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Nikolic A.V.,University of Belgrade | Andric Z.P.,Blood Transfusion Institute of Serbia | Simonovic R.B.,Blood Transfusion Institute of Serbia | Rakocevic Stojanovic V.M.,University of Belgrade | And 3 more authors.
European Journal of Neurology | Year: 2015

Background and purpose: Myasthenia gravis (MG) is an autoimmune disease but certain genetic factors predispose its development. Since susceptibility to different forms of MG is linked to a number of allelic variants, the aim of this study was to explore the human leukocyte antigen (HLA) profile of our patients with muscle-specific tyrosine kinase (MuSK) MG. Methods: Human leukocyte antigen (HLA) typing was performed in our cohort of 31 MuSK MG patients available for the study. The allele groups of DRB1* and DQB1* loci were typed with sequence-specific oligonucleotide probes and high resolution typing for DQB1* was performed using sequence-specific primers. HLA frequencies were compared with unrelated healthy bone marrow donors. Results: Significant association of MuSK MG with alleles DRB1*14 [odds ratio (OR) 3.8], DRB1*16 (OR 3.3) (P < 0.01) and DQB1*05 (OR 2.2) (P < 0.05) was found. In our patients the most frequent DQB1* allele was DQB1*05:02. An absolute absence of DRB1*13 in our cohort of MuSK MG patients was also found, whilst this allele was present in 25% (495/1992) of control subjects (OR 0) (P < 0.01). The HLA DRB1*16-DQB1*05 (OR 2.9) haplotype was found to be associated with MuSK MG (P < 0.05). Conclusions: The strong association of MuSK MG with DQB1*05 alleles observed in patient series from other countries was confirmed. The novel finding in our cohort of MuSK MG patients was the absolute absence of DRB1*13 allele, which might have a protective role in the development of MuSK MG, at least in our population. © 2014 EAN.


Kovac M.,Blood Transfusion Institute of Serbia | Mikovic Z.,Gynaecology and Obstetrics Clinic Narodni Front | Rakicevic L.,Serbian Institute of Molecular Genetics and Genetic Engineering | Srzentic S.,Blood Transfusion Institute of Serbia | And 4 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2010

Objective: D-dimer testing has an important role in the exclusion of acute venous thromboembolism (VTE) in the nonpregnant population. Establishing D-dimers role in the diagnosis of VTE in pregnancy is hampered because of the substantial increase of D-dimer throughout gestational age. Study design: In a prospective study we followed 89 healthy pregnant women to establish the reference range of D-dimer for each trimester. D-dimer testing was also performed in 12 women with clinical suspicion of VTE and their results were compared with the established new reference range of D-dimer, and with the recorded ultrasound findings. Results: In the first trimester, 84% women from reference group had normal D-dimer, in the second 33%, and by the third trimester only 1%, which suggests that D-dimer has no practical diagnostic use in ruling out VTE if the threshold of 230 ng/mL for abnormal is used. All pregnant women with thrombosis who had positive ultrasound findings also had statistically significant elevation of the D-dimer level, considering the established reference range of the corresponding trimester. We found 100% sensitivity of D-dimer test. A women developed thrombosis in the first trimester had 6.7-7.6 time higher level of D-dimer than the mean value in the reference group, and in the third trimester thrombotic women had 2.0-3.8 time higher level of D-dimer, p < 0.0001. Conclusion: D-dimer test with the new threshold for: the first of 286, the second of 457 and the third trimester of 644 ng/mL can be useful in diagnosis of pregnancy related VTE. © 2009 Elsevier Ireland Ltd. All rights reserved.


Andric Z.,Blood Transfusion Institute of Serbia | Popadic D.,University of Belgrade | Jovanovic B.,Blood Transfusion Institute of Serbia | Jaglicic I.,Blood Transfusion Institute of Serbia | And 2 more authors.
Human Immunology | Year: 2014

This study provides the first published detailed analysis of five loci polymorphisms as well as reports of two, three and five loci haplotype frequencies in the Serbian population in a sample of 1992 volunteer bone marrow donors recruited from different part of the country. Typing was performed by PCR SSO method combined with PCR SSP techniques to resolve ambiguities. In total, 16 HLA-A, 28 HLA-B, 14 HLA-C, 13 HLA-DRB1 and 5 HLA-DQB1 allelic groups were identified. The most frequent in allele groups are HLA-A*02 (29.5%), HLA-A*01 (14.2%), HLA-B*35 (13.1%), HLA-B*51 (12.8%), HLA-C*07 (24.8%), HLA-DRB1*11 (16.9%), HLA-DRB1*13 (13.2%), HLA-DQB1*03 (33.3%) and DQB1*05 (33.0%). The most frequent three- and five-loci haplotypes were A*01-B*08-DRB1*03 (5.9%) and A*02-B*18-DRB1*11 (1.9%), A*01-B*08-C*07-DRB1*03-DQB1*02 (6.6%) followed by A*02-B*18-C*07-DRB1*11-DQB1*03 (2.5%), then A*33-B*14-C*08-DRB1*01-DQB1*05 and A*02-B*35-C*04-DRB1*16-DQB1*05 (2.2% both), respectively. The results of cluster analysis showed that the Serbian population is closely related to the populations living in central Balkan and neighboring European regions. The level of allelic diversity found in this study are relevant to facilitate searching for unrelated matched donor and provide a healthy control population from our region that should be useful in the future disease association study. © 2013 American Society for Histocompatibility and Immunogenetics.


Antovic A.,Karolinska Institutet | Mikovic D.,Blood Transfusion Institute of Serbia | Elezovic I.,University of Belgrade | Zabczyk M.,Karolinska Institutet | And 4 more authors.
Thrombosis and Haemostasis | Year: 2014

Patients with haemophilia A have seriously impaired thrombin generation due to an inherited deficiency of factor (F)VIII, making them form unstable fibrin clots that are unable to maintain haemostasis. Data on fibrin structure in haemophilia patients remain limited. Fibrin permeability, assessed by a flow measurement technique, was investigated in plasma from 20 patients with severe haemophilia A treated on demand, before and 30 minutes after FVIII injection. The results were correlated with concentrations of fibrinogen, FVIII and thrombinactivatable fibrinolysis inhibitor (TAFI), and global haemostatic markers: endogenous thrombin potential (ETP) and overall haemostatic potential (OHP). Fibrin structure was visualised using scanning electron microscopy (SEM). The permeability coefficient Ks decreased significantly after FVIII treatment. Ks correlated significantly with FVIII levels and dosage, and with ETP, OHP and levels of TAFI. SEM images revealed irregular, porous fibrin clots composed of thick and short fibers before FVIII treatment. The clots had recovered after FVIII replacement almost to levels in control samples, revealing compact fibrin with smaller intrinsic pores. To the best of our knowledge, this is the first description of fibrin porosity and structure before and after FVIII treatment of selected haemophilia patients. It seems that thrombin generation is the main determinant of fibrin structure in haemophilic plasma. © Schattauer 2014.


Antovic J.P.,Karolinska University Hospital | Mikovic D.,Blood Transfusion Institute of Serbia | Elezovic I.,University of Belgrade | Holmstrom M.,Karolinska University Hospital | And 4 more authors.
Thrombosis and Haemostasis | Year: 2012

Haemophilia A patients with similar levels of factor VIII (FVIII) may have different bleeding phenotypes and responses to treatment with FVIII concentrate. Therefore, a test which determines overall haemostasis may be appropriate for treatment monitoring in some patients. We studied two global haemostatic methods: endogenous thrombin potential (ETP) and overall haemostatic potential (OHP) before and after injection of FVIII concentrate in patients with haemophilia A treated prophylactically and on-demand. A significant correlation between FVIII and both ETP and OHP was observed, while ETP and OHP differed between patients with severe and mild clinical phenotypes. Both ETP and OHP differed significantly between severe, moderate and mild haemophilia A and controls. ETP and OHP increased after intravenous injection of FVIII concentrate in both groups of patients, but in spite of higher pre-treatment values of both ETP and OHP in patients treated prophylactically, and much higher post-treatment FVIII levels in comparison with the values in patients treated on-demand, no difference after treatment was observed for either ETP or OHP. ETP and OHP may be additional alternatives for monitoring (and even for individual tailoring) treatment in patients with haemophilia A. © Schattauer 2012.


Kovac M.K.,Blood Transfusion Institute of Serbia | Maslac A.R.,Blood Transfusion Institute of Serbia | Rakicevic L.B.,Serbian Institute of Molecular Genetics and Genetic Engineering | Radojkovic D.P.,Serbian Institute of Molecular Genetics and Genetic Engineering
Blood Coagulation and Fibrinolysis | Year: 2010

A single nucleotide polymorphism c.-1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral vitamin K antagonist (VKA). Our aim was to study the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in a group of patients under stable anticoagulation, and to estimate the variability in response to VKA. We conducted a retrospective cohort analysis of 200 stable anticoagulation patients followed from the initiation of VKA. Out of 43 low-dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high VKA dose; among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. Patients with GG genotype required 2.6 times higher dose than patients carriers of AA genotype (P < 0.0001). Carriers of AA genotype were more likely to be overanticoagulated during follow-up after initiation of VKA when compared with carriers of the GA and GG genotypes (P < 0.0001). Patients with GG genotype spent more time below therapeutic range compared with patients carriers of AA (P = 0.0328) and GA genotype (P < 0.0001). VKORC1 c.-1639G>A polymorphism significantly influenced VKA dose and represented a good predictor of individuals predisposed to unstable anticoagulation. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients, carriers of AA genotype, before the initiation of anticoagulation. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Mobarrez F.,Karolinska Institutet | Mikovic D.,Blood Transfusion Institute of Serbia | Antovic A.,Karolinska Institutet | Antovic J.P.,Karolinska Institutet | Antovic J.P.,Karolinska University Hospital
Journal of Thrombosis and Haemostasis | Year: 2013

Background: Microparticles (MPs) are small membrane vesicles (0.1-1 μm) released from various cells after activation and/or apoptosis. There are limited data about their role in hemophilia A. Patients and Methods: Blood samples were taken before and 30 min after FVIII injection in 18 patients with severe hemophilia A treated on demand. Flow-cytometric determination of total MPs (TMPs) using lactadherin, platelet MPs (PMPs) (CD42a), endothelial MPs (EMPs) (CD144) and leukocyte MPs (LMPs) (CD45) was performed. The results were compared with data on endogenous thrombin potential (ETP), overall hemostatic potential (OHP), fibrin gel permeability and thrombin-activatable fibrinolysis inhibitor (TAFI). Results and Conclusions: TMPs and PMPs decreased after treatment (to 1015 ± 221 [SEM] and 602 ± 134 × 106 L-1) in comparison with values before treatment (2373 ± 618 and 1316 ± 331; P < 0.01). EMPs also decreased after treatment (78 ± 12 vs. 107 ± 13; P < 0.05) while LMPs were not influenced. Both TMP and PMP counts were inversely correlated, moderately but statistically significantly, with data on OHP, ETP, fibrin network permeability and TAFI/TAFIi (P < 0.05 for all). EMP counts were correlated only with ETP (P < 0.05), while LMP counts did not show any correlation. TMP and PMP counts were also inversely correlated with FVIII levels (P < 0.05). TMP, PMP and EMP counts decreased after on-demand treatment with FVIII concentrate in hemophilia A patients. The decrease in circulating MPs, which were inversely correlated with hemostatic activation, may imply that MPs are incorporated in the hemostatic plug formed after FVIII substitution at the site of injury. © 2012 International Society on Thrombosis and Haemostasis.


Lotta L.A.,University of Milan | Valsecchi C.,University of Milan | Pontiggia S.,University of Milan | Mancini I.,University of Milan | And 5 more authors.
Journal of Thrombosis and Haemostasis | Year: 2014

Background: The formation of ADAMTS13-specific circulating immune complexes (CICs) may be a pathophysiologic mechanism in autoimmune thrombotic thrombocytopenic purpura (TTP), but has not been systematically investigated. Objectives: (a) To develop an assay for ADAMTS13-specific CICs; (b) to evaluate their prevalence in autoimmune TTP; and (c) to assess their association with ADAMTS13-related measurements and clinical features in autoimmune TTP patients. Patients/Methods: We developed and validated an ELISA method for ADAMTS13-specific CICs. ADAMTS13-specific CICs were searched for in 55 patients with autoimmune TTP from the Milan TTP Registry (URL:http://www.ttpdatabase.org/) and 28 controls. The associations between ADAMTS13-specific CIC levels and ADAMTS13 activity, antigen, anti-ADAMTS13 IgGs and acute TTP clinical features were assessed by multivariate linear regression. Results: Intra- and inter-assay coefficients of variation of the new test were 5.3 and 9.6%. In 36 patients with severe ADAMTS13 deficiency and anti-ADAMTS13 autoantibodies, the prevalence of ADAMTS13-specific CICs was 47% (n = 17; 95% confidence interval [CI], 32-63%). ADAMTS13-specific CICs were detected also in seven of 19 (37%; 95% CI, 19-59%) patients with reduced ADAMTS13 activity, but apparently negative anti-ADAMTS13 autoantibodies. ADAMTS13-specific CICs were not associated with ADAMTS13 activity, antigen or anti-ADAMTS13 IgGs. In patients with acute TTP, increasing levels of ADAMTS13-specific CICs were associated with a higher number of plasma-exchange procedures required to attain remission (per 0.1 increase in normalized OD values, beta, 2.9; 95% CI, -0.7 to 6.5). Conclusions: Approximately one to two-thirds of patients with autoimmune TTP display ADAMTS13-specific CICs. A thorough investigation of the prognostic relevance of ADAMTS13-specific CIC levels in autoimmune TTP is warranted. © 2013 International Society on Thrombosis and Haemostasis.


James P.,Queen's University | Salomon O.,Tel Aviv University | Mikovic D.,Blood Transfusion Institute of Serbia | Peyvandi F.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | Peyvandi F.,University of Milan
Haemophilia | Year: 2014

Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FVII, combined FV+FVIII, FX, FXI and FXIII. These disorders usually have a low prevalence in the general population and constitute approximately 3-5% of all coagulation disorders. However, in some countries they may have the same prevalence as haemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs is highly variable and can vary markedly from mild to severe, making both diagnosis and optimal treatment quite challenging. This review focuses on: (i) the efforts to establish a bleeding assessment tool adequate to RBDs, (ii) the optimal management of patients affected with FXI deficiency and (iii) the correlation between clinical severity and laboratory diagnosis when determining the minimum coagulant activity required to prevent bleeding in each RBD. © 2014 John Wiley & Sons Ltd.


Kovac M.,Blood Transfusion Institute of Serbia | Mitic G.,Institute of Laboratory Medicine | Kovac Z.,Serbian Institute for Oncology and Radiology of Serbia
Journal of Clinical Pharmacy and Therapeutics | Year: 2012

What is known and Objective: Medline search disclosed 10 case reports of interactions between oral anticoagulants and miconazole oral gel, but none so far between nystatin solution and anticoagulants. We report on change in anticoagulant activity with use of different topical antifungal drugs, miconazole oral gel and vaginal suppositories, and nystatin solution. Methods: We conducted a retrospective study that included 43 patients on stable anticoagulation before the introduction of topical antifungal drugs. Miconazole oral gel was prescribed for 32 patients, nystatin solution for eight patients and miconazole vaginal suppositories for three patients. Results and Discussion: Nineteen (44·2%) of the patients reported bleeding complications and some of these were severe. Fifteen of 32 who used miconazole oral gel and four of 8 of those who used nystatin solution were affected. Before use of the antifungal drugs, the mean weekly warfarin dose in the nystatin group was 14·5 mg, and after antifungal drugs, 9 mg, P = 0·038, while the mean international normalized ratio (INR) before antifungal drugs was 2·5 (range 1·9-3·5) and afterwards it was 10·6 (range 4·5-19·3), P = 0·0001. In the miconazole oral gel group the mean weekly warfarin dose was 15·7 mg, and after 10·8 mg, P = 0·008, while the mean INR before antifungal drugs was 2·44 (range 1·92-3·18) and afterwards it was 8·8 (range 4·9-16·9), P < 0·0001. What is new and Conclusion: Miconazole oral gel and topically applied nystatin solution have equally strong effects on warfarin activity and can provoke major bleeding. Prospective evaluation of this effect is called for. However, based on our results the warfarin dose adjustment appears necessary when the anticoagulant is used concomitantly with those topical antifungals. © 2011 Blackwell Publishing Ltd.

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