gvozdenov, Maja and Tomić, Branko and Ušjak, Dušan and Đorđević, Valentina",
year = "2023",
abstract = "Introduction: The prothrombin Belgrade variant (c.1787G>A, p.Arg596Gln) is a rare mutation found in
Serbia, Japan, China, America, India and leads to antithrombin resistance. Prothrombin Belgrade mutation influencesthrombin-antithrombin interactions and leadsto impaired inactivation of mutated thrombin. Also, it affectssodium binding site in thrombin, which isimportant forswitching from fast thrombin
configuration (coagulant properties) to slow configuration (anticoagulant properties). It has only been
found in a heterozygous state, which could mean that homozygous carriers are incompatible with life.
By using prothrombin (FII) deficient plasma, we could reconstitute plasma of wild type, heterozygous and
homozygous carrier, which could give more insight into the mechanism of this mutation.
Methods: Recombinant wild type and mutated prothrombin were generated by transient transfection
in HEK293T cell line. Western blot analysis was performed to test the efficiency of transfection. Human
Prothrombin ELISA (Nordic BioSite, Sweden) was used in order to measure recombinant prothrombin
concentration. Overall Hemostasis Potential (OHP) assay was performed to assess recombinant protein
activity. Recombinant wild type and mutated prothrombin were added to FII deficient plasma (Siemens,
Germany) in order to create reconstituted plasma, in the final concentration of 0.1 mg/mL, as it is approximately the level of prothrombin in human plasma.
Results: Reconstituted plasma samples that correspond to non-carrier, heterozygous carrier, and homozygous mutation carrier plasma were reconstructed. Recombinant proteinstested by OHP assay were
functional.
Conclusion: Reconstituted plasma samples allow us to examine the mechanism of prothrombin Belgrade mutation in various assays and in homozygous form as well.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins",
pages = "71-71",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2123"
}

Dunjić Manevski, S., Cumbo, M., Gvozdenov, M., Tomić, B., Ušjak, D.,& Đorđević, V.. (2023). Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 71-71.
https://hdl.handle.net/21.15107/rcub_imagine_2123

Dunjić Manevski S, Cumbo M, Gvozdenov M, Tomić B, Ušjak D, Đorđević V. Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:71-71.
https://hdl.handle.net/21.15107/rcub_imagine_2123 .

Dunjić Manevski, Sofija, Cumbo, Marija, Gvozdenov, Maja, Tomić, Branko, Ušjak, Dušan, Đorđević, Valentina, "Reconstitution of non-carrier, heterozygous and homozygous prothrombin belgrade mutation carrier plasma using recombinant proteins" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):71-71,
https://hdl.handle.net/21.15107/rcub_imagine_2123 .

TY  - JOUR
AU  - Malod-Dognin, Noël
AU  - Ceddia, Gaia
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Manevski Dunjić, Sofija 
AU  - Đorđević, Valentina
AU  - Pržulj, Nataša
PY  - 2023
UR  - https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284084
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1920
AB  - Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects’ phenotypes and the genes’ molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We applied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease.
T2  - Plos one
T1  - A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia
IS  - 4
SP  - e0284084
VL  - 18
DO  - 10.1371/journal.pone.0284084
ER  - 

@article{
author = "Malod-Dognin, Noël and Ceddia, Gaia and Gvozdenov, Maja and Tomić, Branko and Manevski Dunjić, Sofija  and Đorđević, Valentina and Pržulj, Nataša",
year = "2023",
abstract = "Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects’ phenotypes and the genes’ molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We applied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease.",
journal = "Plos one",
title = "A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia",
number = "4",
pages = "e0284084",
volume = "18",
doi = "10.1371/journal.pone.0284084"
}

Malod-Dognin, N., Ceddia, G., Gvozdenov, M., Tomić, B., Manevski Dunjić, S., Đorđević, V.,& Pržulj, N.. (2023). A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia. in Plos one, 18(4), e0284084.
https://doi.org/10.1371/journal.pone.0284084

Malod-Dognin N, Ceddia G, Gvozdenov M, Tomić B, Manevski Dunjić S, Đorđević V, Pržulj N. A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia. in Plos one. 2023;18(4):e0284084.
doi:10.1371/journal.pone.0284084 .

Malod-Dognin, Noël, Ceddia, Gaia, Gvozdenov, Maja, Tomić, Branko, Manevski Dunjić, Sofija , Đorđević, Valentina, Pržulj, Nataša, "A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia" in Plos one, 18, no. 4 (2023):e0284084,
https://doi.org/10.1371/journal.pone.0284084 . .

TY  - CONF
AU  - Cumbo, Marija
AU  - Tomić, Branko
AU  - Dunjić Manevski, Sofija
AU  - Gvozdenov, Maja
AU  - Ušjak, Dušan
AU  - Mitić, Martina Mia
AU  - Đorđević, Valentina
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2135
AB  - Introduction: Thrombin, crucial member of the coagulation cascade, can influence growth and development of different types of cancer. Prothrombin, thrombin precursor, although predominantly secreted
from the liver into the bloodstream, can also be expressed in the cancer cells. According to latest data prothrombin can bind in vitro to transmembrane receptors, which have previously been shown to be up-regulated in cancers and activate migration and invasion. Despite the significant amount of data on the
effects of thrombin in cancer progression, there are little data of prothrombin´s effect. The aim of this
study was to further examine the effects of prothrombin and thrombin in cancer cell lines.
Methods: Colon cancer cell lines (Caco2, SW480, SW620, HT29 and HCT116) were treated with prothrombin, thrombin and direct thrombin inhibitor, dabigatran, for 24h and 48h. To assess the effects of
treatment on cell viability and proliferation MTT test was used, and wound healing assay was used for cell
migration potential.
Results: Detected effects of treatment with prothrombin, thrombin and dabigatran varied between cell
lines. Trend of lower cell viability, proliferation and migration was observed in cells treated with prothrombin in comparison to untreated controls.
Conclusion: Our resultsindicate that prothrombin, although considered an inactive zymogen, can exert
an effect on colon cancer cells proliferation and migration in vitro.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Prothrombin influences proliferation and migration of colon cancer in vitro
EP  - 156
SP  - 156
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2135
ER  - 

@conference{
author = "Cumbo, Marija and Tomić, Branko and Dunjić Manevski, Sofija and Gvozdenov, Maja and Ušjak, Dušan and Mitić, Martina Mia and Đorđević, Valentina",
year = "2023",
abstract = "Introduction: Thrombin, crucial member of the coagulation cascade, can influence growth and development of different types of cancer. Prothrombin, thrombin precursor, although predominantly secreted
from the liver into the bloodstream, can also be expressed in the cancer cells. According to latest data prothrombin can bind in vitro to transmembrane receptors, which have previously been shown to be up-regulated in cancers and activate migration and invasion. Despite the significant amount of data on the
effects of thrombin in cancer progression, there are little data of prothrombin´s effect. The aim of this
study was to further examine the effects of prothrombin and thrombin in cancer cell lines.
Methods: Colon cancer cell lines (Caco2, SW480, SW620, HT29 and HCT116) were treated with prothrombin, thrombin and direct thrombin inhibitor, dabigatran, for 24h and 48h. To assess the effects of
treatment on cell viability and proliferation MTT test was used, and wound healing assay was used for cell
migration potential.
Results: Detected effects of treatment with prothrombin, thrombin and dabigatran varied between cell
lines. Trend of lower cell viability, proliferation and migration was observed in cells treated with prothrombin in comparison to untreated controls.
Conclusion: Our resultsindicate that prothrombin, although considered an inactive zymogen, can exert
an effect on colon cancer cells proliferation and migration in vitro.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Prothrombin influences proliferation and migration of colon cancer in vitro",
pages = "156-156",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2135"
}

Cumbo, M., Tomić, B., Dunjić Manevski, S., Gvozdenov, M., Ušjak, D., Mitić, M. M.,& Đorđević, V.. (2023). Prothrombin influences proliferation and migration of colon cancer in vitro. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 156-156.
https://hdl.handle.net/21.15107/rcub_imagine_2135

Cumbo M, Tomić B, Dunjić Manevski S, Gvozdenov M, Ušjak D, Mitić MM, Đorđević V. Prothrombin influences proliferation and migration of colon cancer in vitro. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:156-156.
https://hdl.handle.net/21.15107/rcub_imagine_2135 .

Cumbo, Marija, Tomić, Branko, Dunjić Manevski, Sofija, Gvozdenov, Maja, Ušjak, Dušan, Mitić, Martina Mia, Đorđević, Valentina, "Prothrombin influences proliferation and migration of colon cancer in vitro" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):156-156,
https://hdl.handle.net/21.15107/rcub_imagine_2135 .

TY  - JOUR
AU  - Kovač, Mirjana
AU  - Basarić, Dušica
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Backović, Dragana
AU  - Lalić-Ćosić, Sanja
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1914
AB  - Direct oral anticoagulants (DOACs) administration significantly interferes with coagulation as-says. The aim of the study was to evaluate the effect of DOACs and DOAC-Remove® on coagulation assays dur-ing thrombophilia testing. Methods. The study was car-ried out from January 2019 to the end of June 2020. It in-cluded 30 DOAC-treated patients, 14 females and 16 males aged 23 to 63 (median age 47.6 years), tested for thrombophilia due to venous thromboembolism (VTE). Thrombophilia testing was performed using DOAC-Remove® tablets (activated charcoal). The results before and after DOAC-Remove® were compared. Results. Posi-tive lupus anticoagulant (LA) results were observed in 20% apixaban, 100% dabigatran, and 70% rivaroxaban-treated patients, while in samples after DOAC-Remove®, the LA positivity was observed only in one from the apix-aban group. Before DOAC-Remove®, the activated pro-tein C (APC) resistance (APC-R) was measurable in 40% dabigatran and 80% rivaroxaban-treated patients, while, after using DOAC-Remove®, the APC-R was measurable in all cases. Comparing the results obtained from the sam-ples before and after DOAC-Remove®, a difference was noted in relation to all dilute Russell's viper venom time (dRVVT) coagulation tests, except for the dRVVT ratio in the apixaban group. Clot-based methods for detecting the APC resistance were significantly affected by dabigatran and less by rivaroxaban. Conclusion. DOACs were prac-tically inactivated after the addition of the DOAC-Remove®, which made it possible to perform analyses for the LA and APC-R testing freely and obtain relevant re-sults.
AB  - Primena direktnih oralnih antikoagulansa (DOAK)značajno utiče na testove koagulacije. Cilj rada bio je da se pro-ceni uticaj DOAK i DOAC-Remove® tableta (aktivni ugalj) natestove koagulacije tokom ispitivanja trombofilije. Metode.Istraživanjem, sprovedenim od januara 2019. do juna 2020.godine, obuhvaćeno je 30 bolesnika lečenih DOAK-om itestiranih na trombofiliju zbog venskog tromboembolzma(VTE). Bilo je 14 žena i 16 muškaraca, starosti od 23 do 63godine (medijana 47,6 godina). Ispitivanje trombofilije izvršenoje upotrebom DOAC-Remove® tableta (aktivni ugalj).Upoređivani su rezultati pre i posle primene DOAC-Remove®.Rezultati. Pozitivni rezultati za lupus antikoagulantni (LA) testdobijeni su kod 20% bolesnika lečenih apiksabanom, kod100% bolesnika lečenih dabigatranom i kod 70% lečenih riva-roksabanom, a u uzorcima posle DOAC-Remove® pozitivnostna LA dobijena je samo kod jednog bolesnika iz grupe lečnihapiksabanom. Pre primene DOAC-Remove®, rezistencija naaktivisani protein C (activated protein C resistance – APC-R) bila jemerljiva kod 40% i 80% bolesnika lečenih dabigatranom, od-nosno rivaroksabanom, dok je posle primene DOAC-Remove®, APC-R bila merljiva u svim slučajevima.Upoređivanjem rezultata dobijenih iz uzoraka pre i posleprimene DOAC-Remove®, primećena je razlika u odnosu nasve testove vremena koagulacije izvršene razblaženim Russell-ovim zmijskim otrovom (dilute Russell’s viper venom time –dRVVT), osim dRVVT u grupi bolesnika lečenih apiksabanom.Na koagulacionu metodu za otkrivanje APC-R značajno je uti-cao dabigatran, a manje rivaroksaban. Zaključak. Nakonprimene DOAC-Remove® tableta, DOAK su praktičnoinaktivisani što je omogućilo izvođenje analiza za LA i APC-R idobijanje relevantnih rezultata testova.
PB  - Inst. Sci. inf., Univ. Defence in Belgrade
T2  - Vojnosanitetski Pregled
T1  - Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients
T1  - Uticaj DOAK i DOAC-REMOVE® na testove koagulacije u toku testiranjatrombofilije kod bolesnika lečenih primenom DOAK
EP  - 1254
IS  - 12
SP  - 1248
VL  - 79
DO  - 10.2298/VSP210217101K
ER  - 

@article{
author = "Kovač, Mirjana and Basarić, Dušica and Tomić, Branko and Gvozdenov, Maja and Backović, Dragana and Lalić-Ćosić, Sanja",
year = "2022",
abstract = "Direct oral anticoagulants (DOACs) administration significantly interferes with coagulation as-says. The aim of the study was to evaluate the effect of DOACs and DOAC-Remove® on coagulation assays dur-ing thrombophilia testing. Methods. The study was car-ried out from January 2019 to the end of June 2020. It in-cluded 30 DOAC-treated patients, 14 females and 16 males aged 23 to 63 (median age 47.6 years), tested for thrombophilia due to venous thromboembolism (VTE). Thrombophilia testing was performed using DOAC-Remove® tablets (activated charcoal). The results before and after DOAC-Remove® were compared. Results. Posi-tive lupus anticoagulant (LA) results were observed in 20% apixaban, 100% dabigatran, and 70% rivaroxaban-treated patients, while in samples after DOAC-Remove®, the LA positivity was observed only in one from the apix-aban group. Before DOAC-Remove®, the activated pro-tein C (APC) resistance (APC-R) was measurable in 40% dabigatran and 80% rivaroxaban-treated patients, while, after using DOAC-Remove®, the APC-R was measurable in all cases. Comparing the results obtained from the sam-ples before and after DOAC-Remove®, a difference was noted in relation to all dilute Russell's viper venom time (dRVVT) coagulation tests, except for the dRVVT ratio in the apixaban group. Clot-based methods for detecting the APC resistance were significantly affected by dabigatran and less by rivaroxaban. Conclusion. DOACs were prac-tically inactivated after the addition of the DOAC-Remove®, which made it possible to perform analyses for the LA and APC-R testing freely and obtain relevant re-sults., Primena direktnih oralnih antikoagulansa (DOAK)značajno utiče na testove koagulacije. Cilj rada bio je da se pro-ceni uticaj DOAK i DOAC-Remove® tableta (aktivni ugalj) natestove koagulacije tokom ispitivanja trombofilije. Metode.Istraživanjem, sprovedenim od januara 2019. do juna 2020.godine, obuhvaćeno je 30 bolesnika lečenih DOAK-om itestiranih na trombofiliju zbog venskog tromboembolzma(VTE). Bilo je 14 žena i 16 muškaraca, starosti od 23 do 63godine (medijana 47,6 godina). Ispitivanje trombofilije izvršenoje upotrebom DOAC-Remove® tableta (aktivni ugalj).Upoređivani su rezultati pre i posle primene DOAC-Remove®.Rezultati. Pozitivni rezultati za lupus antikoagulantni (LA) testdobijeni su kod 20% bolesnika lečenih apiksabanom, kod100% bolesnika lečenih dabigatranom i kod 70% lečenih riva-roksabanom, a u uzorcima posle DOAC-Remove® pozitivnostna LA dobijena je samo kod jednog bolesnika iz grupe lečnihapiksabanom. Pre primene DOAC-Remove®, rezistencija naaktivisani protein C (activated protein C resistance – APC-R) bila jemerljiva kod 40% i 80% bolesnika lečenih dabigatranom, od-nosno rivaroksabanom, dok je posle primene DOAC-Remove®, APC-R bila merljiva u svim slučajevima.Upoređivanjem rezultata dobijenih iz uzoraka pre i posleprimene DOAC-Remove®, primećena je razlika u odnosu nasve testove vremena koagulacije izvršene razblaženim Russell-ovim zmijskim otrovom (dilute Russell’s viper venom time –dRVVT), osim dRVVT u grupi bolesnika lečenih apiksabanom.Na koagulacionu metodu za otkrivanje APC-R značajno je uti-cao dabigatran, a manje rivaroksaban. Zaključak. Nakonprimene DOAC-Remove® tableta, DOAK su praktičnoinaktivisani što je omogućilo izvođenje analiza za LA i APC-R idobijanje relevantnih rezultata testova.",
publisher = "Inst. Sci. inf., Univ. Defence in Belgrade",
journal = "Vojnosanitetski Pregled",
title = "Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients, Uticaj DOAK i DOAC-REMOVE® na testove koagulacije u toku testiranjatrombofilije kod bolesnika lečenih primenom DOAK",
pages = "1254-1248",
number = "12",
volume = "79",
doi = "10.2298/VSP210217101K"
}

Kovač, M., Basarić, D., Tomić, B., Gvozdenov, M., Backović, D.,& Lalić-Ćosić, S.. (2022). Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients. in Vojnosanitetski Pregled
Inst. Sci. inf., Univ. Defence in Belgrade., 79(12), 1248-1254.
https://doi.org/10.2298/VSP210217101K

Kovač M, Basarić D, Tomić B, Gvozdenov M, Backović D, Lalić-Ćosić S. Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients. in Vojnosanitetski Pregled. 2022;79(12):1248-1254.
doi:10.2298/VSP210217101K .

Kovač, Mirjana, Basarić, Dušica, Tomić, Branko, Gvozdenov, Maja, Backović, Dragana, Lalić-Ćosić, Sanja, "Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients" in Vojnosanitetski Pregled, 79, no. 12 (2022):1248-1254,
https://doi.org/10.2298/VSP210217101K . .

TY  - CONF
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Cumbo, Marija
AU  - Dunjić Manevski, Sofija
AU  - Đorđević, Valentina
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1739
AB  - Trombofilija je patofiziološko stanje povećanog rizika za nastanak
hiperkoagulacije, koja može dovesti do začepljenja krvnog suda (tromboze).
Faktori rizika za nastanak ove multifaktorijalne bolesti mogu biti sredinski,
uzrokovani načinom života, i nasledni (genetski). Do sada je identifikovan
veliki broj naslednih faktora rizika, uglavnom tačkastih mutacija u genima za
proteine hemostaznog sistema. Iako se ove mutacije analiziraju u okviru
rutinskih kliničkih testova, kod značajnog broja bolesnika i nakon sprovedenih
dijagnostičkih procedura, uzrok trombotičkog događaja ostaje nepoznat, što
implicira postojanje neidentifikovanih naslednih faktora rizika. U cilju
njihove identifikacije, vrše se dalje genske analize, asocijativne studije,
karakterizacije potencijalnih faktora rizika u in vitro i in vivo studijama na
različitim model sistemima. U našem dosadašnjem radu detektovano je više
varijanti u kodirajućem i nekodirajućem regionu gena, za koje je karakterizacijom
utvrđeno da utiču na ekspresiju i/ili funcionalnost koagulacionih proteina.
Primenom sekvenciranja nove generacije i bioinformatičke obrade, omogućena je
sveobuhvatnija analiza celokupnog genoma i identifikacija klastera gena koji su
povezani sa kompleksnom kliničkom slikom tromboza. Kombinovanjem velikog
broja podataka o genetskim i sredinskim faktorima, primenom veštačke
inteligencije, otvara se mogućnost kompletnijeg sagledavanja mehanizama
trombofilije i multifaktorijalnih bolesti uopšte.
AB  - Тромбофилија је патофизиолошко стање повећаног ризика за настанак
хиперкоагулације, која може довести до зачепљења крвног суда (тромбозе).
Фактори ризика за настанак ове мултифакторијалне болести могу бити средински,
узроковани начином живота, и наследни (генетски). До сада је идентификован
велики број наследних фактора ризика, углавном тачкастих мутација у генима за
протеине хемостазног система. Иако се ове мутације анализирају у оквиру
рутинских клиничких тестова, код значајног броја болесника и након спроведених
дијагностичких процедура, узрок тромботичког догађаја остаје непознат, што
имплицира постојање неидентификованих наследних фактора ризика. У циљу
њихове идентификације, врше се даље генске анализе, асоцијативне студије,
карактеризације потенцијалних фактора ризика у in vitro и in vivo студијама на
различитим модел системима. У нашем досадашњем раду детектовано је више
варијанти у кодирајућем и некодирајућем региону гена, за које је карактеризацијом
утврђено да утичу на експресију и/или фунционалност коагулационих протеина.
Применом секвенцирања нове генерације и биоинформатичке обраде, омогућена је
свеобухватнија анализа целокупног генома и идентификација кластера гена који су
повезани са комплексном клиничком сликом тромбоза. Комбиновањем великог
броја података о генетским и срединским факторима, применом вештачке
интелигенције, отвара се могућност комплетнијег сагледавања механизама
тромбофилије и мултифакторијалних болести уопште.
PB  - Beograd : Srpsko biološko društvo
C3  - Treći kongres biologa Srbije
T1  - Nasledni faktori rizika za trombofiliju – od tačkastih mutacija do primene veštačke inteligencije
T1  - Наследни фактори ризика за тромбофилију – од тачкастих мутација до примене вештачке интелигенције
SP  - 278
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1739
ER  - 

@conference{
author = "Tomić, Branko and Gvozdenov, Maja and Cumbo, Marija and Dunjić Manevski, Sofija and Đorđević, Valentina",
year = "2022",
abstract = "Trombofilija je patofiziološko stanje povećanog rizika za nastanak
hiperkoagulacije, koja može dovesti do začepljenja krvnog suda (tromboze).
Faktori rizika za nastanak ove multifaktorijalne bolesti mogu biti sredinski,
uzrokovani načinom života, i nasledni (genetski). Do sada je identifikovan
veliki broj naslednih faktora rizika, uglavnom tačkastih mutacija u genima za
proteine hemostaznog sistema. Iako se ove mutacije analiziraju u okviru
rutinskih kliničkih testova, kod značajnog broja bolesnika i nakon sprovedenih
dijagnostičkih procedura, uzrok trombotičkog događaja ostaje nepoznat, što
implicira postojanje neidentifikovanih naslednih faktora rizika. U cilju
njihove identifikacije, vrše se dalje genske analize, asocijativne studije,
karakterizacije potencijalnih faktora rizika u in vitro i in vivo studijama na
različitim model sistemima. U našem dosadašnjem radu detektovano je više
varijanti u kodirajućem i nekodirajućem regionu gena, za koje je karakterizacijom
utvrđeno da utiču na ekspresiju i/ili funcionalnost koagulacionih proteina.
Primenom sekvenciranja nove generacije i bioinformatičke obrade, omogućena je
sveobuhvatnija analiza celokupnog genoma i identifikacija klastera gena koji su
povezani sa kompleksnom kliničkom slikom tromboza. Kombinovanjem velikog
broja podataka o genetskim i sredinskim faktorima, primenom veštačke
inteligencije, otvara se mogućnost kompletnijeg sagledavanja mehanizama
trombofilije i multifaktorijalnih bolesti uopšte., Тромбофилија је патофизиолошко стање повећаног ризика за настанак
хиперкоагулације, која може довести до зачепљења крвног суда (тромбозе).
Фактори ризика за настанак ове мултифакторијалне болести могу бити средински,
узроковани начином живота, и наследни (генетски). До сада је идентификован
велики број наследних фактора ризика, углавном тачкастих мутација у генима за
протеине хемостазног система. Иако се ове мутације анализирају у оквиру
рутинских клиничких тестова, код значајног броја болесника и након спроведених
дијагностичких процедура, узрок тромботичког догађаја остаје непознат, што
имплицира постојање неидентификованих наследних фактора ризика. У циљу
њихове идентификације, врше се даље генске анализе, асоцијативне студије,
карактеризације потенцијалних фактора ризика у in vitro и in vivo студијама на
различитим модел системима. У нашем досадашњем раду детектовано је више
варијанти у кодирајућем и некодирајућем региону гена, за које је карактеризацијом
утврђено да утичу на експресију и/или фунционалност коагулационих протеина.
Применом секвенцирања нове генерације и биоинформатичке обраде, омогућена је
свеобухватнија анализа целокупног генома и идентификација кластера гена који су
повезани са комплексном клиничком сликом тромбоза. Комбиновањем великог
броја података о генетским и срединским факторима, применом вештачке
интелигенције, отвара се могућност комплетнијег сагледавања механизама
тромбофилије и мултифакторијалних болести уопште.",
publisher = "Beograd : Srpsko biološko društvo",
journal = "Treći kongres biologa Srbije",
title = "Nasledni faktori rizika za trombofiliju – od tačkastih mutacija do primene veštačke inteligencije, Наследни фактори ризика за тромбофилију – од тачкастих мутација до примене вештачке интелигенције",
pages = "278",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1739"
}

Tomić, B., Gvozdenov, M., Cumbo, M., Dunjić Manevski, S.,& Đorđević, V.. (2022). Nasledni faktori rizika za trombofiliju – od tačkastih mutacija do primene veštačke inteligencije. in Treći kongres biologa Srbije
Beograd : Srpsko biološko društvo., 278.
https://hdl.handle.net/21.15107/rcub_imagine_1739

Tomić B, Gvozdenov M, Cumbo M, Dunjić Manevski S, Đorđević V. Nasledni faktori rizika za trombofiliju – od tačkastih mutacija do primene veštačke inteligencije. in Treći kongres biologa Srbije. 2022;:278.
https://hdl.handle.net/21.15107/rcub_imagine_1739 .

Tomić, Branko, Gvozdenov, Maja, Cumbo, Marija, Dunjić Manevski, Sofija, Đorđević, Valentina, "Nasledni faktori rizika za trombofiliju – od tačkastih mutacija do primene veštačke inteligencije" in Treći kongres biologa Srbije (2022):278,
https://hdl.handle.net/21.15107/rcub_imagine_1739 .

TY  - JOUR
AU  - Pruner, Iva
AU  - Dinčić, Evica
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Kovač, Mirjana
AU  - Đorđević, Valentina
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1646
AB  - Introduction. Ischemic stroke (IS) is a heterogeneous dis-order caused by several genetic and environmental risk factors. It was suggested that coagulation disorders cause 1-4% of cases with IS, especially in patients with early onset of IS. Case report. We describe a case of a young adult male who developed an unprovoked IS. Biochemical, immunological, and thrombophilia screening, as well as DNA sequencing, were performed in order to reveal molecular pathology underlying the stroke of the patient. Thrombophilia testing showed that patient was a homozygous carrier for PAI-1 4G/5G and MTHFR C677T mutations. Additional genetic analysis revealed the presence of the recently reported F2 c.1824C>T gene variant, located in the last exon of the pro-thrombin gene and has previously been shown to cause hy-perprothrombinemia, hypofibrinolysis, and altered fibrin clot phenotype. Conclusion. Our results suggest that the newly reported F2 c.1824C>T gene variant might have a synergistic effect with PAI 4G/4G and MTHFR 677TT genotype in the formation of altered fibrin clot phenotype characterized by thin, densely packed fibrin fibers, which makes clot less susceptible to fibrinolysis and greatly in-creases the risk for early ischemic stroke onset.
AB  - Ishemijski moždani udar (IMU) je heterogeni poremećaj
koji može biti uzrokovan genetskim faktorima rizika i faktorima
sredine. Poremećaji koagulacije mogu biti uzročnici u 1-4%
slučajeva IMU, naročito kod bolesnika kod kojih se IMU dogodi u
mlađem životnom dobu. Prikaz bolesnika. Prikazan je slučaj
bolesnika koji je u mlađem životnom dobu razvio IMU
nepoznatog uzroka. Urađeni su biohemijski, imunološki i testovi za
trombofiliju kao i sekvenciranje DNK sa ciljem da se utvrdi
molekularna patologija koja je mogla biti u osnovi moždanog udara
kod tog bolesnika. Testovima za trombofiliju utvrđeno je da je
bolesnik homozigotni nosilac mutacija PAI-1 4G/5G i MTHFR
C677T. Dodatnom genetičkom analizom otkriveno je prisustvo
nedavno opisane F2 c.1824C>T genske varijante, koja se nalazi u
poslednjem egzonu gena za protrombin i za koju je prethodno
pokazano da izaziva hiperprotrombinemiju, hipofibrinolizu i
izmenjeni fenotip fibrinskog ugruška. Zaključak. Naši rezultati
ukazuju na to da bi nova F2 c.1824C>T genska varijanta mogla
imati sinergistički efekat sa PAI 4G/4G i MTHFR 677TT
genotipom u nastanku fibrinskog ugruška sa izmenjenim
fenotipom, koji se odlikuje tankim, gusto upakovanim fibrinskim
vlaknima, što čini ugrušak manje podložnim fibrinolizi i povećava
rizik od nastanka IMU u ranijem životnom dobu.
T2  - Vojnosanitetski pregled
T2  - Vojnosanitetski pregled
T1  - Early-onset ischaemic stroke in a patient with the novel F2 c.1824C>T gene variant and PAI-1 4G/4G, MTHFR 677TT genotype
EP  - 1043
IS  - 10
SP  - 1039
VL  - 79
DO  - doi.org/10.2298/VSP210323066P
ER  - 

@article{
author = "Pruner, Iva and Dinčić, Evica and Gvozdenov, Maja and Tomić, Branko and Kovač, Mirjana and Đorđević, Valentina",
year = "2022",
abstract = "Introduction. Ischemic stroke (IS) is a heterogeneous dis-order caused by several genetic and environmental risk factors. It was suggested that coagulation disorders cause 1-4% of cases with IS, especially in patients with early onset of IS. Case report. We describe a case of a young adult male who developed an unprovoked IS. Biochemical, immunological, and thrombophilia screening, as well as DNA sequencing, were performed in order to reveal molecular pathology underlying the stroke of the patient. Thrombophilia testing showed that patient was a homozygous carrier for PAI-1 4G/5G and MTHFR C677T mutations. Additional genetic analysis revealed the presence of the recently reported F2 c.1824C>T gene variant, located in the last exon of the pro-thrombin gene and has previously been shown to cause hy-perprothrombinemia, hypofibrinolysis, and altered fibrin clot phenotype. Conclusion. Our results suggest that the newly reported F2 c.1824C>T gene variant might have a synergistic effect with PAI 4G/4G and MTHFR 677TT genotype in the formation of altered fibrin clot phenotype characterized by thin, densely packed fibrin fibers, which makes clot less susceptible to fibrinolysis and greatly in-creases the risk for early ischemic stroke onset., Ishemijski moždani udar (IMU) je heterogeni poremećaj
koji može biti uzrokovan genetskim faktorima rizika i faktorima
sredine. Poremećaji koagulacije mogu biti uzročnici u 1-4%
slučajeva IMU, naročito kod bolesnika kod kojih se IMU dogodi u
mlađem životnom dobu. Prikaz bolesnika. Prikazan je slučaj
bolesnika koji je u mlađem životnom dobu razvio IMU
nepoznatog uzroka. Urađeni su biohemijski, imunološki i testovi za
trombofiliju kao i sekvenciranje DNK sa ciljem da se utvrdi
molekularna patologija koja je mogla biti u osnovi moždanog udara
kod tog bolesnika. Testovima za trombofiliju utvrđeno je da je
bolesnik homozigotni nosilac mutacija PAI-1 4G/5G i MTHFR
C677T. Dodatnom genetičkom analizom otkriveno je prisustvo
nedavno opisane F2 c.1824C>T genske varijante, koja se nalazi u
poslednjem egzonu gena za protrombin i za koju je prethodno
pokazano da izaziva hiperprotrombinemiju, hipofibrinolizu i
izmenjeni fenotip fibrinskog ugruška. Zaključak. Naši rezultati
ukazuju na to da bi nova F2 c.1824C>T genska varijanta mogla
imati sinergistički efekat sa PAI 4G/4G i MTHFR 677TT
genotipom u nastanku fibrinskog ugruška sa izmenjenim
fenotipom, koji se odlikuje tankim, gusto upakovanim fibrinskim
vlaknima, što čini ugrušak manje podložnim fibrinolizi i povećava
rizik od nastanka IMU u ranijem životnom dobu.",
journal = "Vojnosanitetski pregled, Vojnosanitetski pregled",
title = "Early-onset ischaemic stroke in a patient with the novel F2 c.1824C>T gene variant and PAI-1 4G/4G, MTHFR 677TT genotype",
pages = "1043-1039",
number = "10",
volume = "79",
doi = "doi.org/10.2298/VSP210323066P"
}

Pruner, I., Dinčić, E., Gvozdenov, M., Tomić, B., Kovač, M.,& Đorđević, V.. (2022). Early-onset ischaemic stroke in a patient with the novel F2 c.1824C>T gene variant and PAI-1 4G/4G, MTHFR 677TT genotype. in Vojnosanitetski pregled, 79(10), 1039-1043.
https://doi.org/doi.org/10.2298/VSP210323066P

Pruner I, Dinčić E, Gvozdenov M, Tomić B, Kovač M, Đorđević V. Early-onset ischaemic stroke in a patient with the novel F2 c.1824C>T gene variant and PAI-1 4G/4G, MTHFR 677TT genotype. in Vojnosanitetski pregled. 2022;79(10):1039-1043.
doi:doi.org/10.2298/VSP210323066P .

Pruner, Iva, Dinčić, Evica, Gvozdenov, Maja, Tomić, Branko, Kovač, Mirjana, Đorđević, Valentina, "Early-onset ischaemic stroke in a patient with the novel F2 c.1824C>T gene variant and PAI-1 4G/4G, MTHFR 677TT genotype" in Vojnosanitetski pregled, 79, no. 10 (2022):1039-1043,
https://doi.org/doi.org/10.2298/VSP210323066P . .

TY  - CONF
AU  - Dunjić, Sofija
AU  - Cumbo, Marija
AU  - Gvozdenov, Maja
AU  - Taxiarchis, Apostolos
AU  - Tomić, Branko
AU  - Antović, Jovan
AU  - Đorđević, Valentina
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1635
AB  - Prothrombin Belgrade mutation is a result of the c.1787G>T
mutation in the prothrombin gene, which leads to the substitution of
Arg596 by Gln. This mutation is located in the antithrombin binding site
and leads to the impaired inactivation of thrombin by antithrombin and
antithrombin resistance, resulting in a thrombotic phenotype. Previous
studies have shown the complex mechanism of this mutation, manifested with higher endogenous thrombin potential, lower prothrombin
activity with normal prothrombin levels in carriers’ plasma.
C3  - Research and Practice in Thrombosis and Haemostasis
C3  - Research and Practice in Thrombosis and Haemostasis
T1  - The prothrombin Belgrade mutation causing antithrombin resistance does not affect fibrin clot formation
EP  - 1117
IS  - 1
SP  - 1117
VL  - 4
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1635
ER  - 

@conference{
author = "Dunjić, Sofija and Cumbo, Marija and Gvozdenov, Maja and Taxiarchis, Apostolos and Tomić, Branko and Antović, Jovan and Đorđević, Valentina",
year = "2020",
abstract = "Prothrombin Belgrade mutation is a result of the c.1787G>T
mutation in the prothrombin gene, which leads to the substitution of
Arg596 by Gln. This mutation is located in the antithrombin binding site
and leads to the impaired inactivation of thrombin by antithrombin and
antithrombin resistance, resulting in a thrombotic phenotype. Previous
studies have shown the complex mechanism of this mutation, manifested with higher endogenous thrombin potential, lower prothrombin
activity with normal prothrombin levels in carriers’ plasma.",
journal = "Research and Practice in Thrombosis and Haemostasis, Research and Practice in Thrombosis and Haemostasis",
title = "The prothrombin Belgrade mutation causing antithrombin resistance does not affect fibrin clot formation",
pages = "1117-1117",
number = "1",
volume = "4",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1635"
}

Dunjić, S., Cumbo, M., Gvozdenov, M., Taxiarchis, A., Tomić, B., Antović, J.,& Đorđević, V.. (2020). The prothrombin Belgrade mutation causing antithrombin resistance does not affect fibrin clot formation. in Research and Practice in Thrombosis and Haemostasis, 4(1), 1117-1117.
https://hdl.handle.net/21.15107/rcub_imagine_1635

Dunjić S, Cumbo M, Gvozdenov M, Taxiarchis A, Tomić B, Antović J, Đorđević V. The prothrombin Belgrade mutation causing antithrombin resistance does not affect fibrin clot formation. in Research and Practice in Thrombosis and Haemostasis. 2020;4(1):1117-1117.
https://hdl.handle.net/21.15107/rcub_imagine_1635 .

Dunjić, Sofija, Cumbo, Marija, Gvozdenov, Maja, Taxiarchis, Apostolos, Tomić, Branko, Antović, Jovan, Đorđević, Valentina, "The prothrombin Belgrade mutation causing antithrombin resistance does not affect fibrin clot formation" in Research and Practice in Thrombosis and Haemostasis, 4, no. 1 (2020):1117-1117,
https://hdl.handle.net/21.15107/rcub_imagine_1635 .

TY  - JOUR
AU  - Pruner, Iva
AU  - Farm, Maria
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Kovač, Mirjana
AU  - Miljić, Predrag
AU  - Soutari, Nida Mahmoud Hourani
AU  - Antović, Aleksandra
AU  - Radojković, Dragica
AU  - Antović, Jovan P.
AU  - Đorđević, Valentina
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1375
AB  - BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt  T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt  T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt  T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt  T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt  T transfected cells. Our ex vivo study of FII c.1824C gt  T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt  T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt  T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests.
PB  - Oxford Univ Press Inc, Cary
T2  - Clinical Chemistry
T1  - The Silence Speaks, but We Do Not Listen: Synonymous c.1824C  gt  T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor
EP  - 389
IS  - 2
SP  - 379
VL  - 66
DO  - 10.1093/clinchem/hvz015
ER  - 

@article{
author = "Pruner, Iva and Farm, Maria and Tomić, Branko and Gvozdenov, Maja and Kovač, Mirjana and Miljić, Predrag and Soutari, Nida Mahmoud Hourani and Antović, Aleksandra and Radojković, Dragica and Antović, Jovan P. and Đorđević, Valentina",
year = "2020",
abstract = "BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt  T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt  T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt  T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt  T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt  T transfected cells. Our ex vivo study of FII c.1824C gt  T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt  T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt  T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests.",
publisher = "Oxford Univ Press Inc, Cary",
journal = "Clinical Chemistry",
title = "The Silence Speaks, but We Do Not Listen: Synonymous c.1824C  gt  T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor",
pages = "389-379",
number = "2",
volume = "66",
doi = "10.1093/clinchem/hvz015"
}

Pruner, I., Farm, M., Tomić, B., Gvozdenov, M., Kovač, M., Miljić, P., Soutari, N. M. H., Antović, A., Radojković, D., Antović, J. P.,& Đorđević, V.. (2020). The Silence Speaks, but We Do Not Listen: Synonymous c.1824C  gt  T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor. in Clinical Chemistry
Oxford Univ Press Inc, Cary., 66(2), 379-389.
https://doi.org/10.1093/clinchem/hvz015

Pruner I, Farm M, Tomić B, Gvozdenov M, Kovač M, Miljić P, Soutari NMH, Antović A, Radojković D, Antović JP, Đorđević V. The Silence Speaks, but We Do Not Listen: Synonymous c.1824C  gt  T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor. in Clinical Chemistry. 2020;66(2):379-389.
doi:10.1093/clinchem/hvz015 .

Pruner, Iva, Farm, Maria, Tomić, Branko, Gvozdenov, Maja, Kovač, Mirjana, Miljić, Predrag, Soutari, Nida Mahmoud Hourani, Antović, Aleksandra, Radojković, Dragica, Antović, Jovan P., Đorđević, Valentina, "The Silence Speaks, but We Do Not Listen: Synonymous c.1824C  gt  T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor" in Clinical Chemistry, 66, no. 2 (2020):379-389,
https://doi.org/10.1093/clinchem/hvz015 . .

TY  - CONF
AU  - Tomić, Branko
AU  - Kovač, Mirjana
AU  - Pruner, Iva
AU  - Gvozdenov, Maja
AU  - Dunjić, Sofija
AU  - Cumbo, Marija
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2145
AB  - PURPOSE: Thrombosis is multicausal disease in which both acquired and genetic risk factors play
important roles. The most frequent genetic risk factors known to date are the Factor V G1691A (FV
Leiden) and FII G20210A mutations. On the other hand, inherited antithrombin (AT) deficiency, caused
by mutations in the AT gene (SERPINC1) is a very rare disorder, but it is associated with significant risk
for thrombotic complications. AT deficiency is classified into two types: type-I is a quantitative disorder
characterized by decreased amount and activity of AT, while type-II is a qualitative - functional disorder.
Aim of our study was to analyze the frequency of FV Leiden and FII G20210A mutations in patients with
inherited AT deficiency from Serbia.
METHODOLOGY: A study was carried out in large group of AT deficiency patients from Serbia. Cohort
of 42 subjects (15m/27f; 36.7±18.7y) from 18 Serbian families included 24 symptomatic and 18
asymptomatic first-degree relatives. Among them, type-I AT deficiency were detected in 9 families (19
members: 6m/13f; 37.1±19.0y) and type-II in 9 families (23 members: 9m/14f; 36.5±18.8y). FV Leiden
and FII G2010A mutations were detected by PCR, followed by digestion with specific restriction enzymes
(PCR-RFLP).
RESULTS: We have detected 3 FV Leiden heterozygous carriers in 3 different families (1 with type-I
and 2 with type-II AT deficiency). All 3 carriers were symptomatic. Regarding FII G20210A mutation, 2
heterozygous carriers, both asymptomatic and from same family with type-I deficiency, were identified.
According to our findings in families with AT deficiency from Serbia frequency of FV Leiden and FII
G20210A mutation are 16.7% and 5.6%, respectively.
CONCLUSION: This is the first study in which frequency of FV Leiden and FII G20210A mutations in
patients with inherited AT deficiency from Serbia were examined. Results of our study suggest that
these mutations can be relevant for AT deficiency patients’ phenotype, but further studies are required.
C3  - 16th International  Hemophilia Congress of Turkey
T1  - Frequency of FV Leiden and FII G20210A Mutations in Patients with Inherited Antithrombin Deficiency from Serbia
EP  - 212
SP  - 212
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2145
ER  - 

@conference{
author = "Tomić, Branko and Kovač, Mirjana and Pruner, Iva and Gvozdenov, Maja and Dunjić, Sofija and Cumbo, Marija and Radojković, Dragica and Đorđević, Valentina",
year = "2019",
abstract = "PURPOSE: Thrombosis is multicausal disease in which both acquired and genetic risk factors play
important roles. The most frequent genetic risk factors known to date are the Factor V G1691A (FV
Leiden) and FII G20210A mutations. On the other hand, inherited antithrombin (AT) deficiency, caused
by mutations in the AT gene (SERPINC1) is a very rare disorder, but it is associated with significant risk
for thrombotic complications. AT deficiency is classified into two types: type-I is a quantitative disorder
characterized by decreased amount and activity of AT, while type-II is a qualitative - functional disorder.
Aim of our study was to analyze the frequency of FV Leiden and FII G20210A mutations in patients with
inherited AT deficiency from Serbia.
METHODOLOGY: A study was carried out in large group of AT deficiency patients from Serbia. Cohort
of 42 subjects (15m/27f; 36.7±18.7y) from 18 Serbian families included 24 symptomatic and 18
asymptomatic first-degree relatives. Among them, type-I AT deficiency were detected in 9 families (19
members: 6m/13f; 37.1±19.0y) and type-II in 9 families (23 members: 9m/14f; 36.5±18.8y). FV Leiden
and FII G2010A mutations were detected by PCR, followed by digestion with specific restriction enzymes
(PCR-RFLP).
RESULTS: We have detected 3 FV Leiden heterozygous carriers in 3 different families (1 with type-I
and 2 with type-II AT deficiency). All 3 carriers were symptomatic. Regarding FII G20210A mutation, 2
heterozygous carriers, both asymptomatic and from same family with type-I deficiency, were identified.
According to our findings in families with AT deficiency from Serbia frequency of FV Leiden and FII
G20210A mutation are 16.7% and 5.6%, respectively.
CONCLUSION: This is the first study in which frequency of FV Leiden and FII G20210A mutations in
patients with inherited AT deficiency from Serbia were examined. Results of our study suggest that
these mutations can be relevant for AT deficiency patients’ phenotype, but further studies are required.",
journal = "16th International  Hemophilia Congress of Turkey",
title = "Frequency of FV Leiden and FII G20210A Mutations in Patients with Inherited Antithrombin Deficiency from Serbia",
pages = "212-212",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2145"
}

Tomić, B., Kovač, M., Pruner, I., Gvozdenov, M., Dunjić, S., Cumbo, M., Radojković, D.,& Đorđević, V.. (2019). Frequency of FV Leiden and FII G20210A Mutations in Patients with Inherited Antithrombin Deficiency from Serbia. in 16th International  Hemophilia Congress of Turkey, 212-212.
https://hdl.handle.net/21.15107/rcub_imagine_2145

Tomić B, Kovač M, Pruner I, Gvozdenov M, Dunjić S, Cumbo M, Radojković D, Đorđević V. Frequency of FV Leiden and FII G20210A Mutations in Patients with Inherited Antithrombin Deficiency from Serbia. in 16th International  Hemophilia Congress of Turkey. 2019;:212-212.
https://hdl.handle.net/21.15107/rcub_imagine_2145 .

Tomić, Branko, Kovač, Mirjana, Pruner, Iva, Gvozdenov, Maja, Dunjić, Sofija, Cumbo, Marija, Radojković, Dragica, Đorđević, Valentina, "Frequency of FV Leiden and FII G20210A Mutations in Patients with Inherited Antithrombin Deficiency from Serbia" in 16th International  Hemophilia Congress of Turkey (2019):212-212,
https://hdl.handle.net/21.15107/rcub_imagine_2145 .

TY  - JOUR
AU  - Cumbo, Marija
AU  - Tomić, Branko
AU  - Dunjić Manevski, Sofija
AU  - Jovanović, Tamara
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Aralica, Gorana
AU  - Kapitanović, Sanja
AU  - Cacev, Tamara
AU  - Đorđević, Valentina
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1219
AB  - Background/ Aim: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. Materials and Methods: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. Results: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. Conclusion: Prothrombin 3' end gene variants may play a role in colorectal cancer.
PB  - Int Inst Anticancer Research, Athens
T2  - Anticancer Research
T1  - Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma
EP  - 6071
IS  - 11
SP  - 6067
VL  - 39
DO  - 10.21873/anticanres.13814
ER  - 

@article{
author = "Cumbo, Marija and Tomić, Branko and Dunjić Manevski, Sofija and Jovanović, Tamara and Gvozdenov, Maja and Pruner, Iva and Aralica, Gorana and Kapitanović, Sanja and Cacev, Tamara and Đorđević, Valentina",
year = "2019",
abstract = "Background/ Aim: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. Materials and Methods: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. Results: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. Conclusion: Prothrombin 3' end gene variants may play a role in colorectal cancer.",
publisher = "Int Inst Anticancer Research, Athens",
journal = "Anticancer Research",
title = "Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma",
pages = "6071-6067",
number = "11",
volume = "39",
doi = "10.21873/anticanres.13814"
}

Cumbo, M., Tomić, B., Dunjić Manevski, S., Jovanović, T., Gvozdenov, M., Pruner, I., Aralica, G., Kapitanović, S., Cacev, T.,& Đorđević, V.. (2019). Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma. in Anticancer Research
Int Inst Anticancer Research, Athens., 39(11), 6067-6071.
https://doi.org/10.21873/anticanres.13814

Cumbo M, Tomić B, Dunjić Manevski S, Jovanović T, Gvozdenov M, Pruner I, Aralica G, Kapitanović S, Cacev T, Đorđević V. Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma. in Anticancer Research. 2019;39(11):6067-6071.
doi:10.21873/anticanres.13814 .

Cumbo, Marija, Tomić, Branko, Dunjić Manevski, Sofija, Jovanović, Tamara, Gvozdenov, Maja, Pruner, Iva, Aralica, Gorana, Kapitanović, Sanja, Cacev, Tamara, Đorđević, Valentina, "Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma" in Anticancer Research, 39, no. 11 (2019):6067-6071,
https://doi.org/10.21873/anticanres.13814 . .

TY  - JOUR
AU  - Kovač, Mirjana
AU  - Kovac, Zeljko
AU  - Tomasević, Zorica
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Radojković, Dragica
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1250
PB  - Wiley, Hoboken
T2  - Breast Journal
T1  - Breast cancer and recurrent thrombosis - Results from prospective single center study
EP  - 785
IS  - 4
SP  - 783
VL  - 25
DO  - 10.1111/tbj.13326
ER  - 

@article{
author = "Kovač, Mirjana and Kovac, Zeljko and Tomasević, Zorica and Tomić, Branko and Gvozdenov, Maja and Radojković, Dragica",
year = "2019",
publisher = "Wiley, Hoboken",
journal = "Breast Journal",
title = "Breast cancer and recurrent thrombosis - Results from prospective single center study",
pages = "785-783",
number = "4",
volume = "25",
doi = "10.1111/tbj.13326"
}

Kovač, M., Kovac, Z., Tomasević, Z., Tomić, B., Gvozdenov, M.,& Radojković, D.. (2019). Breast cancer and recurrent thrombosis - Results from prospective single center study. in Breast Journal
Wiley, Hoboken., 25(4), 783-785.
https://doi.org/10.1111/tbj.13326

Kovač M, Kovac Z, Tomasević Z, Tomić B, Gvozdenov M, Radojković D. Breast cancer and recurrent thrombosis - Results from prospective single center study. in Breast Journal. 2019;25(4):783-785.
doi:10.1111/tbj.13326 .

Kovač, Mirjana, Kovac, Zeljko, Tomasević, Zorica, Tomić, Branko, Gvozdenov, Maja, Radojković, Dragica, "Breast cancer and recurrent thrombosis - Results from prospective single center study" in Breast Journal, 25, no. 4 (2019):783-785,
https://doi.org/10.1111/tbj.13326 . .

TY  - JOUR
AU  - Dunjić Manevski, Sofija
AU  - Cumbo, Marija
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Pruner, Iva
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1244
AB  - The link between thrombotic disorders and cancer has been known for over 150 years, although the precise mechanism of this relationship has not yet been resolved. Current data show that thrombin has a significant role in cancer metabolism, invasiveness, adhesion and survival. However, data regarding the expression of the thrombin precursor prothrombin in various cancer cell lines are scarce. Therefore, it was our objective to determine whether common cancer-derived cell lines (Caco-2, MCF-7, SK-BR-3, U-87 and U-251) express prothrombin. The prothrombin RNA expression level was assessed by qPCR, and the presence of prothrombin was analyzed by Western blot analysis. Our results show that Caco-2 cells originating from colorectal adenocarcinoma express prothrombin, whereas other analyzed cell lines do not. Our results provide a background for further research into the role of (pro) thrombin in cancer etiopathology.
PB  - Srpsko biološko društvo, Beograd, i dr.
T2  - Archives of Biological Sciences
T1  - Prothrombin expression in cancer-derived cell lines
EP  - 54
IS  - 1
SP  - 49
VL  - 71
DO  - 10.2298/ABS180829046D
ER  - 

@article{
author = "Dunjić Manevski, Sofija and Cumbo, Marija and Gvozdenov, Maja and Tomić, Branko and Pruner, Iva and Radojković, Dragica and Đorđević, Valentina",
year = "2019",
abstract = "The link between thrombotic disorders and cancer has been known for over 150 years, although the precise mechanism of this relationship has not yet been resolved. Current data show that thrombin has a significant role in cancer metabolism, invasiveness, adhesion and survival. However, data regarding the expression of the thrombin precursor prothrombin in various cancer cell lines are scarce. Therefore, it was our objective to determine whether common cancer-derived cell lines (Caco-2, MCF-7, SK-BR-3, U-87 and U-251) express prothrombin. The prothrombin RNA expression level was assessed by qPCR, and the presence of prothrombin was analyzed by Western blot analysis. Our results show that Caco-2 cells originating from colorectal adenocarcinoma express prothrombin, whereas other analyzed cell lines do not. Our results provide a background for further research into the role of (pro) thrombin in cancer etiopathology.",
publisher = "Srpsko biološko društvo, Beograd, i dr.",
journal = "Archives of Biological Sciences",
title = "Prothrombin expression in cancer-derived cell lines",
pages = "54-49",
number = "1",
volume = "71",
doi = "10.2298/ABS180829046D"
}

Dunjić Manevski, S., Cumbo, M., Gvozdenov, M., Tomić, B., Pruner, I., Radojković, D.,& Đorđević, V.. (2019). Prothrombin expression in cancer-derived cell lines. in Archives of Biological Sciences
Srpsko biološko društvo, Beograd, i dr.., 71(1), 49-54.
https://doi.org/10.2298/ABS180829046D

Dunjić Manevski S, Cumbo M, Gvozdenov M, Tomić B, Pruner I, Radojković D, Đorđević V. Prothrombin expression in cancer-derived cell lines. in Archives of Biological Sciences. 2019;71(1):49-54.
doi:10.2298/ABS180829046D .

Dunjić Manevski, Sofija, Cumbo, Marija, Gvozdenov, Maja, Tomić, Branko, Pruner, Iva, Radojković, Dragica, Đorđević, Valentina, "Prothrombin expression in cancer-derived cell lines" in Archives of Biological Sciences, 71, no. 1 (2019):49-54,
https://doi.org/10.2298/ABS180829046D . .

TY  - JOUR
AU  - Pruner, Iva
AU  - Tomić, Branko
AU  - Dragojević, Marija
AU  - Gvozdenov, Maja
AU  - Kovač, Mirjana
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1209
AB  - Breast cancer is the leading cause of cancer-related death among women. An increased burden of thrombotic events among breast cancer patients, leading to higher mortality and morbidity rates, is well established. There are a number of genetic risk factors associated with thrombosis, but their contribution to thrombotic tendencies in patients with cancer is not completely elucidated. We aimed to investigate possible role of FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G gene variants in etiopathology of breast cancer and accompanying thrombosis in cohort of Serbian patients. Our study included 316 subject divided in three groups: breast cancer patients with (97) or without (99) accompanying thrombosis and healthy control group (120). According to our results, the prevalence for all four prothrombotic gene variants were similar in cancer patients with and without thrombosis and no statistically significant difference was observed between these groups. We detected lower frequency of MTHFR 677TT genotype in breast cancer patients when compared to control group (P=0.014; OR=0.145 (95%CI 0.031-0.679)), indicated that MTHFR C677T homozygosity could play a protective role in breast cancer susceptibility. Our study noted the lack of association between common prothrombotic gene variants and increased prothrombotic risk in Serbian breast cancer patients. Also, our results point out possible role of MTHFR 677TT genotype in etiology of breast cancer, but further studies on larger cohort of patients are needed.
PB  - Društvo genetičara Srbije, Beograd
T2  - Genetika-Belgrade
T1  - Inherited thrombophilic risk factors in Serbian breast cancer patients
EP  - 472
IS  - 2
SP  - 463
VL  - 51
DO  - 10.2298/GENSR1902463P
ER  - 

@article{
author = "Pruner, Iva and Tomić, Branko and Dragojević, Marija and Gvozdenov, Maja and Kovač, Mirjana and Radojković, Dragica and Đorđević, Valentina",
year = "2019",
abstract = "Breast cancer is the leading cause of cancer-related death among women. An increased burden of thrombotic events among breast cancer patients, leading to higher mortality and morbidity rates, is well established. There are a number of genetic risk factors associated with thrombosis, but their contribution to thrombotic tendencies in patients with cancer is not completely elucidated. We aimed to investigate possible role of FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G gene variants in etiopathology of breast cancer and accompanying thrombosis in cohort of Serbian patients. Our study included 316 subject divided in three groups: breast cancer patients with (97) or without (99) accompanying thrombosis and healthy control group (120). According to our results, the prevalence for all four prothrombotic gene variants were similar in cancer patients with and without thrombosis and no statistically significant difference was observed between these groups. We detected lower frequency of MTHFR 677TT genotype in breast cancer patients when compared to control group (P=0.014; OR=0.145 (95%CI 0.031-0.679)), indicated that MTHFR C677T homozygosity could play a protective role in breast cancer susceptibility. Our study noted the lack of association between common prothrombotic gene variants and increased prothrombotic risk in Serbian breast cancer patients. Also, our results point out possible role of MTHFR 677TT genotype in etiology of breast cancer, but further studies on larger cohort of patients are needed.",
publisher = "Društvo genetičara Srbije, Beograd",
journal = "Genetika-Belgrade",
title = "Inherited thrombophilic risk factors in Serbian breast cancer patients",
pages = "472-463",
number = "2",
volume = "51",
doi = "10.2298/GENSR1902463P"
}

Pruner, I., Tomić, B., Dragojević, M., Gvozdenov, M., Kovač, M., Radojković, D.,& Đorđević, V.. (2019). Inherited thrombophilic risk factors in Serbian breast cancer patients. in Genetika-Belgrade
Društvo genetičara Srbije, Beograd., 51(2), 463-472.
https://doi.org/10.2298/GENSR1902463P

Pruner I, Tomić B, Dragojević M, Gvozdenov M, Kovač M, Radojković D, Đorđević V. Inherited thrombophilic risk factors in Serbian breast cancer patients. in Genetika-Belgrade. 2019;51(2):463-472.
doi:10.2298/GENSR1902463P .

Pruner, Iva, Tomić, Branko, Dragojević, Marija, Gvozdenov, Maja, Kovač, Mirjana, Radojković, Dragica, Đorđević, Valentina, "Inherited thrombophilic risk factors in Serbian breast cancer patients" in Genetika-Belgrade, 51, no. 2 (2019):463-472,
https://doi.org/10.2298/GENSR1902463P . .

TY  - CONF
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Tomić, Branko
AU  - Kovač, Mirjana
AU  - Miljić, Predrag
AU  - Antić, Darko
AU  - Đorđević, Valentina
AU  - Radojković, Dragica
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1136
PB  - Nature Publishing Group, London
C3  - European Journal of Human Genetics
T1  - Functional analyses of the FIIc.*64_*66del gene variant and its potential role in fetal loss etiology
EP  - 828
SP  - 827
VL  - 26
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1136
ER  - 

@conference{
author = "Gvozdenov, Maja and Pruner, Iva and Tomić, Branko and Kovač, Mirjana and Miljić, Predrag and Antić, Darko and Đorđević, Valentina and Radojković, Dragica",
year = "2018",
publisher = "Nature Publishing Group, London",
journal = "European Journal of Human Genetics",
title = "Functional analyses of the FIIc.*64_*66del gene variant and its potential role in fetal loss etiology",
pages = "828-827",
volume = "26",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1136"
}

Gvozdenov, M., Pruner, I., Tomić, B., Kovač, M., Miljić, P., Antić, D., Đorđević, V.,& Radojković, D.. (2018). Functional analyses of the FIIc.*64_*66del gene variant and its potential role in fetal loss etiology. in European Journal of Human Genetics
Nature Publishing Group, London., 26, 827-828.
https://hdl.handle.net/21.15107/rcub_imagine_1136

Gvozdenov M, Pruner I, Tomić B, Kovač M, Miljić P, Antić D, Đorđević V, Radojković D. Functional analyses of the FIIc.*64_*66del gene variant and its potential role in fetal loss etiology. in European Journal of Human Genetics. 2018;26:827-828.
https://hdl.handle.net/21.15107/rcub_imagine_1136 .

Gvozdenov, Maja, Pruner, Iva, Tomić, Branko, Kovač, Mirjana, Miljić, Predrag, Antić, Darko, Đorđević, Valentina, Radojković, Dragica, "Functional analyses of the FIIc.*64_*66del gene variant and its potential role in fetal loss etiology" in European Journal of Human Genetics, 26 (2018):827-828,
https://hdl.handle.net/21.15107/rcub_imagine_1136 .

TY  - THES
AU  - Gvozdenov, Maja
PY  - 2017
UR  - https://nardus.mpn.gov.rs/handle/123456789/8364
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=5098
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:15910/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025154994
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/44
AB  - Protrombin predstavlja zimogen trombina (koagulacinog faktora II), koji ima  centralnu ulogu u održanju hemostazne ravnoteže. Zahvaljujući alosteričnoj regulaciji,  trombin može da vrši i prokoagulantnu i antikoagulantnu funkciju. Region 3' kraja gena  za protrombin ima nekanonsku organizaciju i podložan je nastanku genskih varijanti  koje mogu imati značajnu ulogu u regulaciji ekspresije i funkcije protrombina. Do sada  opisane varijante u ovom regionu su povezivane sa povišenom ekspresijom protrombina  koja može dovesti do hiperkoagulacije i povećane sklonosti ka trombozama, odnosno  trombofiliji.  U Laboratoriji za molekularnu biologiju, Instituta za molekularnu genetiku i  genetičko inženjerstvo, u 3' kraju gena za protrombin opisane su FIIc.1787G>A i  FIIc.*64_*66del varijante čiji mehanizmi do sada nisu rasvetljeni. Varijanta  FIIc.1787G>A (protrombin Beograd) se nalazi u poslednjem egzonu gena za  protrombin i dovodi do aminokiselinske zamene Arg596Gln u proteinu. Ova varijanta  se nalazi u regionu za koji se vezuju joni natrijuma, neophodni za prokoagulantnu  aktivnost trombina, kao i prirodni trombinski inhibitor- antitrombin. Varijanta  FIIc.*64_*66del se nalazi u 3' netranslatirajućem regionu gena i predstavlja deleciju 3  nukleotida. Imajući u vidu pozicije u različitim strukturnim elementima 3' kraja gena,  pretpostavlja se da su mehanizmi delovanja ovih varijanti različiti.  Prvi deo studije je imao za cilj određivanje učestalosti FIIc.1787G>A i  FIIc.*64_*66del varijanti kod 353 pacijenta sa različitim trombotičkim poremećajima i  250 zdravih ispitanika u srpskoj populaciji. Pacijenti su u zavisnosti od tipa  trombotičkog poremećaja podeljeni u 4 grupe: tromboze dubokih vena (94 pacijenta),  izolovani plućni embolizam (104 pacijenta), kombinovani trombotički poremećaji (49  pacijenata) i spontani pobačaji (106 pacijentkinja).  Drugi deo studije je obuhvatio ex vivo analize, s ciljem da se ispita uticaj  navedenih varijanti na funkcionalnost i raspoloživu količinu protrombina u plazmi  ispitanika...
AB  - Prothrombin is a zymogen of thrombin (coagulation factor II), which plays a  central role in maintaining hemostatic balance. Due to the allosteric regulation,  thrombin has dual function: procoagulant and anticoagulant. The 3' end of prothrombin  gene has noncanonical organization, which is susceptible to the genetic variants that  might have a significant role in the regulation of prothrombin expression and function.  Variants reported within this region lead to increased prothrombin expression which is  associated with hypercoagulability and increased tendency to thrombophilia.  In the Laboratory for Molecular Biology at the Institute of Molecular Genetics  and Genetic Engineering, we have reported FIIc.1787G>A and FIIc.*64_*66del  variants in 3' end of prothrombin gene, but their mechanisms of action have not been  elucidated so far. The FIIc.1787G>A (prothrombin Belgrade) is located in the last exon  of the prothrombin gene, leading to amino acid substitution Arg596Gln in the protein.  This variant is positioned in a region of antithrombin (thrombin inhibitor) binding site,  as well as in Na+ binding loop, which is significant for procoagulant activity of  thrombin. The FIIc.*64_*66del is located in the 3' untranslated gene region and  represents a deletion of three nucleotides. Taking into account the position of these two  variants in different structural elements of 3' end of prothrombin gene, it is assumed that  they differ in the mechanisms of action.  In the first part of the study, we determined the frequency of FIIc.1787G>A and  FIIc.*64_*66del variants in 353 patients with thrombotic disorders and 250 healthy  subjects in Serbian population. Patients were divided into 4 groups according to the type  of thrombotic disorders: deep vein thrombosis (94 patients), isolated pulmonary  embolism (104 patients), combined thrombotic disorders (49 patients) and fetal loss  (106 patients).  The second part of the study included the ex vivo analyses, with aim to  investigate the impact of these variants on the functionality and available amount of  prothrombin in the subjects plasma samples...
PB  - Univerzitet u Beogradu, Biološki fakultet
T1  - Funkcionalna analiza genskih varijanti FIIc.1787G>A (protrombin, Beograd) i FIIc.*64_*66del i njihova povezanost sa trombofolijom
T1  - Functional analysis of FIIc.1787G>A (protrombin, Belgrade) and FIIc.*64_*66del gene variants and their assotiation with trombophilia
UR  - https://hdl.handle.net/21.15107/rcub_nardus_8364
ER  - 

@phdthesis{
author = "Gvozdenov, Maja",
year = "2017",
abstract = "Protrombin predstavlja zimogen trombina (koagulacinog faktora II), koji ima  centralnu ulogu u održanju hemostazne ravnoteže. Zahvaljujući alosteričnoj regulaciji,  trombin može da vrši i prokoagulantnu i antikoagulantnu funkciju. Region 3' kraja gena  za protrombin ima nekanonsku organizaciju i podložan je nastanku genskih varijanti  koje mogu imati značajnu ulogu u regulaciji ekspresije i funkcije protrombina. Do sada  opisane varijante u ovom regionu su povezivane sa povišenom ekspresijom protrombina  koja može dovesti do hiperkoagulacije i povećane sklonosti ka trombozama, odnosno  trombofiliji.  U Laboratoriji za molekularnu biologiju, Instituta za molekularnu genetiku i  genetičko inženjerstvo, u 3' kraju gena za protrombin opisane su FIIc.1787G>A i  FIIc.*64_*66del varijante čiji mehanizmi do sada nisu rasvetljeni. Varijanta  FIIc.1787G>A (protrombin Beograd) se nalazi u poslednjem egzonu gena za  protrombin i dovodi do aminokiselinske zamene Arg596Gln u proteinu. Ova varijanta  se nalazi u regionu za koji se vezuju joni natrijuma, neophodni za prokoagulantnu  aktivnost trombina, kao i prirodni trombinski inhibitor- antitrombin. Varijanta  FIIc.*64_*66del se nalazi u 3' netranslatirajućem regionu gena i predstavlja deleciju 3  nukleotida. Imajući u vidu pozicije u različitim strukturnim elementima 3' kraja gena,  pretpostavlja se da su mehanizmi delovanja ovih varijanti različiti.  Prvi deo studije je imao za cilj određivanje učestalosti FIIc.1787G>A i  FIIc.*64_*66del varijanti kod 353 pacijenta sa različitim trombotičkim poremećajima i  250 zdravih ispitanika u srpskoj populaciji. Pacijenti su u zavisnosti od tipa  trombotičkog poremećaja podeljeni u 4 grupe: tromboze dubokih vena (94 pacijenta),  izolovani plućni embolizam (104 pacijenta), kombinovani trombotički poremećaji (49  pacijenata) i spontani pobačaji (106 pacijentkinja).  Drugi deo studije je obuhvatio ex vivo analize, s ciljem da se ispita uticaj  navedenih varijanti na funkcionalnost i raspoloživu količinu protrombina u plazmi  ispitanika..., Prothrombin is a zymogen of thrombin (coagulation factor II), which plays a  central role in maintaining hemostatic balance. Due to the allosteric regulation,  thrombin has dual function: procoagulant and anticoagulant. The 3' end of prothrombin  gene has noncanonical organization, which is susceptible to the genetic variants that  might have a significant role in the regulation of prothrombin expression and function.  Variants reported within this region lead to increased prothrombin expression which is  associated with hypercoagulability and increased tendency to thrombophilia.  In the Laboratory for Molecular Biology at the Institute of Molecular Genetics  and Genetic Engineering, we have reported FIIc.1787G>A and FIIc.*64_*66del  variants in 3' end of prothrombin gene, but their mechanisms of action have not been  elucidated so far. The FIIc.1787G>A (prothrombin Belgrade) is located in the last exon  of the prothrombin gene, leading to amino acid substitution Arg596Gln in the protein.  This variant is positioned in a region of antithrombin (thrombin inhibitor) binding site,  as well as in Na+ binding loop, which is significant for procoagulant activity of  thrombin. The FIIc.*64_*66del is located in the 3' untranslated gene region and  represents a deletion of three nucleotides. Taking into account the position of these two  variants in different structural elements of 3' end of prothrombin gene, it is assumed that  they differ in the mechanisms of action.  In the first part of the study, we determined the frequency of FIIc.1787G>A and  FIIc.*64_*66del variants in 353 patients with thrombotic disorders and 250 healthy  subjects in Serbian population. Patients were divided into 4 groups according to the type  of thrombotic disorders: deep vein thrombosis (94 patients), isolated pulmonary  embolism (104 patients), combined thrombotic disorders (49 patients) and fetal loss  (106 patients).  The second part of the study included the ex vivo analyses, with aim to  investigate the impact of these variants on the functionality and available amount of  prothrombin in the subjects plasma samples...",
publisher = "Univerzitet u Beogradu, Biološki fakultet",
title = "Funkcionalna analiza genskih varijanti FIIc.1787G>A (protrombin, Beograd) i FIIc.*64_*66del i njihova povezanost sa trombofolijom, Functional analysis of FIIc.1787G>A (protrombin, Belgrade) and FIIc.*64_*66del gene variants and their assotiation with trombophilia",
url = "https://hdl.handle.net/21.15107/rcub_nardus_8364"
}

Gvozdenov, M.. (2017). Funkcionalna analiza genskih varijanti FIIc.1787G>A (protrombin, Beograd) i FIIc.*64_*66del i njihova povezanost sa trombofolijom. 
Univerzitet u Beogradu, Biološki fakultet..
https://hdl.handle.net/21.15107/rcub_nardus_8364

Gvozdenov M. Funkcionalna analiza genskih varijanti FIIc.1787G>A (protrombin, Beograd) i FIIc.*64_*66del i njihova povezanost sa trombofolijom. 2017;.
https://hdl.handle.net/21.15107/rcub_nardus_8364 .

Gvozdenov, Maja, "Funkcionalna analiza genskih varijanti FIIc.1787G>A (protrombin, Beograd) i FIIc.*64_*66del i njihova povezanost sa trombofolijom" (2017),
https://hdl.handle.net/21.15107/rcub_nardus_8364 .

TY  - JOUR
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Simić, Jelena M.
AU  - Kovač, Mirjana
AU  - Radojković, Dragica 
AU  - Đorđević, Valentina
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1025
AB  - Background: Deep vein thrombosis (DVT) represents a common disorder involving genetic and acquired risk factors. It has been proposed that acquired risk factors are more important with aging than genetic factors, indicating different prevalence of prothrombotic mutations throughout the lifespan. Objective: To determine the role of the most frequent prothrombotic genetic risk factors (Factor V [FV] Leiden and Factor II [FII] G20210A mutations) in first-time DVT etiology in patients of different ages. Method: This retrospective study included 701 patients living in Serbia with diagnosed DVT as a first-time thrombotic event. Results: Risk assessment for mutations as age-related markers showed no statistical difference (FV Leiden mutation-OR, 1.027; 95% confidence interval [CI],.87-1.22; P=.76 and FII G20210A mutation-OR, 0.940, 95% CI,.74-1.19; P=.61). Our results show similar mutation prevalence regardless of how old the patients were at the time of the first DVT occurrence. Conclusion: Our results indicate that these 2 mutations cannot be used as prognostic marker for time-to-event first DVT in the Serbian population; however, further studies are required.
PB  - Oxford Univ Press, Oxford
T2  - Laboratory Medicine
T1  - Are Prothrombotic Mutations a Time-to-Event Risk Factor?
EP  - 331
IS  - 4
SP  - 326
VL  - 48
DO  - 10.1093/labmed/lmx046
ER  - 

@article{
author = "Tomić, Branko and Gvozdenov, Maja and Pruner, Iva and Simić, Jelena M. and Kovač, Mirjana and Radojković, Dragica  and Đorđević, Valentina",
year = "2017",
abstract = "Background: Deep vein thrombosis (DVT) represents a common disorder involving genetic and acquired risk factors. It has been proposed that acquired risk factors are more important with aging than genetic factors, indicating different prevalence of prothrombotic mutations throughout the lifespan. Objective: To determine the role of the most frequent prothrombotic genetic risk factors (Factor V [FV] Leiden and Factor II [FII] G20210A mutations) in first-time DVT etiology in patients of different ages. Method: This retrospective study included 701 patients living in Serbia with diagnosed DVT as a first-time thrombotic event. Results: Risk assessment for mutations as age-related markers showed no statistical difference (FV Leiden mutation-OR, 1.027; 95% confidence interval [CI],.87-1.22; P=.76 and FII G20210A mutation-OR, 0.940, 95% CI,.74-1.19; P=.61). Our results show similar mutation prevalence regardless of how old the patients were at the time of the first DVT occurrence. Conclusion: Our results indicate that these 2 mutations cannot be used as prognostic marker for time-to-event first DVT in the Serbian population; however, further studies are required.",
publisher = "Oxford Univ Press, Oxford",
journal = "Laboratory Medicine",
title = "Are Prothrombotic Mutations a Time-to-Event Risk Factor?",
pages = "331-326",
number = "4",
volume = "48",
doi = "10.1093/labmed/lmx046"
}

Tomić, B., Gvozdenov, M., Pruner, I., Simić, J. M., Kovač, M., Radojković, D.,& Đorđević, V.. (2017). Are Prothrombotic Mutations a Time-to-Event Risk Factor?. in Laboratory Medicine
Oxford Univ Press, Oxford., 48(4), 326-331.
https://doi.org/10.1093/labmed/lmx046

Tomić B, Gvozdenov M, Pruner I, Simić JM, Kovač M, Radojković D, Đorđević V. Are Prothrombotic Mutations a Time-to-Event Risk Factor?. in Laboratory Medicine. 2017;48(4):326-331.
doi:10.1093/labmed/lmx046 .

Tomić, Branko, Gvozdenov, Maja, Pruner, Iva, Simić, Jelena M., Kovač, Mirjana, Radojković, Dragica , Đorđević, Valentina, "Are Prothrombotic Mutations a Time-to-Event Risk Factor?" in Laboratory Medicine, 48, no. 4 (2017):326-331,
https://doi.org/10.1093/labmed/lmx046 . .

TY  - JOUR
AU  - Miljić, Predrag
AU  - Gvozdenov, Maja
AU  - Takagi, Y.
AU  - Takagi, A.
AU  - Pruner, Iva
AU  - Dragojević, M.
AU  - Tomić, Branko
AU  - Bodrozić, J.
AU  - Kojima, T.
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1045
AB  - Background: The recently reported c.1787G gt A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives: We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods: Nineteen family members were investigated, among whom 10 were carriers of the c.1787G gt A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results: Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions: Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.
PB  - Wiley, Hoboken
T2  - Journal of Thrombosis and Haemostasis
T1  - Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism
EP  - 677
IS  - 4
SP  - 670
VL  - 15
DO  - 10.1111/jth.13618
ER  - 

@article{
author = "Miljić, Predrag and Gvozdenov, Maja and Takagi, Y. and Takagi, A. and Pruner, Iva and Dragojević, M. and Tomić, Branko and Bodrozić, J. and Kojima, T. and Radojković, Dragica and Đorđević, Valentina",
year = "2017",
abstract = "Background: The recently reported c.1787G gt A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives: We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods: Nineteen family members were investigated, among whom 10 were carriers of the c.1787G gt A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results: Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions: Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.",
publisher = "Wiley, Hoboken",
journal = "Journal of Thrombosis and Haemostasis",
title = "Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism",
pages = "677-670",
number = "4",
volume = "15",
doi = "10.1111/jth.13618"
}

Miljić, P., Gvozdenov, M., Takagi, Y., Takagi, A., Pruner, I., Dragojević, M., Tomić, B., Bodrozić, J., Kojima, T., Radojković, D.,& Đorđević, V.. (2017). Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism. in Journal of Thrombosis and Haemostasis
Wiley, Hoboken., 15(4), 670-677.
https://doi.org/10.1111/jth.13618

Miljić P, Gvozdenov M, Takagi Y, Takagi A, Pruner I, Dragojević M, Tomić B, Bodrozić J, Kojima T, Radojković D, Đorđević V. Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism. in Journal of Thrombosis and Haemostasis. 2017;15(4):670-677.
doi:10.1111/jth.13618 .

Miljić, Predrag, Gvozdenov, Maja, Takagi, Y., Takagi, A., Pruner, Iva, Dragojević, M., Tomić, Branko, Bodrozić, J., Kojima, T., Radojković, Dragica, Đorđević, Valentina, "Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism" in Journal of Thrombosis and Haemostasis, 15, no. 4 (2017):670-677,
https://doi.org/10.1111/jth.13618 . .

TY  - JOUR
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Tomić, Branko
AU  - Kovač, Mirjana
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1055
AB  - The FII c. 1787G gt A (prothrombin Belgrade) is a novel prothrombotic mutation which leads to impaired inhibition of thrombin by antithrombin (antithrombin resistance). So far, the mechanism of this variant has not been fully elucidated. To investigate the effect of FII c. 1787G gt A mutation on the prothrombin gene expression, its functional analysis was performed in vitro. By Real-Time PCR, expression levels of FII gene variants were evaluated in Cos-7 cells transiently transfected with c. 1787G (wild-type) and c. 1787A prothrombin expression vectors, with no differences observed. The relative quantification of prothrombin protein amounts was accomplished by Western blot analysis, also with no differences observed. Therefore, the mechanism of FII c. 1787G gt A mutation does not alter prothrombin expression profile.
PB  - Maik Nauka/Interperiodica/Springer, New York
T2  - Molecular Biology
T1  - The Effect of FII c.1787G  gt  A (Prothrombin Belgrade) Mutation on Prothrombin Gene Expression In Vitro
EP  - 52
IS  - 1
SP  - 49
VL  - 51
DO  - 10.1134/S0026893316060078
ER  - 

@article{
author = "Gvozdenov, Maja and Pruner, Iva and Tomić, Branko and Kovač, Mirjana and Radojković, Dragica and Đorđević, Valentina",
year = "2017",
abstract = "The FII c. 1787G gt A (prothrombin Belgrade) is a novel prothrombotic mutation which leads to impaired inhibition of thrombin by antithrombin (antithrombin resistance). So far, the mechanism of this variant has not been fully elucidated. To investigate the effect of FII c. 1787G gt A mutation on the prothrombin gene expression, its functional analysis was performed in vitro. By Real-Time PCR, expression levels of FII gene variants were evaluated in Cos-7 cells transiently transfected with c. 1787G (wild-type) and c. 1787A prothrombin expression vectors, with no differences observed. The relative quantification of prothrombin protein amounts was accomplished by Western blot analysis, also with no differences observed. Therefore, the mechanism of FII c. 1787G gt A mutation does not alter prothrombin expression profile.",
publisher = "Maik Nauka/Interperiodica/Springer, New York",
journal = "Molecular Biology",
title = "The Effect of FII c.1787G  gt  A (Prothrombin Belgrade) Mutation on Prothrombin Gene Expression In Vitro",
pages = "52-49",
number = "1",
volume = "51",
doi = "10.1134/S0026893316060078"
}

Gvozdenov, M., Pruner, I., Tomić, B., Kovač, M., Radojković, D.,& Đorđević, V.. (2017). The Effect of FII c.1787G  gt  A (Prothrombin Belgrade) Mutation on Prothrombin Gene Expression In Vitro. in Molecular Biology
Maik Nauka/Interperiodica/Springer, New York., 51(1), 49-52.
https://doi.org/10.1134/S0026893316060078

Gvozdenov M, Pruner I, Tomić B, Kovač M, Radojković D, Đorđević V. The Effect of FII c.1787G  gt  A (Prothrombin Belgrade) Mutation on Prothrombin Gene Expression In Vitro. in Molecular Biology. 2017;51(1):49-52.
doi:10.1134/S0026893316060078 .

Gvozdenov, Maja, Pruner, Iva, Tomić, Branko, Kovač, Mirjana, Radojković, Dragica, Đorđević, Valentina, "The Effect of FII c.1787G  gt  A (Prothrombin Belgrade) Mutation on Prothrombin Gene Expression In Vitro" in Molecular Biology, 51, no. 1 (2017):49-52,
https://doi.org/10.1134/S0026893316060078 . .

TY  - JOUR
AU  - Tomić, Branko
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Kovač, Mirjana
AU  - Antonijević, Nebojša
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/967
AB  - Venous thromboembolism is a multifactorial disorder with two manifestations: deep-vein thrombosis and pulmonary embolism. Pulmonary embolism is usually considered as the complication of deep-vein thrombosis, but there are reported cases of isolated pulmonary embolism. FV Leiden and FII G20210A mutations are most common genetic risk factors for the venous thromboembolism. Several studies reported "FV Leiden paradox": lower prevalence of FV Leiden mutation among patients with isolated pulmonary embolism than among those with deep-vein thrombosis. The aim of this study was to determine FV Leiden and FII G20210A mutations frequency in thrombophilic patients in Serbian population. We tested prevalence of these mutations carriers in 1427 individuals divided in three groups of patients (with deep-vein thrombosis, deep-vein thrombosis/pulmonary embolism and isolated pulmonary embolism) and control group. All subjects were tested for these mutations using PCR-RFLP analysis. Detected frequency of FV Leiden heterozygous carriers in patients with isolated pulmonary embolism was 6.9% (for FII G20210A 11.6%), while in other two groups of patients with deep-vein thrombosis and deep vein thrombosis/pulmonary embolism, frequency was 18.6% (for FII G20210A mutation were 11.6% and 8.3%, respectively). Our results showed that FV Leiden mutation is less frequent in patients with isolated pulmonary embolism than in patients with deep-vein thrombosis or deep-vein thrombosis accompanied with pulmonary embolism, confirming "FV Leiden paradox". On the other hand, detected frequency of FII G20210A mutation carriers was similar in all three groups of patients.
PB  - Društvo genetičara Srbije, Beograd
T2  - Genetika-Belgrade
T1  - The frequencies of fv leiden and fii g20210a mutations in patients with different clinical manifestations of venous thromboembolism: experience from large Serbian cohort
EP  - 616
IS  - 2
SP  - 609
VL  - 48
DO  - 10.2298/GENSR1602609T
ER  - 

@article{
author = "Tomić, Branko and Gvozdenov, Maja and Pruner, Iva and Kovač, Mirjana and Antonijević, Nebojša and Radojković, Dragica and Đorđević, Valentina",
year = "2016",
abstract = "Venous thromboembolism is a multifactorial disorder with two manifestations: deep-vein thrombosis and pulmonary embolism. Pulmonary embolism is usually considered as the complication of deep-vein thrombosis, but there are reported cases of isolated pulmonary embolism. FV Leiden and FII G20210A mutations are most common genetic risk factors for the venous thromboembolism. Several studies reported "FV Leiden paradox": lower prevalence of FV Leiden mutation among patients with isolated pulmonary embolism than among those with deep-vein thrombosis. The aim of this study was to determine FV Leiden and FII G20210A mutations frequency in thrombophilic patients in Serbian population. We tested prevalence of these mutations carriers in 1427 individuals divided in three groups of patients (with deep-vein thrombosis, deep-vein thrombosis/pulmonary embolism and isolated pulmonary embolism) and control group. All subjects were tested for these mutations using PCR-RFLP analysis. Detected frequency of FV Leiden heterozygous carriers in patients with isolated pulmonary embolism was 6.9% (for FII G20210A 11.6%), while in other two groups of patients with deep-vein thrombosis and deep vein thrombosis/pulmonary embolism, frequency was 18.6% (for FII G20210A mutation were 11.6% and 8.3%, respectively). Our results showed that FV Leiden mutation is less frequent in patients with isolated pulmonary embolism than in patients with deep-vein thrombosis or deep-vein thrombosis accompanied with pulmonary embolism, confirming "FV Leiden paradox". On the other hand, detected frequency of FII G20210A mutation carriers was similar in all three groups of patients.",
publisher = "Društvo genetičara Srbije, Beograd",
journal = "Genetika-Belgrade",
title = "The frequencies of fv leiden and fii g20210a mutations in patients with different clinical manifestations of venous thromboembolism: experience from large Serbian cohort",
pages = "616-609",
number = "2",
volume = "48",
doi = "10.2298/GENSR1602609T"
}

Tomić, B., Gvozdenov, M., Pruner, I., Kovač, M., Antonijević, N., Radojković, D.,& Đorđević, V.. (2016). The frequencies of fv leiden and fii g20210a mutations in patients with different clinical manifestations of venous thromboembolism: experience from large Serbian cohort. in Genetika-Belgrade
Društvo genetičara Srbije, Beograd., 48(2), 609-616.
https://doi.org/10.2298/GENSR1602609T

Tomić B, Gvozdenov M, Pruner I, Kovač M, Antonijević N, Radojković D, Đorđević V. The frequencies of fv leiden and fii g20210a mutations in patients with different clinical manifestations of venous thromboembolism: experience from large Serbian cohort. in Genetika-Belgrade. 2016;48(2):609-616.
doi:10.2298/GENSR1602609T .

Tomić, Branko, Gvozdenov, Maja, Pruner, Iva, Kovač, Mirjana, Antonijević, Nebojša, Radojković, Dragica, Đorđević, Valentina, "The frequencies of fv leiden and fii g20210a mutations in patients with different clinical manifestations of venous thromboembolism: experience from large Serbian cohort" in Genetika-Belgrade, 48, no. 2 (2016):609-616,
https://doi.org/10.2298/GENSR1602609T . .

TY  - JOUR
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Tomić, Branko
AU  - Aradjanski, Marijana
AU  - Antonijević, Nebojša
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/871
AB  - Objective Pulmonary embolism is usually considered as a complication of deep vein thrombosis, but there are still a number of cases of isolated pulmonary embolism. We aimed to investigate whether prothrombin 3’ end gene variants might play a signifi cant role in the pathogenesis of isolated pulmonary embolism. Methods and results In this study 100 patients with isolated pulmonary embolism and 100 controls were screened by DNA sequencing. Screening included last intron, last exon, 3’UTR and part of the 3’FR region of the prothrombin gene. Our results have shown that heterozygous carriers of the FII G20210A variant have a signifi cantly higher risk of isolated pulmonary embolism (OR 4.83; 95%CI 1.33-17.52; P = 0.02). Carriers of the FII 19911GG genotype (OR 1.41; 95%CI 0.72-2.73; P = 0.31) and FII 20068CT genotype (OR 3.06; 95%CI 0.31-29.95; P = 0.34) were more frequent in patients with isolated pulmonary embolism compared to controls. We also detected the novel gene variants, FIIc.*64_*66del and FII c.*303T gt C, in two patients. Conclusions Our results suggest that FII G20210A represents a signifi cant risk factor for isolated pulmonary embolism. The FII G19911A and FII C20068T are potentially associated with an increased risk for the occurrence of isolated pulmonary embolism, but the results did not reach statistical signifi cance. This is the fi rst study in which the two novel 3’ end prothrombin gene variants, FIIc.*64_*66del and FII c.*303T gt C, were reported.
PB  - Acta Cardiologica
T2  - Acta Cardiologica
T1  - Prothrombin 3’ end gene variants in isolated pulmonary embolism – The first report of FIIc.*64_*66del and FIIc.*303T gt C variants
EP  - 182
IS  - 2
SP  - 177
VL  - 70
DO  - 10.2143/AC.70.2.3073509
ER  - 

@article{
author = "Gvozdenov, Maja and Pruner, Iva and Tomić, Branko and Aradjanski, Marijana and Antonijević, Nebojša and Radojković, Dragica and Đorđević, Valentina",
year = "2015",
abstract = "Objective Pulmonary embolism is usually considered as a complication of deep vein thrombosis, but there are still a number of cases of isolated pulmonary embolism. We aimed to investigate whether prothrombin 3’ end gene variants might play a signifi cant role in the pathogenesis of isolated pulmonary embolism. Methods and results In this study 100 patients with isolated pulmonary embolism and 100 controls were screened by DNA sequencing. Screening included last intron, last exon, 3’UTR and part of the 3’FR region of the prothrombin gene. Our results have shown that heterozygous carriers of the FII G20210A variant have a signifi cantly higher risk of isolated pulmonary embolism (OR 4.83; 95%CI 1.33-17.52; P = 0.02). Carriers of the FII 19911GG genotype (OR 1.41; 95%CI 0.72-2.73; P = 0.31) and FII 20068CT genotype (OR 3.06; 95%CI 0.31-29.95; P = 0.34) were more frequent in patients with isolated pulmonary embolism compared to controls. We also detected the novel gene variants, FIIc.*64_*66del and FII c.*303T gt C, in two patients. Conclusions Our results suggest that FII G20210A represents a signifi cant risk factor for isolated pulmonary embolism. The FII G19911A and FII C20068T are potentially associated with an increased risk for the occurrence of isolated pulmonary embolism, but the results did not reach statistical signifi cance. This is the fi rst study in which the two novel 3’ end prothrombin gene variants, FIIc.*64_*66del and FII c.*303T gt C, were reported.",
publisher = "Acta Cardiologica",
journal = "Acta Cardiologica",
title = "Prothrombin 3’ end gene variants in isolated pulmonary embolism – The first report of FIIc.*64_*66del and FIIc.*303T gt C variants",
pages = "182-177",
number = "2",
volume = "70",
doi = "10.2143/AC.70.2.3073509"
}

Gvozdenov, M., Pruner, I., Tomić, B., Aradjanski, M., Antonijević, N., Radojković, D.,& Đorđević, V.. (2015). Prothrombin 3’ end gene variants in isolated pulmonary embolism – The first report of FIIc.*64_*66del and FIIc.*303T gt C variants. in Acta Cardiologica
Acta Cardiologica., 70(2), 177-182.
https://doi.org/10.2143/AC.70.2.3073509

Gvozdenov M, Pruner I, Tomić B, Aradjanski M, Antonijević N, Radojković D, Đorđević V. Prothrombin 3’ end gene variants in isolated pulmonary embolism – The first report of FIIc.*64_*66del and FIIc.*303T gt C variants. in Acta Cardiologica. 2015;70(2):177-182.
doi:10.2143/AC.70.2.3073509 .

Gvozdenov, Maja, Pruner, Iva, Tomić, Branko, Aradjanski, Marijana, Antonijević, Nebojša, Radojković, Dragica, Đorđević, Valentina, "Prothrombin 3’ end gene variants in isolated pulmonary embolism – The first report of FIIc.*64_*66del and FIIc.*303T gt C variants" in Acta Cardiologica, 70, no. 2 (2015):177-182,
https://doi.org/10.2143/AC.70.2.3073509 . .

TY  - JOUR
AU  - Mitrović, Mirjana
AU  - Suvajdžić, Nada
AU  - Elezović, Ivo
AU  - Bogdanović, Andrija
AU  - Đorđević, Valentina
AU  - Miljić, Predrag
AU  - Djunić, Irena
AU  - Gvozdenov, Maja
AU  - Čolović, Nataša
AU  - Virijević, Marijana
AU  - Leković, Danijela
AU  - Vidović, Ana
AU  - Tomin, Dragica
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/891
AB  - Introduction: Thrombotic events (TE) appear to be more common in acute promyelocytic leukemia (APL) than in other acute leukemias, with reported prevalence ranging from 2 to 10-15%. Materials and Methods: We retrospectively analyzed the data on TE appearance in 63 APL patients. Results: TE occured in 13 (20.6%) cases, four arterial (6.3%) and nine venous (14.3%). TE were more frequently diagnosed after initiation of weekly D-dimer monitoring (7 TE during 20 months vs 6 during 76 months, P = 0.032). Patients with and without venous thrombosis were significantly different regarding female/male ratio (P = 0.046), PT (P = 0.022), a PTT (P = 0.044), ISTH DIC score (P = 0.001), bcr3 (P = 0.02) and FLT3-ITD (P = 0.028) mutation. The most significant risk factor for venous TE occurrence in multivariate analysis was FLT3-ITD mutation (P = 0.034). PAI-1 4G/4G polymorphism was five times more frequent in patients with venous TE than without it (P = 0.05). Regarding risk factors for arterial TE we failed to identify any. Conclusions: We have demonstrated that APL-related TE rate is higher than previously reported and that weekly D-dimer monitoring might help to identify patients with silent thrombosis. Moreover, our study suggests a possible relationship between venous TE occurrence and several laboratory findings (PT, aPTT, ISTH DIC score, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G). Prophylactic use of heparin might be considered in patients with ISTH DIC score  lt  5, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Thrombosis Research
T1  - Thrombotic events in acute promyelocytic leukemia
EP  - 593
IS  - 4
SP  - 588
VL  - 135
DO  - 10.1016/j.thromres.2014.11.026
ER  - 

@article{
author = "Mitrović, Mirjana and Suvajdžić, Nada and Elezović, Ivo and Bogdanović, Andrija and Đorđević, Valentina and Miljić, Predrag and Djunić, Irena and Gvozdenov, Maja and Čolović, Nataša and Virijević, Marijana and Leković, Danijela and Vidović, Ana and Tomin, Dragica",
year = "2015",
abstract = "Introduction: Thrombotic events (TE) appear to be more common in acute promyelocytic leukemia (APL) than in other acute leukemias, with reported prevalence ranging from 2 to 10-15%. Materials and Methods: We retrospectively analyzed the data on TE appearance in 63 APL patients. Results: TE occured in 13 (20.6%) cases, four arterial (6.3%) and nine venous (14.3%). TE were more frequently diagnosed after initiation of weekly D-dimer monitoring (7 TE during 20 months vs 6 during 76 months, P = 0.032). Patients with and without venous thrombosis were significantly different regarding female/male ratio (P = 0.046), PT (P = 0.022), a PTT (P = 0.044), ISTH DIC score (P = 0.001), bcr3 (P = 0.02) and FLT3-ITD (P = 0.028) mutation. The most significant risk factor for venous TE occurrence in multivariate analysis was FLT3-ITD mutation (P = 0.034). PAI-1 4G/4G polymorphism was five times more frequent in patients with venous TE than without it (P = 0.05). Regarding risk factors for arterial TE we failed to identify any. Conclusions: We have demonstrated that APL-related TE rate is higher than previously reported and that weekly D-dimer monitoring might help to identify patients with silent thrombosis. Moreover, our study suggests a possible relationship between venous TE occurrence and several laboratory findings (PT, aPTT, ISTH DIC score, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G). Prophylactic use of heparin might be considered in patients with ISTH DIC score  lt  5, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Thrombosis Research",
title = "Thrombotic events in acute promyelocytic leukemia",
pages = "593-588",
number = "4",
volume = "135",
doi = "10.1016/j.thromres.2014.11.026"
}

Mitrović, M., Suvajdžić, N., Elezović, I., Bogdanović, A., Đorđević, V., Miljić, P., Djunić, I., Gvozdenov, M., Čolović, N., Virijević, M., Leković, D., Vidović, A.,& Tomin, D.. (2015). Thrombotic events in acute promyelocytic leukemia. in Thrombosis Research
Pergamon-Elsevier Science Ltd, Oxford., 135(4), 588-593.
https://doi.org/10.1016/j.thromres.2014.11.026

Mitrović M, Suvajdžić N, Elezović I, Bogdanović A, Đorđević V, Miljić P, Djunić I, Gvozdenov M, Čolović N, Virijević M, Leković D, Vidović A, Tomin D. Thrombotic events in acute promyelocytic leukemia. in Thrombosis Research. 2015;135(4):588-593.
doi:10.1016/j.thromres.2014.11.026 .

Mitrović, Mirjana, Suvajdžić, Nada, Elezović, Ivo, Bogdanović, Andrija, Đorđević, Valentina, Miljić, Predrag, Djunić, Irena, Gvozdenov, Maja, Čolović, Nataša, Virijević, Marijana, Leković, Danijela, Vidović, Ana, Tomin, Dragica, "Thrombotic events in acute promyelocytic leukemia" in Thrombosis Research, 135, no. 4 (2015):588-593,
https://doi.org/10.1016/j.thromres.2014.11.026 . .

TY  - JOUR
AU  - Pruner, Iva
AU  - Đorđević, Valentina
AU  - Gvozdenov, Maja
AU  - Tomić, Branko
AU  - Kovač, Mirjana
AU  - Miljić, Predrag
AU  - Radojković, Dragica
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/830
AB  - Recurrent pregnancy loss (RPL) is a health problem affecting up to 5% of women of reproductive age. Several thrombophilic risk factors might contribute to RPL. To investigate relationship between a novel C20068T gene variant in the 3' end of prothrombin gene and RPL, we tested 153 women with RPL and 111 controls for the presence of this gene variant. In patients, we have detected four heterozygous (2.61%) and no homozygous carriers. In controls, no carriers were detected. Our results indicate higher prevalence of C20068T gene variant in women with RPL but this difference was not statistically significant. However, in patients who suffered 5 or more RPL, frequency of C20068T gene variant was significantly increased compared to controls (12.5% vs. 0%, P = 0.02). This is the first study which points out a possible role of C20068T gene variant in etiology of RPL, but larger studies should be carried out to confirm our findings.
PB  - Društvo genetičara Srbije, Beograd
T2  - Genetika-Belgrade
T1  - The c20068t gene variant in the 3 ' end of the prothrombin gene and recurrent pregnancy loss: a pilot study
EP  - 476
IS  - 2
SP  - 469
VL  - 47
DO  - 10.2298/GENSR1502469P
ER  - 

@article{
author = "Pruner, Iva and Đorđević, Valentina and Gvozdenov, Maja and Tomić, Branko and Kovač, Mirjana and Miljić, Predrag and Radojković, Dragica",
year = "2015",
abstract = "Recurrent pregnancy loss (RPL) is a health problem affecting up to 5% of women of reproductive age. Several thrombophilic risk factors might contribute to RPL. To investigate relationship between a novel C20068T gene variant in the 3' end of prothrombin gene and RPL, we tested 153 women with RPL and 111 controls for the presence of this gene variant. In patients, we have detected four heterozygous (2.61%) and no homozygous carriers. In controls, no carriers were detected. Our results indicate higher prevalence of C20068T gene variant in women with RPL but this difference was not statistically significant. However, in patients who suffered 5 or more RPL, frequency of C20068T gene variant was significantly increased compared to controls (12.5% vs. 0%, P = 0.02). This is the first study which points out a possible role of C20068T gene variant in etiology of RPL, but larger studies should be carried out to confirm our findings.",
publisher = "Društvo genetičara Srbije, Beograd",
journal = "Genetika-Belgrade",
title = "The c20068t gene variant in the 3 ' end of the prothrombin gene and recurrent pregnancy loss: a pilot study",
pages = "476-469",
number = "2",
volume = "47",
doi = "10.2298/GENSR1502469P"
}

Pruner, I., Đorđević, V., Gvozdenov, M., Tomić, B., Kovač, M., Miljić, P.,& Radojković, D.. (2015). The c20068t gene variant in the 3 ' end of the prothrombin gene and recurrent pregnancy loss: a pilot study. in Genetika-Belgrade
Društvo genetičara Srbije, Beograd., 47(2), 469-476.
https://doi.org/10.2298/GENSR1502469P

Pruner I, Đorđević V, Gvozdenov M, Tomić B, Kovač M, Miljić P, Radojković D. The c20068t gene variant in the 3 ' end of the prothrombin gene and recurrent pregnancy loss: a pilot study. in Genetika-Belgrade. 2015;47(2):469-476.
doi:10.2298/GENSR1502469P .

Pruner, Iva, Đorđević, Valentina, Gvozdenov, Maja, Tomić, Branko, Kovač, Mirjana, Miljić, Predrag, Radojković, Dragica, "The c20068t gene variant in the 3 ' end of the prothrombin gene and recurrent pregnancy loss: a pilot study" in Genetika-Belgrade, 47, no. 2 (2015):469-476,
https://doi.org/10.2298/GENSR1502469P . .