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 lt .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

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 lt .05). Thrombosis of the upper limb was more frequent in a group without thrombophilia than in patients with mutations (P lt .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

Efficacy and Safety of Nadroparin and Unfractionated Heparin for the Treatment of Venous Thromboembolism During Pregnancy and Puerperium

Introduction The optimal treatment of pregnancy associated VTE (venous thromboembolism) has not been established yet. Objective The assessment of the efficacy and safety of low molecular weight heparin (LMWH) nadroparin and unfractionated heparin (UFH) used for the treatment of pregnancy and puerperium related VTE. Primary study goals were to analyze the incidence of recurrent VTE (proximal extension or pulmonary thromboembolism), thrombocytopenia, major and minor hemorrhages and skin allergic reactions. The study also included the incidence of miscarriages, stillbirth and neonatal abnormalities. We also studied the relationship between the presence of thrombophilia and the occurrence of complications during VIE treatment. Methods Seventy-two women with antepartal VTE treated with s.c. LMWH during entire pregnancy and 88 women with postpartal VIE initially treated with either s.c. LMWH or i.v.UFH were under follow-up during the entire treatment. Thrombophilia testing included antithrombin, protein C and protein S activity levels, Activated protein C (APC) resistance, LA, ACL, FV Leiden, FII G20210A and MTHFR C677T mutations. Results Twice a day weight based therapeutic regimen was applied for LMWH and activated partial thromboplastin time (aPTT) adjusted UFH dosages. After 2-6 weeks of antepartal deep vein thrombosis (DVT) treatment the dose of nadroparin was reduced to intermediate level. The duration of LMWH therapy during pregnancy was 1-35 weeks, on average 16 weeks. One case (0.62%) of DVT propagation into the vena cava occurred in a woman with antithrombin deficiency treated with LMWH. Two women (1.25%) had minor bleeding and 5 (3.125%) had minimal bleeding, while 3 (1.9%) had skin allergic reactions. The rate of successful pregnancy outcome was 97.2%. There were no cases of stillbirth or neonatal congenital abnormalities. Thrombophilia was found in 86 women (53.7%). No statistically significant correlation between the presence of thrombophilia and treatment complications were found. Conclusion Nadroparin is both safe and effective for the treatment of DVT during pregnancy and puerperium

Distinct effects of virgin coconut oil supplementation on the glucose and lipid homeostasis in non-diabetic and alloxan-induced diabetic rats

Non-diabetic and alloxan-induced diabetic rats were fed with standard laboratory food enriched with 20% virgincoconut oil for 16 weeks. In non-diabetic animals coconut oil improved insulin sensitivity and ability to controlglycaemia and decreased the serum triglycerides for almost 50% in comparison with controls. Supplementationwith coconut oil caused liver steatosis in both non-diabetic and diabetic animals. However, the severity ofsteatosis was lower in diabetic animals compared to non-diabetic animals. Coconut oil had no effects on hearthistology, ascending and abdominal aorta wall thickening and atherosclerotic plaques development neither innon-diabetic nor in diabetic animals. While alloxan treatment caused Type I diabetes in rats, supplementationwith coconut oil in combination with the alloxan unexpectedly resulted in Type II diabetes. The development ofsevere insulin resistance and deterioration in serum lipid profile implied that the use of coconut oil is contra-indicated in diabetic condition

Effects of C60 Fullerene on Thioacetamide-Induced Rat Liver Toxicity and Gut Microbiome Changes

Thioacetamide (TAA) is widely used to study liver toxicity accompanied by oxidative stress, inflammation, cell necrosis, fibrosis, cholestasis, and hepatocellular carcinoma. As an efficient free radical’s scavenger, C60 fullerene is considered a potential liver-protective agent in chemically-induced liver injury. In the present work, we examined the hepatoprotective effects of two C60 doses dissolved in virgin olive oil against TAA-induced hepatotoxicity in rats. We showed that TAA-induced increase in liver oxidative stress, judged by the changes in the activities of SOD, CAT, GPx, GR, GST, the content of GSH and 4-HNE, and expression of HO-1, MnSOD, and CuZnSOD, was more effectively ameliorated with a lower C60 dose. Improvement in liver antioxidative status caused by C60 was accompanied by a decrease in liver HMGB1 expression and an increase in nuclear Nrf2/NF-κB p65 ratio, suggesting a reduction in inflammation, necrosis and fibrosis. These results were in accordance with liver histology analysis, liver comet assay, and changes in serum levels of ALT, AST, and AP. The changes observed in gut microbiome support detrimental effects of TAA and hepatoprotective effects of low C60 dose. Less protective effects of a higher C60 dose could be a consequence of its enhanced aggregation and related pro-oxidant role

Early onset of abdominal venous thrombosis in a newborn with homozygous type II heparin-binding site antithrombin deficiency

The overall incidence of thromboembolic events in the neonatal period is 5 per 100 000 births, wherein more than 40% of all such manifestations are symptomatic renal vein thromboses. We describe the case of a newborn female who developed extensive thrombosis, which filled the inferior vena cava and renal vein and was diagnosed in the first weeks of life. A homozygous type II heparin-binding site antithrombin deficiency (c.391C gt T, p.Leu131Phe) was detected in the background. Despite the timely diagnosis and appropriate treatment, clinical signs of renal insufficiency, because of left kidney atrophy and arterial hypertension, were observed. Our case demonstrates the seriousness of the consequences arising after early onset of venous thrombosis caused by homozygous type II heparin-binding site antithrombin deficiency. In addition to prompt diagnosis, of huge importance is the determination of inherited thrombophilia, as it significantly affects therapeutic treatment and indicates that long-term follow-up is mandatory

Clinical characteristics of first venous thrombosis among women under and over 45 years of age

Uvod. Venski tromboembolizam je multifaktorijalna bolest koja nastaje u interakciji genetskog i stečenog faktora rizika. Nakon bolesti koronarnih krvnih sudova i moždanog udara, najčešći je razlog kardiovaskularne smrti ili onesposobljenosti. Materijal i metode. Sa ciljem da se utvrde kliničke krakteristike prvog venskog tromboembolizma, u studiju je uključeno 447 žena mlađih od 45 i 174 žene starije od 45 godina, koje su testirane na prisustvo trombofilije u periodu 1998-2012. godine. Rezultati. Proksimalna duboka venska tromboza češće je zastupljena kod mladih žena, dok je distalna učestalija u grupi starijih. Najčešći faktor rizika za trombozu, koji je utvrđen kod 49,8% mladih žena je trudnoća i stanje posle porođaja, dok se kod 25,2% tromboza razvila bez jasno prepoznatljivog faktora rizika. U grupi starijih žena, tromboza nastaje kod 38,5% bez faktora rizika, dok je malignitet kao najznačajniji faktor rizika utvrđen kod 23%. Prisustvo trombofilije zabeleženo je kod 48,7% mladih, odnosno kod 28,7% starijih žena, p lt 0,001. Razlika se beleži i u odnosu na ponavljane venske tromboze koje su zabeležene kod 26,3% mladih, odnosno kod 17,8% starijih žena, p = 0,03. Zaključak. Kod mladih žena se razvijaju klinički teže venske tromboze nego kod starijih. Urođeni faktor rizika otkriven je kod skoro polovine mladih ispitanica, odnosno kod svake četvrte starije žene. Sa izuzetkom faktora V Leiden mutacije ostali tipovi urođene trombofilije su gotovo zanemarljivi u grupi starijih žena. Stoga je testiranje na prisustvo trombofilije u slučaju prve tromboze, u potpunosti opravdano samo kod mlađih žena.Introduction. Venous thromboembolism is a multifactorial disease defined by multiple interactions between genetic and acquired risk factors. After coronary heart disease and stroke, venous thromboembolism is the most common cause of cardiovascular death and disability. Material and Methods. In order to investigate the clinical characteristics of first venous thromboembolism, 447 women younger than 45 and 174 over 45 years of age with confirmed venous thromboembolism, who had been tested for the presence of thrombophilia in the period 1998-2012, were included in the study. Results. Proximal deep vein thrombosis occurred most often among young women, while distal deep vein thrombosis was the most frequent in the older group. The most common reported risk for venous thromboembolism observed in 49.8% of the young women was pregnancy and puerperium, while 25.2% of them developed venous thromboembolism without any obvious cause. Among women over the age of 45, venous thromboembolism developed without an obvious cause in 38.5%, while malignant disease was identified as the most important risk factor in 23% of them. Thrombophilia was observed in 48.7% of the young women in comparison to 28.7% of the older ones (p lt 0.0001). As for venous thromboembolism recurrence, it developed in 26.3% of young women and 17.8% of the older ones (p = 0.03). Conclusion. Younger women developed more severe forms of thrombosis than the older ones. Inherited risk factor for thrombosis was detected in almost half of all young women, and in every fourth elderly women. With the exception of factor V Leiden mutation, other types of congenital thrombophilia are almost negligible among older women. Therefore, thrombophilia testing in case of first thrombosis is fully justified only in young women

PHARMACOLOGICAL EXERCISE MIMETICS IN THERAPY: DELUSION OR FUTURE?

The increase in the prevalence of a large number of metabolic disorders is attributed to the sedentary lifestyle associated with increased energy intake of food. Scientists warn that our genes are not selected for a sedentary existence and that the complex homeostatic system is being seriously undermined. Regular physical activity induces a number of physiological adaptations both within skeletal muscle and the whole organism, which have positive effects in the prevention and treatment of many metabolic disorders. Recognizing the impact of these beneficial effects of physical activity on health outcomes, and taking into account the trend of inactivity population, researchers have focused on the active substances that mimic or potentiate the effects of exercise without the actual energy consumption, and big pharmaceutical companies see a potentially huge market and profit in this. This paper discusses the real possibility and potential of pharmacological mimetic of exercise in the treatment of metabolic diseases

The influence of hyperprolactinemia on coagulation parameters in females with prolactinomas

Introduction. Currently there is little information on the effects of prolactin (PRL) on the coagulation and fibrinolytic systems. Objective. The aim of this study was to evaluate the effects of hypeprolactinemia on the parameters of the hemostatic system and activation of the coagulation system. Methods. We studied PRL levels, body mass index (BMI), values of activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), D-dimer level, von Willebrand factor antigen (vWFAg) and fibrinogen in 15 young female patients with microprolactinomas before and after therapy and in 15 healthy female controls. Results. As expected, pretreatment PRL levels were significantly higher in patients than in controls (140.90±42.87 vs. 12.53±4.05 ng/ml; p<0.001). PT, although still in the normal range, was prolonged in patients with hyperprolactinemia as compared to the control group (13.53±1.39 vs. 12.65±0.53 s; p=0.03) and normalized after therapy (12.69±0.65 vs. 12.65±0.53 s; p=0.88). TT, although in normal range, was significantly shorter in the hypeprolactinemic patients than in the controls (14.34±4.52 vs. 17.21±1.35 s; p<0.025) and after treatment remained significantly shorter than in the controls (15.17±1.55 vs. 17.21±1.35 s; p<0.0001). D-dimer values before treatment in the patients with hyperproplactinemia were above the normal range (239.47±107.93 vs. 131.27±50.64 ng/ml, p=0.002) and decreased to normal values after therapy (239.47±107.93 vs. 146.60±39.15 ng/ml; p<0.001). D-dimer levels correlated with PRL (r=0.30) and the change in serum D-dimer values significantly correlated with the change in PRL levels during therapy (r=0.62). aPTT, vWFAg and fibrinogen were similar in patients and controls. Conclusion. In our study, increased thrombin generation that resulted in elevated D-dimer levels may be one of the contributing factors to the prethrombotic state in patients with hyperprolactinemia. [Projekat Ministarstva nauke Republike Srbije, br. 175033 i br. 174016