Regina Komsa-Penkova

Association of inherited thrombophilia with embryonic and postembryonic recurrent pregnancy loss

To investigate the impact of maternal-inherited thrombophilia: effects of factor V Leiden (FVL) and prothrombin gene mutation (FII 20210G>A) on the development of recurrent pregnancy loss in embryonic and postembryonic periods. A total of 153 patients were analysed for FVL and FII 20210G>A according to placenta gestation: 94 women with embryonic loss prior 10 weeks of gestation and 59 women with postembryonic (early fetal) loss occurring between 10 and 14 weeks of gestation. The control group consisted of 100 healthy women, with at least one uncomplicated full-term pregnancy. FVL prevalence was not significantly associated with pregnancy loss prior to 10 weeks of gestation (9.6%) compared with controls (7%) [odds ratio (OR) 1.41; 95% confidence interval (CI) 0.454–4.416, P > 0.05], but it was much more pronounced in women with postembryonic loss (10–14 weeks of gestation) – 18.6% (OR 3.05; 95% CI 1.010–9.387, P = 0.047). FII 20210G>A was significantly higher in both groups with embryonic (17%) and early fetal losses (16.9%) as compared to controls (3%) (OR 6.63; 95% CI 1.731–29.752, P = 0.003; OR 6.60; 95% CI 1.572–31.856, P = 0.006). FII 20210G>A is significantly associated with an increased risk of early recurrent pregnancy loss throughout the entire first trimester. FVL was significantly higher only in early fetal period after starting of the placentation process, but not associated with embryonic recurrent pregnancy loss. These results suggested that the first trimester should be viewed rather as a heterogeneous interval, with different relation to FVL in the embryonic and postembryonic fetal period. Genetic testing should be applied according to the diverse contribution of thrombophilic markers to embryonic and postembryonic period.

Inherited thrombophilia and IVF failure: the impact of coagulation disorders on implantation process.

In connection with the embryo acceptance process after IVF procedure, endometrial cells surface receptors, extracellular matrix (ECM) molecules, endothelium and blood circulation factors were involved in remodelling of endometrium. Plasminogen activator inhibitor type 1 plays a significant role during the early phases of placental vascular remodelling and regulates the trophoblast invasion through controlling plasmin activity. Endometrial cell surface protein integrin alphaV/beta3, responsible for the adhesion of the embryo, has had also the same subunit beta3, which is component of integrin alphaIIb/beta3 connected with platelet aggregability. Prothrombin, furthermore, has had a debatable effect upon endothelial and mesenchymal cells and possible contribution on embryo vascular development. Confoundable data have been present about the role of coagulation factor V and its role for implantation. These and other coagulation factors have relatively common gene polymorphisms that enhanced their activity. This review discusses the effect of increased coagulation activity on implantation process, which is not yet fully determined. The establishment of the positive or negative impact of mother hypercoagulability on the success of embryo implantation after assisted reproduction technology could determine the timing of preventing anticoagulant therapy in women with history of early embryo loss.

IL-17 producing T cells correlate with polysensitization but not with bronchial hyperresponsiveness in patients with allergic rhinitis

BackgroundTh2-type T cell response has a considerable role in atopic diseases. The involvement of Th17 and IL-17 in atopy process provided new understanding of allergic diseases. Bronchial hyperresponsiveness is quite common in allergic rhinitis. We aimed to explore the expression of IL-17 producing CD3+ CD4+ T cells in peripheral blood of rhinitic patients, with/without bronchial hyperresponsiveness and sensitized to common allergens, as this relationship has not been examined.MethodsSixty one patients with allergic rhinitis and thirty controls were examined. IL-17 producing T cells were detected by flow cytometry, IL-17, IL-4 and IL-13 levels in peripheral blood were evaluated by ELISA. Bronchial hyperresponsiveness was investigated with methacholine challenge test. Atopy was evaluated by skin prick tests with common allergens.ResultsIL-17 producing T cell percentage of AR group was significantly higher: 2.59 ± 1.32 than in controls 1.24 ± 0.22, (p = 0.001). Significant sex related difference in CD3+ CD4+ IL-17 T cells was observed: respectively in male patients versus female 3.15 ± 1.8% and 2.31 ± 0.9%, (p = 0.02). Rhinitics had greater bronchodilator responses compared to controls (p = 0.001), however the percentages of T cells in both groups appeared equal. Serum IL-17 levels in AR group were significantly higher (5.10 ± 4.40) pg/ml than in controls (3.46 ±1.28) pg/ml, (p = 0.04). IL-4 levels (0.88 ± 1.27) and IL-13 levels (3.14 ± 5.85) in patients were significantly higher than in control’s (0.54 ± 0.10) pg/ml, (p = 0.001) and (1.19 ± 0.64) pg/ml; (p = 0.001) respectively.The percentages of T cells in patients sensitized to 5 allergens (group I) were significantly lower (1.91 ± 0.62) than those sensitized to more than 5 allergens (group II) (2.91 ± 1.5) (p = 0.004).ConclusionsThe observed higher levels of IL-17 producing T cells in polysensitized males suggest a role of IL-17 in pathogenesis of AR. The higher airway responsiveness in AR may not be Th17 dependent. The higher serum values of IL-17, IL-4 and IL-13 demonstrate the presence of cytokine balance in atopic diseases.

Polymorphism A1/A2 in the cell surface integrin subunit β3 and disturbance of implantation and placentation in women with recurrent pregnancy loss.

Polymorphism A1/A2 in the β3 subunit of integrins αIIb/β3 and αV/β3 is implicated in the risk of development of embryonic and fetal recurrent pregnancy loss (RPL). In 191 women with RPL, polymorphism A1/A2 was statistically significantly associated with RPL at <10 weeks of gestation (29.3% versus 16.4% in controls), but it was much more pronounced in 67 women with RPL between 10 and 20 weeks of gestation (41.8%), illustrating its role in recurrent fetal loss.

Rs5918ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women

Objective: To evaluate the contribution of rs5918ITGB3 on the incidence and recurrence of deep venous thrombosis (DVT) in women and the relationship with body mass index (BMI) and smoking and to compare with data in men. Results: Rs5918(C) polymorphism in ITGB3 gene was assessed in 224 patients diagnosed with DVT and 216 controls. Thrombophilic genetic variant rs5918(C) was significantly pronounced in women (χ2 =7.565, P = .008) and total patients (χ2 = 9.266, P = .002) but not in men. Women patients (<45 years) who were carriers of rs5918ITGB3 polymorphism had an early onset of DVT (34.5 vs 39.4 years, χ2 = 7.027, P = .008) as analyzed by Kaplan-Meier and a higher risk of the recurrent event (χ2 = 3.405, odds ratio = 2.581, P = .044). The period before recurrent venous thromboembolism event was related to smoking status and BMI in young female who were carriers of rs5918 polymorphism but not in the males. Conclusions: Carriage of genetic variant rs5918(C) polymorphism in ITGB3 gene in women contributes to higher risk of single and recurrent DVT events at younger age.

Fetuin-A – Alpha2-Heremans-Schmid Glycoprotein: From Structure to a Novel Marker of Chronic Diseases Part 1. Fetuin-A as a Calcium Chaperone and Inflammatory Marker

Summary Fetuin-A is a major plasma glycoprotein released mainly by the liver. Its functions include inhibition of the activity of insulin receptor, regulation of response to inflammation, inhibition of calcified matrix metabolism and ectopic mineralization, etc. Three major functional domains of fetuin-A have been identified: one similar to the Ca-binding domains, one inhibiting cysteine protease, and a domain with high affinity to insulin receptor. The fetuin-A molecule may be considered as a highly pleomorphic protein with an important impact in a variety of clinically expressed metabolic and pathological processes. It could be used as a marker in clinical practice in the future.

PlA2 Polymorphism in Glycoprotein IIb/IIIa Modulates the Morphology and Nanomechanics of Platelets

Glycoprotein IIb/IIIa (GPIIb/IIIa) is the most abundant platelet surface receptor for fibrinogen and von Willebrand factor. Polymorphism PlA1/A2 in the gene of GPIIb/IIIa is among the risk factors for the development of arterial and venous thrombosis. The aim of this study is to evaluate the effect of the carriage of PlA1/A2 on the size, topographic features, and membrane stiffness of platelets from healthy controls and patients with deep venous thrombosis (DVT). Atomic force microscopy (AFM) imaging and nanoindentation (force–distance curves) were applied to investigate the morphological and nanomechanical properties (Young’s modulus) of platelets immobilized on glass surface. The surface roughness (Ra) and height (h) of platelets from patients with DVT, carriers of mutant allele PlA2 (Ra = 30.2 ± 6 nm; h = 766 ± 182 nm) and noncarriers (Ra = 28.6 ± 6 nm; h = 865 ± 290 nm), were lower than those of healthy carriers of allele PlA2 (Ra = 48.1 ± 12 nm; h = 1072 ± 338 nm) and healthy noncarriers (Ra = 49.7 ± 14 nm; h = 1021 ± 433 nm), respectively. Platelets isolated from patients with DVT, both carriers and noncarriers, exhibit much higher degree of stiffness at the stage of spreading (E = 327 ± 85 kPa and 341 ± 102 kPa, respectively) compared to healthy noncarriers (E = 198 ± 50 kPa). In addition, more pronounced level of platelet activation was found in polymorphism carriers. In conclusion, the carriage of PlA2 allele modulates the activation state, morphology, and membrane elasticity of platelets.

Recurrent Arterial and Venous Thrombotic Events in a Patient with Psoriasis. Impact of PAI-1 Polymorphism: A Case Report

Summary Psoriasis isachronic autoimmune multisystem disease, mainly affecting the skin and joints. Its origin is related to both environmental and genetic factors. The condition affects 1-3%of the population worldwide. Psoriasis is also associated with cardiovascular risk factors, atherothrombotic events, and markers of hypercoagulation (platelet activation and hyperhomocysteinemia). Venous thromboembolism (VTE) isawidespread severe disease. Both VTEand psoriasis are connected with risk factors for cardiovascular disorders (obesity and hypertension). The incidence of VTEevents in patients with psoriasis is higher. Patients with psoriasis should be checked for risk factors (metabolic disorders and cardiovascular diseases).We reportacase of a 53-year old man, diagnosed with plaque psoriasis 20 years ago, andafive year history of hypertension. In 2006, he hadastroke, and in 2011 ‒aheart attack. In 2013 he was diagnosed with thrombophlebitis. The patient was recently diagnosed with Type IIdiabetes, dyslipidemia and metabolic syndrome. The DNAanalysis revealed that the patient wasahomozygous carrier of 4G/4G (rs1799889) polymorphism in plasminogen activator inhibitor 1 (PAI-1) -a risk factor for thrombophilia. This case is important because of the major comorbidities, more particularly thrombotic events in combination withaprothrombotic mutation.

SND Rs1799889(-) In The Promotor Of The Plasminogen Activator Inhibitor-1 Gene Contributes To The Risk Of DVT In Women

Summary The incidence of deep venous thrombosis (DVT) depends on the specific genotype, inheritance of prothrombotic polymorphisms and the influence of environmental risk factors. Rs1799889(-) polymorphism in the promotor of PAI-1 gene has been described as a risk factor for hypercoagulable state. Objective: To evaluate the contribution of thrombophilic rs1799889 (-) in the promotor of PAI-1 gene on the incidence of DVT in women and men in groups below and above 45 years of age. Тhere was significantly higher rs1799889 (-) polymorphism carriage among female patients with DVT vs controls (Chi squared =5.506, OR=2.170, p=0.021) but not in male patients (Chi squared =0.090 OR=1.147, p=0.825). A significant contribution of rs1799889 (-) polymorphism to early onset of the disease was found in female patients aged 45+ and carriers of the polymorphism (Chi squared =7.476, p=0.006), but not in young women.

Predisposition to Thrombophilia and Hypofibrinolysis in Pulmonary Embolism: Analysis of Inherited Factors

Summary Pulmonary embolism (PE) is a relatively common cardiovascular emergency, though its exact incidence is difficult to assess. Accurate diagnosis is critical because of the high 30-day mortality in patients in whom the diagnosis is missed on admission. Doubt for PE is often raised by the presence of risk factors for venous thromboembolism (VTE), which are categorized into inherited and acquired. Among these, the importance of inherited/genetic thrombophilic factors is increasingly recognized. The most frequent markers of inherited thrombophilia are Factor V Leiden (FVL) and G2021OA prothrombin gene mutation. Among the inherited factors causal to thrombophilia, the C677T variant in methylentetrahydrofolate reductase (MTHFR) gene as well as factors like P1A1/P1A2 polymorphism in platelet glycoprotein Ilb/IIIa (P1A2) and hypofibrinolytic polymorphism 4G/4G in PAI-1 gene are discussed with controversial results. In our study, thrombophilic and hypofibrinolytic genetic variants were identified in 54.2% of 115 patients with PE. The most common significant genetic defects were FVL- 16.5% in patients versus 6.2% in controls (OR=3.102; p=0.05), G20210A PT 5.7% versus 2.1% (OR=2.983; p>0.05). P1A2 was found in 27.3% patients versus 19.9% in controls (OR= 1.523, p>0.05) and PAM 27.8% versus 22.6% (OR =1.501 p>0.05). MTHFR C677T carriage was inverse: 6.7% in patients versus 13.4% in controls. (OR=0.461 p=0.05). Of all the patients studied, 15.65% had a history of recurrent embolic incidents. The risk of recurrence was higher for the carriers of FVL and G20210A prothrombin gene mutation. The association between carriage of thrombophilic genetic factor and the early onset of the first embolic episode was found in the patients with PE. The awareness of risk factors and risk stratification is a critical issue in treatment and prevention policy. Preventive measures should be taken in particular medical conditions.