Vascular Cell Activation, Cell-Derived Microparticles and In Vitro Fertilisation, and In Vitro Fertilisation (PREDHSO)

Vascular Cell Activation Throughout Ovarian Hyperstimulation for In Vitro Fertilisation: Role of Cell-Derived Microparticles in the Adverse Outcomes

Introduction: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic phenomenon, poorly understood and difficult to predict, complicating intense ovarian stimulation cycle. The most severe symptoms, which associate vascular permeability disorders and hypercoagulability, occur in 0.2 to 1% of the cases and often require intensive care.

Activation of endothelial, platelet, erythrocyte or leukocyte cells trigger the release of small specific vesicles, called microparticles, used as markers.

Classically leading to endothelial dysfunction and hypercoagulability, the endothelial activation phenomenon could constitute the main cause of OHSS or help predict its severity, as established for various other diseases (cerebral stroke, infarct and lupus…). However, so far, this endothelial activation role has never been studied.

Objectives:

Evaluate the serum level of microparticles as a predictor of adverse outcomes; correlate it to hypercoagulability and changes of endothelial permeability associated with this syndrome.

Methodology: Prospective Pilote Cohort study, evaluating before and throughout the ovarian stimulation cycle (6 samples/patient), the serum modulation of:

• Endothelial activation markers (endothelial-derived microparticles, E-selectin)
• Procoagulant markers (microparticles from platelet, erythrocyte or leukocyte origin, Von Willbrand factor, thrombin-antithrombin complex, prothrombin fragment 1+2)
• Endothelial disjunction marker (soluble CD 146) A group of 50 patients will be assessed Techniques: Flow cytometry for measurement of microparticles expressing non specific (Annexin V) and cell specific surface determinants (CD 31, CD 41, CD 45 or glycophorin A). Use of commercial kits for other serum markers.

Study Overview

• Status: Completed
• Conditions: Infertility; Thrombosis; Hyperstimulation Syndrome, Ovaian

• Study Type: Observational
• Enrollment (Actual): 50

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 43 years (Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Infertile volunteers, aged 18 to 35 years, with neither cardiovascular disease nor Lupus erythematosus related disease, scheduled for In Vitro fertilisation, and assessed from their day 3 basal hormonal assessment, at least to the ovarian triggering of their IVF cycle were included.

Description

Inclusion Criteria:

• Between 18 and 35 years old
• With Health Insurance
• Scheduled for their first ovarian stimulation in an IVF or ICSI program in our centre
• Whose blood samples will be collected in our hospital

Exclusion Criteria:

• Suffering or having suffered from a disease likely to alter their vascular system and thus modulate their rates of microparticles:

  • auto-immune disease (systemic lupus erythematosus26, antiphospholipid syndrome)
  • cardiovascular risk factors: cardiovascular disease history, diabetes, arterial hypertension, dyslipidemia
  • Tobacco addiction.
• Presenting a blood œstradiol rate > 5000 pg/ml at ovulation triggering (criterion of stimulation cancellation) and more generally, every patient which ovulation has not been triggered.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Studied group; Women exposed to ovarian hyperstimulation for In Vitro fertilisation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of prothrombin fragment 1+2 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	At day 3 of an unstimulated (i.e. natural) menstrual cycle, before IVF cycle, when basal hormonal assessments is performed for fertility work-up
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of prothrombin fragment 1+2 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at first day of FSH stimulation
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of prothrombin fragment 1+2 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	During ovarian stimulation for IVF (first cycle), at ovarian triggering day, i.e.when ≥ 3 ovarian follicles rich 17mm
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of prothrombin fragment 1+2 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	4 days after ovarian triggering for IVF (first cycle), at the day of embryo transfer of the Day 2 embryos
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	9 days after ovarian triggering for IVF (first cycle), at mid-luteal phase
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Microparticles subsets from endothelial origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Microparticles subsets from erythrocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Microparticles subsets from leukocyte origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Microparticles subsets from platelet origin in the circulating blood	Venipuncture for blood sampling and exam with flow cytometry	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Tissue Factor-Dependent Procoagulant Activity (MP-TF) in the circulating blood	Venipuncture for blood sampling and exam with home made device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Plasmin Generation Capacity (MP-PGC) in the circulating blood	Venipuncture for blood sampling and exam with home made device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Fibrin monomer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of D-dimer in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of E-selectin in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of soluble CD 146 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of Von Willbrand factor in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of thrombin-antithrombin complex in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test
Quantification of prothrombin fragment 1+2 in the circulating blood	Venipuncture for blood sampling and exam with commercial device	16 days after ovarian triggering for IVF (first cycle), at the day of pregnancy test

Collaborators and Investigators

• Sponsor: Poissy-Saint Germain Hospital
• Collaborators: Agence de La Biomédecine

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): January 2, 2015
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: February 1, 2017
• First Submitted That Met QC Criteria: February 8, 2017
• First Posted (Actual): February 13, 2017

Study Record Updates

• Last Update Posted (Actual): February 13, 2017
• Last Update Submitted That Met QC Criteria: February 8, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Biomarkers; Blood Coagulation Disorders; Fertilization in Vitro; Superovulation; Cell-Derived Microparticles
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Infertility; Thrombosis
• Other Study ID Numbers: PREDHSO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No