Gorana Mitic

Endocan is useful biomarker of survival and severity in sepsis.

INTRODUCTION Coagulation abnormalities which occur as a consequence of endothelial changes are recognized as diagnostic criteria for sepsis, but significance of these changes in the outcome prognosis and prediction of the course of sepsis is still not accurately defined. MATERIALS AND METHODS 60 patients who fulfilled the criteria for diagnosis of sepsis were included in our study. Patients were categorized in two groups according to sepsis severity and organ failure and MODS development was assessed in the first 48 h from ICU admission. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and endothelial cell specific molecule-1(endocan) levels, as well as procalcitonin (PCT) and C-reactive protein (CRP) were determined within the first 24h of the onset of the disease. Predictive APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment) scores were calculated on the day of ICU admission. Data were used to determine an association between day 1 biomarker levels, organ dysfunction score values and the development of organ failure, multiple organ dysfunction syndrome (MODS), and mortality during 28 days. These connections were determined by plotting of receiver operating characteristic (ROC) curves. Differences between groups were assessed by Mann-Whitney U test. Categorical variables were compared using chi-square test. RESULTS Concentration of endocan was significantly higher in the group of patients with sepsis induced organ failure, MODS development and in the group of non- survivors in contrast to group with less severe form of the disease, without multiorgan failure, and in contrast to group of survivors (p<0.05). Values of areas under the ROC curves showed that endocan levels had good discriminative power for more severe course of sepsis, MODS development and possible discriminative power for mortality prediction (AUC: 0.81, 0.67, 0.71 retrospectively), better than PCT for fatality (AUC:053) and better than APACHE II (AUC:0.55) and SOFA (AUC: 0.57) scores for organ failure. CONCLUSIONS Results of our study show that endocan can be used as strong and significant predictor of sepsis severity and outcome, perhaps even better than SOFA and APACHE II scores.

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.

Cystatin C in pre-eclampsia.

Objective: To evaluate diagnostic value of cystatin C serum levels as alternative marker of renal function in pre-eclamsia (PE) and compare it with the traditional markers of renal function, creatinine and uric acid. In order to investigate the possible influence of inflammation on biochemical markers of renal function, serum levels of high sensitive CRP were measured (hsCRP). Methods: In this prospective study markers of kidney function were investigated in two groups of pregnant women: one with PE (n = 32) and the other of healthy pregnant women (n = 60). Serum cystatin C levels were measured as well as levels of traditional renal markers creatinin and uric acid and levels of high sensitive C-reactive protein. Results: Serum levels of cystatin C, creatinine and uric acid were significantly higher in the PE group than in the control group. Serum levels of hsCRP were higher in approximately the same number of patients with PE (50%) as in normal pregnancies (40%), without significant differences in CRP values between the two groups of patients. Conclusions: Cystatin C serum level may have significant role as a marker of pre-eclampsia specially when used in combination with uric acid levels.

Thrombophilia in Women with Pregnancy-Associated Complications: Fetal Loss and Pregnancy-Related Venous Thromboembolism

Backgound/Aims: Existing data regarding the prevalence of thrombophilia in women with pregnancy complications are conflicting. Methods: To investigate the relationship between pregnancy-associated complications and the presence of thrombophilia, we studied the records of 453 women with pregnancy-associated complications. In 55 women, intrauterine fetal death (fetus mortus in utero, FMU) after 20 weeks of gestation was recorded, in 231 two or more consecutive recurrent fetal losses (RFL) were recorded, while 167 had a venous thromboembolism (VTE) during one of their pregnancies. The control group consisted of 128 healthy women, with no previous history of thrombotic events or miscarriages. Results: In the FMU group we found 54.5% of women had thrombophilia, in the RFL group 38%, and in the VTE group 52.7%. The most frequent thrombophilia in the VTE group was the FV Leiden (OR 17.9, 95% CI 4.2–75.9). The most frequent thrombophilia in the FMU group was the FII G20210A (OR 7.09, 95% CI 1.8–27.9). Statistical difference between RFL and the control group was observed only for FV Leiden (OR 6.8, 95% CI 1.6–29.7). Conclusion: Thrombophilia was found to be considerably more common in women with pregnancy-associated complications in comparison with the women with normal pregnancies, most frequently in patients with VTE or FMU.

Inherited Thrombophilia is Associated With Pregnancy Losses That Occur After 12th Gestational Week in Serbian Population

Recurrent fetal loss (RFL) is a significant clinical problem, occurring in 1% to 5% of reproductive females. Inherited or acquired thrombophilia has been diagnosed in 50% to 65% of women with history of unexplained fetal loss. The objective of our study was to determine the prevalence of thrombophilia in women with unexplained RFL in Serbian population and to find out whether the presence of thrombophilia is associated with pregnancy losses that occur later than 12th gestational week. We have examined 147 women with unexplained RFL or intrauterine fetal death and 128 healthy women with at least 1 uncomplicated pregnancy. The antithrombin (AT), protein C (PC), protein S (PS), activated protein C (APC) resistance, factor V (FV) G1691A, factor II (FII) G20210A, and MTHFR C677T were determined. At least 1 inherited thrombophilic defect was found in 54 (36.7%) of 147 women with repeated fetal losses and in 11 (8.59%) of 128 controls (P < .001, OR 6.17, 95% CI 3.06-12.48). The most common thrombophilic abnormalities were homozygosity for MTHFR 677TT, FV Leiden, and FII G20210A. Deficiency of natural anticoagulants occurred in 10 patients, with protein S deficiency being the most frequent one. Thrombophilia was found in 46 of 94 women with RFL that occurred later than the 12th gestational week and in only 8 of 53 with RPL earlier than 12th week (P = .001). Our study has shown the association between the hereditary thrombophilia and RFL that occurred after the 12th gestational week in Serbian population.

Does anticoagulant therapy improve pregnancy outcome equally, regardless of specific thrombophilia type?

The study was conducted to evaluate the effect of anticoagulant therapy in women with thrombophilia and to detect the possible differences among carriers of mutations (factor V [FV] Leiden and FIIG20210) and those with natural anticoagulant deficiency. The 4-year prospective investigation included 85 pregnant women, with a history of recurrent fetal loss (RFL). They were treated with prophylactic doses of low-molecular-weight heparin (nadroparin) starting from 6 to 8 weeks of gestation. Pregnancy outcomes were evaluated based on the thrombophilia type. Carriers of thrombophilic mutations had a live birth rate of 93%, compared to 41.6% for women with natural anticoagulant deficiencies. Significant differences between the groups were also observed for intrauterine fetal death, intrauterine growth restriction, and postpartum thrombosis. The optimal therapy for women with natural anticoagulant deficiency and RFL remains unclear and future prospective study with a large number of patients is required to determine the best treatment for these severe thrombophilic conditions.

The oncology treatment of patients who use oral anticoagulants is connected with high risk of bleeding complications

The data about risk for bleeding complications during anticoagulation in cancer patients with different oncology treatment are conflicting. To investigate the rate of bleeding in the course of oral anticoagulants, during treatment of malignant diseases, we conducted a retrospective study including 75 patients on stable anticoagulation prior to commencing their different oncology treatment. All patients were treated according to the consiliar decision, made based on the localization and pathohistological findings of the malignant disease. During their treatment the regular laboratory monitoring of INR was done. Every dose of oral anticoagulants, INR changes, as well as the size and localization of bleeding were recorded. During all the malignancy treatment 22 (30%) of patients were overanticoagulated. In 15 (20%) patients it was associated with bleeding, while 3 (4%) of them had to be transfused with fresh frozen plasma to stop the major bleeding. Most bleeding complications occurred in the group of patients treated with chemotherapy or with analgesics in the group with advanced disease. None of the bleeding complications were observed in patients treated with irradiation and surgery alone, where the bridging of oral anticoagulants with low molecular weight heparin was done before surgery. The oncology treatment of patients who take oral anticoagulants was connected with high risk for bleeding especially if chemotherapy as a therapeutic options was used. Therefore physicians should be aware of this risk and carefully monitor the intensity of anticoagulant therapy, especially during the first treatment weeks when the risk of bleeding is greatest.

Thrombomodulin is a Strong Predictor of Multiorgan Dysfunction Syndrome in Patients With Sepsis

Background: Biomarkers of endothelial dysfunction are not recommended for routine laboratory investigation of the outcome prognosis and prediction of the course of sepsis. Methods: A total of 60 patients who fulfilled the criteria for diagnosis of sepsis were included in our study. Development of multiorgan dysfunction syndrome (MODS) in the first 48 hours was assessed. Differences between groups of patients with sepsis were assessed by Mann-Whitney U test and by Kruskal-Wallis test. Logistic regression analysis was performed to test the joint effect of different predictors. Results: Level of thrombomodulin was significantly higher in group of patients with MODS than without MODS (P = .015). Levels of antithrombin (P = .026) and protein C (P = .035) were significantly lower in patients with MODS. Level of thrombomodulin was the strongest predictor in MODS development in first 48 hours (P = .028). Conclusion: The level of thrombomodulin not only was able to distinguish the severity of sepsis but also was a significant predictor of MODS development.

Clinical characteristics and type of thrombophilia in women with pregnancy-related venous thromboembolic disease.

Background: Normal pregnancy is characterized by numerous changes in the hemostatic system, creating the hypercoagulable state which increases the risk of venous thromboembolic event (VTE) occurrence. The risk is further increased by the presence of inherited or acquired thrombophilia. Objective: In this study, we aimed to determine the prevalence of different types of thrombophilia in women with pregnancy-related VTE, and to investigate the possible connection between the type of thrombophilia and localization of VTE as well as the gestational age of VTE occurrence. Participants and Methods: Two hundred and two women with the first episode of pregnancy-related VTE and 130 controls were investigated. The antithrombin, protein C and protein S activity, APC resistance, FVG1691A, and FIIG20210A were determined. None of the investigated women was pregnant at the time of thrombophilia testing, and none was using oral contraceptives. Results: Thrombophilia was diagnosed in 95 patients (47%) and 7 controls (5.4%). The prevalence of FV Leiden, FIIG20210A mutations, antithrombin, PC and PS deficiencies taken together and combined thrombophilia was 22.3, 10.4, 6.9 and 6.9%, respectively. Significantly more frequent antepartum occurrence of VTE (11 vs. 3, p < 0.05) was found in women with natural coagulation inhibitor deficiency. Pulmonary embolism occurred more frequently in nonthrombophilic women (25 vs. 3, p < 0.001). Conclusion: Inherited thrombophilia was found to be considerably more frequently present in women with pregnancy- and puerperium-related VTE compared to healthy controls. Women with thrombophilia are at higher risk of developing thromboses localized in the iliacofemoral region, and women without thrombophilia are at higher risk of developing pulmonary embolism. Deficiency in natural coagulation inhibitors is associated with antepartum VTE occurrence.

Treatment of pregnancy related venous thromboembolism

INTRODUCTION Prevention and treatment of venous thromboembolism during pregnancy are complicated since the use of antithrombotic drugs carries a certain risk to the mother, the fetus or both. Coumarins cross the placental barrier and may be responsible for bleeding, teratogenicity and central nervous system abnormalities. The risk of embriopathy is particularly high between 6 and 12 weeks of gestation. TREATMENT Heparin is the treatment of choice for thrombosis during pregnancy because it is entirely safe for the fetus, unlike oral anticoagulants. The frequency of heparin-induced thrombocytopenia and osteoporosis is significantly lower if LMWH is applied, so this heparin type is preferable to UFH during pregnancy. Treatment of women with VTE during pregnancy, especially those with thrombophilia, requires individualized dosing and duration of antithrombotic therapy. PERIPARTAL MANAGEMENT: In order to avoid the peripartum anticoagulant heparin effect and possible bleeding, heparin should be discontinued prior to the delivery and reintroduced after the parturition. PROPHYLACTIC REGIMEN Prophylactic antithrombotic regimen during subsequent pregnancies should also be individualized. The use of low molecular weight heparins is becoming more widespread. They have reliable pharmacokinetics, require less frequent injections than unfractionated heparin and carry a lower risk of treatment complications. LMW heparins are safe and effective and they are replacing UFH as the anticoagulant of choice during pregnancy. Both UFH and LMWH are not secreted into breast milk and can be safely given to nursing mothers. Warfarin does not induce an anticoagulant effect in the breast-fed infant, so it can be safely used in women who require postpartum anticoagulant therapy.