The Influence of Hyperthyroidism on the Coagulation and on the Risk of Thrombosis.

Introduction: Apart from the well-known fact that hyperthyroidism induces multiple prothrombotic disorders, there is no consensus in clinical practice as to the impact of hyperthyroidism on the risk of thrombosis. The aim of this study was to examine the various hemostatic and immunologic parameters in patients with hyperthyroidism. Methods: Our study consists of a total of 200 patients comprised of 64 hyperthyroid patients, 68 hypothyroid patients, and 68 euthyroid controls. Patient thyroid status was determined with standard tests. Detailed hemostatic parameters and cardiolipin antibodies of each patient were determined. Results: The values of factor VIII (FVIII), the Von Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and anticardiolipin antibodies of the IgM class were significantly higher in the hyperthyroid patients than in the hypothyroid patients and euthyroid controls. The rate of thromboembolic manifestations was much higher in hyperthyroid patients (6.25%) than in hypo-thyroid patients (2.9%) and euthyroid controls (1.4%). Among hyperthyroid patients with an FVIII value of ≥1.50 U/mL, thrombosis was recorded in 8.3%, while in hyperthyroid patients with FVIII value ≤ 1.50 U/mL the occurrence of thrombosis was not recorded. The incidence of atrial fibrillation (AF) was significantly higher (8.3%) in the hyperthyroid patients compared to the hypothyroid patients (1.5%) and euthyroid controls (0%). Conclusions: High levels of FVIII, vWF, fibrinogen, PAI-1, and anticardiolipin antibodies along with other hemostatic factors contribute to the presence of a hypercoaguable state in patients with hyperthyroidism. The risk of occurrence of thrombotic complications is especially pronounced in patients with a level of FVIII exceeding 150% and positive anticardiolipin antibodies of the IgM class. Patients with AF are at particularly high risk of thrombotic complications due to a hyperthyroid prothrombotic milieu.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

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

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 F8 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 F8, and five mutations not previously associated with FVIII:C discrepancy was identified. Global hemostatic assays did not contribute to distinguish assay discrepancy in PwHA.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.