The effect of high circulating estradiol levels on thrombin generation during in vitro fertilization

Brummel‐Ziedins, Kathleen E.; Gissel, Matthew; Francis, Charles; Queenan, John T.; Mann, Kenneth G.

doi:10.1016/j.thromres.2009.02.006

Cited by 17 publications

(30 citation statements)

References 23 publications

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“…The data from the present study are in accordance with those recently published by Olausson et al which demonstrate that platelet, endothelial and monocyte-derived microparticles and inflammation biomarkers are significantly increased in women undergoing IVF [28]. Thrombin generation was also significantly enhanced but the baseline levels of FVIII, FvW, D-Dimers and fibrinogen were similar to those observed in the control group, confirming previous studies [4]. To the best of our knowledge, this is the first study showing that infertility is linked to a systemic cell activation that offers procoagulant substances, mainly endothelial cells and platelets.…”

Section: Discussionsupporting

confidence: 93%

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

et al. 2017

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Background: Blood coagulation plays a crucial role in the blastocyst implantation process and its alteration may be related to in vitro fertilization (IVF) failure. We conducted a prospective observational longitudinal study in women eligible for IVF to explore the association between alterations of coagulation with the IVF outcome and to identify the biomarkers of hypercoagulability which are related with this outcome. Methods: Thirty-eight women eligible for IVF (IVF-group) and 30 healthy, age-matched women (control group) were included. In the IVF-group, blood was collected at baseline, 5-8 days after administration of gonadotropin-releasing hormone agonist (GnRH), before and two weeks after administration of human follicular stimulating hormone (FSH). Pregnancy was monitored by measurement of βHCG performed 15 days after embryo transfer. Thrombin generation (TG), minimal tissue factor-triggered whole blood thromboelastometry (ROTEM®), procoagulant phospholipid clotting time (Procoag-PPL®), thrombomodulin (TMa), tissue factor activity (TFa), factor VIII (FVIII), factor von Willebrand (FvW), D-Dimers and fibrinogen were assessed at each time point. Results: Positive IVF occurred in 15 women (40%). At baseline, the IVF-group showed significantly increased TG, TFa and TMa and significantly shorter Procoag-PPL versus the control group. After initiation of hormone treatment TG was significantly higher in the IVF-positive as compared to the IVF-negative group. At all studied points, the Procoag-PPL was significantly shorter and the levels of TFa were significantly higher in the IVF-negative group compared to the IVF-positive one. The D-Dimers were higher in the IVF negative as compared to IVF positive group. Multivariate analysis retained the Procoag-PPL and TG as predictors for the IVF outcome. Conclusions: Diagnosis of women with hypercoagulability and their stratification to risk of IVF failure using a model based on the Procoag-PPL and TG is a feasible strategy for the optimization of IVF efficiency that needs to be validated in prospective trials.

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Section: Discussionsupporting

confidence: 93%

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

et al. 2017

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“…We have shown that small differences in the ensemble of factor levels, all within the normal range, can lead to large differences in thrombin generation profiles [15], [16], [21], [22]. In this case, the focus is on the opposite effect.…”

Section: Resultsmentioning

confidence: 96%

“…Many efforts are currently under way to decrease the risk of thrombosis seen in women on oral contraceptives [31], [32]. Previously, we have shown that women on high dose hormones, undergoing in vitro fertilization, had increased thrombin generation profiles [16] and that this effect on thrombin generation was in part due to alterations in plasma factors fVIII, TFPI and AT. In this study, we determined that the increases in fXa generation seen in oral contraceptive users were due to elevated levels of fIX and decreased levels of TFPI.…”

Section: Discussionmentioning

confidence: 99%

Factor Xa Generation by Computational Modeling: An Additional Discriminator to Thrombin Generation Evaluation

et al. 2012

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Factor (f)Xa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473) and control (n = 426) population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC), the maximum rate (MaxR) and level (MaxL) and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use). The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3–6 fold) in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ∼2.2 fold increased risk for individuals exceeding the 90th percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6). Grouping defined by oral contraceptive (OC) use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals.

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“…We believe that the sum of developmental, environmental, genetic, nutritional, and pharmacological influences are reflected in the protein levels at any given time that specifically alter the synthesis and/or presentation of the proteins and active enzymes. We have described changes in thrombin generation and related these changes to plasma coagulation factor composition in the following groups: genetic bleeding tendencies30, 31, 32, 33 and clotting tendencies34, 35; women undergoing in vitro fertilization36; chronic obstructive pulmonary disease37; stroke38; rheumatoid arthritis39; and cardiovascular disease 40. In all cases, thrombin generation was more pronounced in individuals with procoagulant vs bleeding tendencies 30, 31, 32.…”

Section: Introductionmentioning

confidence: 99%

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

Brummel‐Ziedins

Gissel

Neuhaus

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundEffective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non‐AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro‐ and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.MethodsIn a nested case‐control study of HIV+ individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non‐violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue‐factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F)II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor, and protein C (PC) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve (AUC).ResultsLevels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls (P < 0.05 for all).ConclusionsAntithrombin, FV, FVIII, and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro‐ and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.

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The effect of high circulating estradiol levels on thrombin generation during in vitro fertilization

Cited by 17 publications

References 23 publications

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

Factor Xa Generation by Computational Modeling: An Additional Discriminator to Thrombin Generation Evaluation

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

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