Publications by authors named "Danijela Mikovic"

22 Publications

  • Page 1 of 1

Genetics and Hemostatic Potential in Persons with Mild to Moderate Hemophilia A with a Discrepancy between One-Stage and Chromogenic FVIII Assays.

Thromb Haemost 2021 Jan 13;121(1):27-35. Epub 2020 Aug 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background:  Factor VIII (FVIII) activity (FVIII:C) can be measured by different methods including one-stage clotting assays (OSAs) and chromogenic assays (CSAs). Discrepancy between FVIII:C assays is known and associated with genetic variations causing mild and moderate hemophilia A (HA). We aimed to study the discrepancy phenomenon and to identify associated genetic alterations. Further, we investigated if hemostatic global assays could discriminate the group with discrepant FVIII:C from them.

Methods:  The study contained plasma samples from 45 patients with HA (PwHA) from Hemophilia Centers in Stockholm, Sweden, and Belgrade, Serbia. We measured FVIII:C with OSA and CSA, sequenced the gene, and performed two global hemostatic assays; endogenous thrombin potential and overall hemostatic potential.

Results:  Nineteen of 45 PwHA had a more than twofold higher FVIII:C using OSA compared to CSA and were considered discrepant. Thirty-four causal mutations were detected, where of five had not previously been associated with assay discrepancy. These novel mutations were p.Tyr25Cys, p.Phe698Leu, p.Met699Leu, p.Ile1698Thr, and Ala2070Val. We found no difference between discrepant and nondiscrepant cases with either of the global assays.

Conclusion:  There was a discrepancy between FVIII:C assays in almost half of the PwHA, which for some could lead to missed HA diagnoses or misclassification of severity. Genotyping confirmed that mutations associated with FVIII:C discrepancy cluster in the A domains of , and five mutations not previously associated with FVIII:C discrepancy was identified. Global hemostatic assays did not contribute to distinguish assay discrepancy in PwHA.
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http://dx.doi.org/10.1055/s-0040-1715443DOI Listing
January 2021

Clinical and Laboratory Features of Patients with Acquired Thrombotic Thrombocytopenic Purpura: Fourteen Years of the Milan TTP Registry.

Thromb Haemost 2019 May 12;119(5):695-704. Epub 2019 Mar 12.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione Luigi Villa, Milan, Italy.

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by the immune-mediated severe deficiency of ADAMTS13. We hereby report the demographic and disease-related data of acquired TTP patients recorded in the Milan TTP Registry (www.ttpdatabase.org). We performed a cross-sectional study of 302 individuals enrolled in our registry for an acute episode of acquired TTP occurred between 2002 and 2015 (female 77%; median age at onset 40 years, interquartile range: 30-50). Twenty per cent of patients had concomitant autoimmune disorders. Among potential triggers of acute episodes, infections were the most prevalent (27%), followed by estroprogestinics use and pregnancy (5 and 4% of women, respectively). At presentation, systemic (72%), bleeding (68%) and neurological (43%) symptoms were the most frequent, whereas a lower prevalence of renal (18%) and cardiovascular (10%) signs and symptoms was observed. Almost all acute events were treated by plasma exchange and steroids, and 15% by rituximab. Exacerbation of acute TTP occurred in 15% of events. The TTP-related mortality was 5%. In survivors, the median number of plasma exchange procedures to remission was 9 (interquartile range: 6-14), longer for first events than relapses (median difference 3, 95% confidence interval: 2-4). Of 251 survivors of the first TTP episode with at least a 6-month follow-up, 55% had a relapse. In conclusion, acquired TTP is a severe disease with highly variable clinical presentation, usually requiring a long hospitalization. The Milan TTP Registry represents a powerful tool to improve our knowledge and management of acquired TTP.
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http://dx.doi.org/10.1055/s-0039-1679907DOI Listing
May 2019

Presence of thrombophilia and levels of coagulation factors, coagulation inhibitors and TAFI do not affect global haemostasis or bleeding phenotype in patients with haemophilia A.

Thromb Res 2019 01 8;173:1-3. Epub 2018 Nov 8.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2018.11.008DOI Listing
January 2019

Correlation to FVIII:C in Two Thrombin Generation Tests: TGA-CAT and INNOVANCE ETP.

Mediterr J Hematol Infect Dis 2017 1;9(1):e2017064. Epub 2017 Nov 1.

Department of Translational Medicine & Centre for Thrombosis and Haemostasis, Malmö, Lund University, Sweden.

Introduction: Several thrombin-generation tests are available, but few have been directly compared. Our primary aim was to investigate the correlation of two thrombin generation tests, thrombin generation assay-calibrated automated thrombogram (TGA-CAT) and INNOVANCE ETP, to factor VIII levels (FVIII:C) in a group of patients with hemophilia A. The secondary aim was to investigate inter-laboratory variation for the TGA-CAT method.

Methods: Blood samples were taken from 45 patients with mild, moderate and severe hemophilia A. The TGA-CAT method was performed at both centers while the INNOVANCE ETP was only performed at the Stockholm center. Correlation between parameters was evaluated using Spearman's rank correlation test. For determination of the TGA-CAT inter-laboratory variability, Bland-Altman plots were used.

Results: The correlation for the INNOVANCE ETP and TGA-CAT methods with FVIII:C in persons with hemophilia (PWH) was r=0.701 and r=0.734 respectively.The correlation between the two methods was r=0.546.When dividing the study material into disease severity groups (mild, moderate and severe) based on FVIII levels, both methods fail to discriminate between them.The variability of the TGA-CAT results performed at the two centers was reduced after normalization; before normalization, 29% of values showed less than ±10% difference while after normalization the number increased to 41%.

Conclusions: Both methods correlate in an equal manner to FVIII:C in PWH but show a poor correlation with each other. The level of agreement for the TGA-CAT method was poor though slightly improved after normalization of data. Further improvement of standardization of these methods is warranted.
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http://dx.doi.org/10.4084/MJHID.2017.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667533PMC
November 2017

Does the intensity and quality of treatment and not only the factor VIII level influence global hemostasis in patients with hemophilia A?

Thromb Res 2016 Aug 25;144:133-5. Epub 2016 May 25.

Institute for Molecular Medicine and Surgery and Department of Clinical Chemistry, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1016/j.thromres.2016.05.024DOI Listing
August 2016

Meeting Report: 18th International Meeting of the Danubian League against Thrombosis and Haemorrhagic Disorders.

Semin Thromb Hemost 2015 Nov 19;41(8):903-6. Epub 2015 Oct 19.

Institute of Nuclear Medicine, ISOTOPIX, Vienna, Austria.

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http://dx.doi.org/10.1055/s-0035-1564803DOI Listing
November 2015

A novel CD46 mutation in a patient with microangiopathy clinically resembling thrombotic thrombocytopenic purpura and normal ADAMTS13 activity.

Haematologica 2015 Mar 7;100(3):e87-9. Epub 2014 Nov 7.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan and Luigi Villa Foundation, Milan, Italy

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http://dx.doi.org/10.3324/haematol.2014.111062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349284PMC
March 2015

Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand.

Thromb Haemost 2014 Apr 21;111(4):656-61. Epub 2013 Nov 21.

Aleksandra Antovic, Karolinska Institutet, Dept. of Clinical Sciences, Danderyd Hospital, 182 88 Stockholm, Sweden, Tel.: + 46 734294448, E-mail:

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 thrombin-activatable 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.
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http://dx.doi.org/10.1160/TH13-06-0479DOI Listing
April 2014

Diagnostic relevance of ADAMTS13 activity: evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis.

Srp Arh Celok Lek 2013 Jul-Aug;141(7-8):466-74

Clinic of Digestive Surgery, Clinical Center of Serbia, Dr Koste Todorovića 6, 11000 Belgrade, Serbia.

Introduction: The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue.

Objective: The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS.

Methods: At presentation, we analyzed patients with idiopathic TTP (n = 18), secondary TTP (n = 4), diarrhea positive HUS (n = 3) and diarrhea negative HUS (n = 3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy.

Results: There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p = 0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p = 0.017) and lactate dehydrogenase levels (p = 0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p = 0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p = 0.002), blood urea nitrogen (p = 0.000), and creatinine level (p = 0.000).

Conclusion: Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS.
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http://dx.doi.org/10.2298/sarh1308466vDOI Listing
November 2015

Clinical experience in treatment of thrombotic thrombocytopenic purpura--hemolytic uremic syndrome with 28 patients.

Acta Chir Iugosl 2013 ;60(1):29-38

Background: Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13.

Design And Methods: 28 patients clinically diagnosed with idiopathic TTP (n = 18), secondary TTP (n = 4), atypical HUS (n = 3) and typical HUS (n = 3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies.

Results: PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p = 0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p = 0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with > 1 volume exchange (p = 0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients.

Conclusion: Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.
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http://dx.doi.org/10.2298/aci1301029vDOI Listing
October 2015

Two global haemostatic assays as additional tools to monitor treatment in cases of haemophilia A.

Thromb Haemost 2012 Jul 26;108(1):21-31. Epub 2012 Apr 26.

Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1160/TH11-11-0811DOI Listing
July 2012

Obstacles in the diagnostics and therapy of heparin-induced thrombocytopenia.

Srp Arh Celok Lek 2010 Jan;138 Suppl 1:69-73

Institute of Cardiovascular Diseases, Clinical Centre of Serbia, Belgrade, Serbia.

An immune-mediated, severe, acquired prothrombotic disorder, heparin-induced thrombocytopenia type II (HIT II) occurs in 0.5-5% of patients exposed to unfractionated heparin longer than 5-7 days. Arterial and venous thromboses are induced by HIT II in about 35-50% of patients. Typical death rate for HIT is about 29%, while 21% of HIT patients result in amputation of a limb. The trend towards the occurrence of HIT due to the administration of low molecular weight heparins (LMWH) taking ever conspicuous place in the standard venous thromboembolism (VTE) prophylaxis has been more frequently observed recently. It is considered that LMWH may cause HIT II in about 0.25-1%. The need for further modification of HIPA assays with LMWH has been imposed in the HIT laboratory diagnostics, heretofore overburdened with complexity. There are several constantly opposing problems arising in HIT laboratory diagnostics, one of which is that in a certain number of patients immunologic assays detect nonpathogenic antibodies (mainly IgM or IgA heparin-PF4 antibodies) while, on the other hand, the occurrence of HIT pathogenetically mediated by minor antigens (neutrophil-activating peptide 2 or interleukin 8) may be neglected in certain cases. The following factors play an important role in the interpretation of each laboratory HIT assays performed: 1. correlation with HIT clinical probability test, the best known of which is 4T'score, 2. the interpretation of the laboratory findings dependent on the time of the thrombocytopenia onset, as well as 3. the sensitivity and specificity of each test respectively. The HIT diagnostics in the presence of other comorbid states which may also induce thrombocytopenia, more precisely known as pseudo HIT (cancer, sepsis, disseminated intravascular coagulation, pulmonary embolism, antiphospholipid syndrome, etc), represents a specific clinical problem.
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http://dx.doi.org/10.2298/sarh10s1069aDOI Listing
January 2010

Changes in platelets and anticoagulant protein activity during adenosine-exercise single-photon emission computed tomography stress test.

Srp Arh Celok Lek 2010 Jan;138 Suppl 1:28-32

Clinic of Emergency Internal Medicine, Military Medical Academy, Belgrade, Serbia.

Introduction: Activation of haemostasis during physical stress or during myocardial ischemia could be an important mechanism to trigger coronary and stent thrombosis. We examined changes in haemostatic parameters and its association with myocardial ischemia during adenosine-exercise-SPECT (adeno-EX) stress test in coronary patients at least 4 months after coronary stenting.

Objective: The aim of this study was to examine relationship between changes in haemostatic parameters and stress induced myocardial ischemia quantified by perfusion scintigraphy in stented coronary patients.

Methods: Thirty-seven patients on dual antiplatelet therapy (26 on clopidogrel plus aspirin and 11 on aspirin only) 4-8 months after successful intracoronary stent implantation were enrolled in the study. We determined the levels of platelet aggregability (PA) on ADP (PA-ADP) and epinephrine (PA-EPI), beta-thromboglobulin, platelet factor-4, protein C (PC) and antithrombin (AT) before and 15 minutes after intravenous injection of 150 micro/kg adenosine for4 minutes concomitant with supine ergo-bicycle exercise test for 50 W. The size of stress perfusion defect was measured 15 minutes after stress and in rest 4 hours later by 99mTc-tetrofosmin single photon emission computed tomography (SPECT) within 17 myocardial segments.

Results: There were no differences between haemostatic parameters before and after stress. A significant myocardial ischemia after exercise was registered in 12 patients on combined antiaggregation therapy and in 5 patients on aspirin. In this preliminary report, because of a small number of patients in the aspirin group we did not analyse difference in the levels of haemostatic markers and their correlations with the size of perfusion defect. The only significant difference between measured haemostatic parameters in the patients with stress induced ischemia compared to the patients without it, was a lower level of AT activity after stress (81.0% vs. 87.5%; p = 0.027). Antithrombin activity before stress had significant negative correlation with the size of perfusion defect in rest (R2 = 0.219; p = 0.016) and PC activity before stress had significant linear correlation with stress perfusion defect (R2 = 0.248; p = 0.010).

Conclusion: Baseline activities of natural anticoagulant proteins AT and PC are associated with the size of myocardial perfusion defect during adeno-EX-SPECT test. Patients with significant stress-induced ischemia had lower levels of AT activity after stress.
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http://dx.doi.org/10.2298/sarh10s1028oDOI Listing
January 2010

Quality of haemophilia treatment in Serbia: National Haemophilia Registry Report.

Srp Arh Celok Lek 2010 Jan;138 Suppl 1:23-7

Haemostasis Department and Haemophilia Centre, Blood Transfusion Institute of Serbia, Belgrade, Serbia.

Introduction: The National Registry of patients with inherited bleeding disorders was established in 1963 and ever since it has been in charge of the Haemophilia Centre, Blood Transfusion Institute of Serbia, Belgrade.

Objective: Purpose was to assess the quality of haemophilia treatment in Serbia from 2000 to 2008 based on the National Registry data related with the organization of care and quantities, and the choice of products.

Methods: Analysis of data collected by the National Registry from January 2000 to December 2008.

Results: The National Registry of patients with hereditary coagulopathy encompasses a database of 392 patients with haemophilia A (HA), 64 haemophilia B (HB), 217 von Willebrand's disease and 19 with rare bleeding disorders. Treatment can be obtained in seven haemophilia treatment centres; haematological and paediatric institutes and hospitals in Belgrade, Nis and Novi Sad, as well as in other twenty local hospitals. From 2000 to 2003 about three million units of FVIII concentrate were administered annually, e.g. 0.25 IU/capita/year. Besides, national cryoprecipitate was available for the treatment. In 2003, National Haemophilia Committee was founded and centralized products supply was introduced. During 2004 and 2005, about five million units of FVIII concentrate were provided: annually, i.e. 0.65 IU/capita/ year. The choice of products was also improved. Namely, until 2004 the availability of DDAVP, antifibrinolytic drugs and rFVIIa concentrate was limited, while from 2004 these products became available for haemophilia treatment in Serbia. In order to improve haemophilia care we established international cooperation; education, training, consulting and participation in clinical and research projects. As the result, FVIII concentrate consumption in 2008 was 10.5 million units, e.g. 1.35 IU/capita/year.

Conclusion: The considerable improvement of treatment is the result of efforts made by health care and regulatory institutions in Serbia. Significant support has been provided by cooperation within twinning programmes between Stockholm and Belgrade Haemophilia Centres in 2003-2004 and Hamilton and Belgrade Haemophilia Centres in 2005-2008.
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http://dx.doi.org/10.2298/sarh10s1023mDOI Listing
January 2010

Type and location of venous thromboembolism in carriers of Factor V Leiden or prothrombin G20210A mutation versus patients with no mutation.

Clin Appl Thromb Hemost 2010 Feb 15;16(1):66-70. Epub 2008 Sep 15.

Blood Transfusion Institute of Serbia, Belgrade, Serbia.

Factor V Leiden (FVLeiden) and prothrombin G20210A are the most common genetic causes of thrombophilia and established risk factors for different clinical manifestations of venous thromboembolism (VTE). This study investigated whether the clinical manifestation of VTE, the extension of deep vein thrombosis (DVT) and the presence of transient risk factors at the time of the first VTE, differed among patients with mutations (97 with FVLeiden; 33 with prothrombin G20210A) and in 109 patients without thrombophilia. Isolated pulmonary embolism (PE) was less prevalent in patients with FVLeiden (6%) and no thrombophilia (6%) than in those with prothrombin G20210A (15%). No difference was found in the incidence of distal DVT. Regarding the extension of proximal DVT, the lowest incidence for isolated popliteal vein and the highest for iliofemoral vein were observed in patients with prothrombin G20210A. No difference was observed between groups of patients with or without thrombophilia by unprovoked VTE. The pregnancy/puerperium was the most prevalent risk factor in carriers of prothrombin G20210A. Among FVLeiden carriers, the most prevalent risk factor was surgery, and in patients without thrombophilia, it was trauma (P < .05). Thrombosis of the upper limb was more frequent in a group without thrombophilia than in patients with mutations (P < .01). Transverse sinus venous thrombosis was present only in patients with prothrombin G20210A. Carriers of prothrombin G20210A have an increased risk of developing isolated PE and more severe clinical manifestations than those with FVLeiden or without thrombophilia.
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http://dx.doi.org/10.1177/1076029608320721DOI Listing
February 2010

ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission.

Haematologica 2008 Feb 26;93(2):232-9. Epub 2008 Jan 26.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan, Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy.

Background: From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established.

Design And Methods: In 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients.

Results: Median values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p=0.007; antigen: 36% vs. 58%; p=0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p=0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p=0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p=0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence.

Conclusions: Survivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.
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http://dx.doi.org/10.3324/haematol.11739DOI Listing
February 2008

Clinical challenge: heparin-induced thrombocytopenia type II (HIT II) or pseudo-HIT in a patient with antiphospholipid syndrome.

J Thromb Thrombolysis 2008 Oct 9;26(2):142-6. Epub 2007 Sep 9.

Institute of Cardiovascular Diseases, University Clinical Center of Serbia, Pasterova 2, Belgrade, 11000, Serbia.

Treatment of patients with heparin-induced thrombocytopenia type II (HIT II) and thrombosis in some cases that represents a clinical challenge, which, if unrecognized, may lead to treatment delay or disease progression with potentially lethal outcome. We present a case of a 19-year-old patient with antiphospholipid syndrome, factor V (FV) Leiden mutation in heterozygous state, and venous thromboembolism. The patient was subjected to intravenous infusions of unfractionated heparin (UFH), and 16 days after the beginning of the treatment, his condition worsened, with thrombocytopenia and extension of thrombosis. Whereas the patient had a high clinical score for HIT II, functional and antigenic assays for the presence of HIT antibodies were negative. After repeated negative functional and antigenic assays, pseudo-HIT was suspected and nadroparin was introduced, which resulted in further worsening of the clinical presentation. Disease remission, along with complete normalization of platelet count, was finally accomplished with the introduction of lepirudin. The presence of multiple comorbid states, such as antiphospholipid syndrome, can potentially make laboratory confirmation of disease more difficult in patients with HIT II. In our opinion, it is of great importance that HIT II diagnosis be primarily clinical and that laboratory test results are carefully interpreted, especially when HIT is indicated by high clinical score values.
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http://dx.doi.org/10.1007/s11239-007-0076-yDOI Listing
October 2008

FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population.

J Thromb Thrombolysis 2008 Jun 5;25(3):284-7. Epub 2007 Jun 5.

Blood Transfusion Institute of Serbia, Svetog Save 39, Belgrade, Serbia.

The absolute rate of recurrence of venous thromboembolism (VTE) is approximately 5% per year. There is a lower rate of recurrence in provoked VTE, and higher in idiopathic one. So far, there is no consensus whether hereditary thrombophilia should be considered as a persistent risk factor, and whether it requires long-term anticoagulant therapy. The aim of our study was to estimate the risk of recurrent VTE in patients carrying FV Leiden mutation in Serbian population. In retrospective study (1994-2006), we have evaluated the risk of recurrent VTE in 56 patients who are carriers of FV Leiden mutation, in comparison to group consisting of 56 patients non-carriers of FV Leiden mutation. Patients with FII G20210A and MTHFR C677T mutations, antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, malignancies and diabetes were excluded from the study. Recurrent VTE occurred in 44.6% of the patients, carriers of the FV Leiden mutations, vs. 26.7% in non-carriers group (P<0.05). The incidence rate was 3.7 and 2.2% per year, respectively. The estimated relative risk of recurrence for FV Leiden carriers was 1.67 (95% CI 0.99-2.81, P=0.049). The 60% of patients with mutation and only 13% without mutation develop rethrombosis during first year after discontinuance of therapy (P<0.01). In our study patients with symptomatic VTE who are carriers of the FV Leiden gene mutations have a higher risk of recurrent VTE than non-carriers. Our data suggest the importance of the FV Leiden mutation detection and the estimation of the clinical condition for successful secondary prophylaxis of VTE.
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http://dx.doi.org/10.1007/s11239-007-0059-zDOI Listing
June 2008

Salvage late plasmapheresis in a patient with pulmonary embolism caused by heparin-induced thrombocytopenia primarily resistant to danaparoid sodium and lepirudin.

J Clin Apher 2006 Dec;21(4):252-5

Institute of Cardiovascular Diseases, Clinical Centre of Serbia, Belgrade, Serbia and Montenegro.

We report the case of 64-year-old female patient with pulmonary embolism and bilateral femoropopliteal deep vein thrombosis caused by heparin-induced thrombocytopenia type II (HIT II) resistant to danaparoid sodium and subsequently administered lepirudin in whom a single late plasmapheresis performed on day 6 of the initiation of treatment of HIT reversed the course of the disease, preventing its highly potential fatal outcome. Primarily administered lepirudin was not only ineffective but even led to further aggravation of the patient's clinical state and platelet count drop in the first stage of the HIT treatment. The improvement of the patient's clinical state was not achieved before therapeutic plasma exchange (TPE) had removed the greatest part of pathogenetic circulating substrate. Only after TPE, lepirudin, introduced again, led to the platelet count recovery. In the subsequent course of the treatment, lepirudin was combined with an overlapping oral anticoagulant. Previously positive heparin aggregation test and fast particle gel heparin-platelet factor 4 immunoassay were normalized as well as the patient's clinical status. Early plasmapheresis, administered within 4 days of the onset of thrombocytopenia in HIT, as a beneficial therapeutic measure in certain individual cases, is indisputable. However, our results do not concur with previously reported findings of the so far most comprehensive study on plasmapheresis performed in the management of HIT with thrombosis, discrediting late plasmapheresis administered 4 days after the onset of the disease not only as ineffective, but even as an aggravating factor. Our results suggest the possible beneficial impact of late plasmapheresis as a method that may reverse a prothrombotic process and lead to a fast improvement in the patient's platelet count, especially in cases initially resistant to thrombin inhibitors.
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http://dx.doi.org/10.1002/jca.20099DOI Listing
December 2006

Combined thrombophilic risk factors and essential thrombocythemia in patient with recurrent venous thromboembolic episodes-thirty-three-year follow-up.

J Thromb Thrombolysis 2005 Apr;19(2):93-5

Institute of Cardiovascular Diseases, Clinical Centre of Serbia, Pasterova 2, Belgrade, Serbia and Montenegro.

We present the case of a 64 year-old female patient, with a clearly positive family history of venous thromboembolism (VTE), multiple VTE episodes (massive pulmonary embolism, ovarian venous plexus thrombosis, deep venous thrombosis with submassive pulmonary embolism and second deep venous thrombosis) and myocardial infarction. Laboratory tests revealed the resistance to the activated protein C, elevated FVIII and PAI-1. The patient was found to be a heterozygous carrier of FV Leiden, MTHFR C677T and PAI-1 4G/5G mutations. She was diagnosed with essential thrombocythemia at the age of 60. The thirty-three-year follow-up of our patient and detection of recurrent thrombotic episodes in the light of multiple coagulation defects with proved acquired risk factors, contributes to the risk stratification in the group of patients with very high risk. In case of our patient, we stress inadequacy of widely-accepted standard prevention measures. In our opinion, patients with very high risk require additional mechanic and specific medicament methods of VTE prevention.
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http://dx.doi.org/10.1007/s11239-005-0783-1DOI Listing
April 2005

[Factor V Leiden, FII G20210A, MTHFR C677T mutations as risk factors for venous thrombosis during pregnancy and puerperium].

Vojnosanit Pregl 2005 Mar;62(3):201-5

Institut za molekularnu genetiku i geneticko inzenjerstvo, Beograd, Klinicki centar Srbije.

Background: Venous thrombosis is the most common cause of obstetric morbidity and mortality during pregnancy and puerperium. The incidence of pregnancy-associated venous thrombosis varies from 1 in 1000 to 1 in 2000 deliveries. Factor V G1691A (FV Leiden), FII G20210A and MTHFR C677T mutations are the most common genetic risk factors for thromboembolism. The aim of this study was to establish the presence of these risk factors in a group of women with an episode of deep venous thrombosis during pregnancy or puerperium.

Methods: The study was carried in a group of 45 women with the first episode of deep venous thrombosis during pregnancy or puerperium. The patients with antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, and autoimmune and malignant diseases were excluded from the study. FV Leiden, FII G20210A, and MTHFR C677T mutations were detected by polymerase chain reaction, followed by digestion with specific restriction enzymes.

Results: Twenty heterozygous carriers of the FV Leiden mutation and one homozygous carrier were detected, which represents the frequencies of 44.4% and 2.2%, respectively. For the FII G20210A mutation, six heterozygous carriers were identified, giving the frequency of 13.3%. The MTHFR C677T mutation was observed in 31 patients (22 heterozygous and 9 homozygous carriers) which represents the frequencies of 48.9% and 20%, respectively.

Conclusion: Our study suggested that the obligatory testing for FV Leiden and FII G20210A mutations was strongly recommended in women with history of venous thrombosis during pregnancy and puerperium. We found a slight effect of MTHFR 677T allele, but it should be considered in association with other risk factors.
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http://dx.doi.org/10.2298/vsp0503201dDOI Listing
March 2005

[Heparin-induced type II thrombocytopenia--new views on diagnosis and therapy].

Med Pregl 2003 May-Jun;56(5-6):247-50

Institut za kardiovaskularne bolesti, KCS, Beograd.

HEPARIN-INDUCED THROMBOCYTOPENIA (HIT): Management of heparin-induced thrombocytopenia (HIT) and treatment options have significantly changed recently. Heparin may induce two types of thrombocytopenia. Type I, occurring earlier with a much higher rate of incidence (5-30%), is characterized by mild thrombocytopenia without significant clinical manifestations. Type II, is less frequent (0.5-2%), life threatening immune type, develops following a period of minimum 5-7 days upon introduction of heparin therapy (patients earlier treated with heparin are excluded). Type II heparin-induced thrombocytopenia with severely reduced platelet count may be clinically manifested by thrombosis in 20-50% cases within the period of 30 days. HIT is suspected in persons resistant to heparin with relatively reduced platelet count, though HIT is described in person with normal platelet counts, as well. None of available assays used for HIT detection is completely reliable. Sensitivity of a highly specific platelet aggregation assay is only 36%, sensitivity and specificity of 14C-serotonin release assays amounts to 95%, while ELISA using a heparin/platelet factor-4 target has a sensitivity of 85%. Thus, it is sometimes necessary to combine functional and antigen assays. Furthermore, new classes of antigen assays, like antibody detection tests of complexes between heparin and neutrophil-activating peptide-2 as well as those between heparin and interleukin-8, have been used. CURRENT THERAPY OPTIONS: Current therapy options exclude formerly applied low-molecular-weight heparins due to the existing cross-reactivity of 80-100%. Danaparoid sodium exhibits in vitro cross-reactivity of 10-61%, clinically manifested in less than 5% of patients. Two drugs are drugs of choice in HIT type II treatment: lepirudin, especially in patients without renal failure, and argatroban, particularly in patients with renal failure. The following procedures and agents are also efficient: asmapheresis in the first four days, high-dose intravenous gammaglobulin, antiaggregans, especially ADP antagonists, aspirin, dipirydamole, dextran, prostacyclin analagoues, thrombolytic therapy as well as thromboembolectomy. Oral anticoagulants are not administered in active HIT type II, in deep vein thrombosis with high international normalized ratio (INR) and thrombin-antithrombin complexes, and low protein C levels to avoid the possibility of venous limb gangrene development. They can be administered in a stable phase, when the thrombin generation is controlled by previous administration of one of the above-mentioned alternative anticoagulants.
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http://dx.doi.org/10.2298/mpns0306247aDOI Listing
November 2003
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