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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.

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.

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.

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.

James P.,Queens 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.

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