Vascular Endothelial Growth Factor in Stage V ROP

November 21, 2007 updated by: Asociación para Evitar la Ceguera en México

Vascular Endothelial Growth Factor Levels in Aqueous, Vitreous and Subretinal Fluid in Patients With Retinopathy of Prematurity Stage V.

Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in epithelial and tumor cells (1). Normal Retinal vascularization has two phases: In the first fase, cells of mesenquimatous origin form the first superficial plexus (14-21 weeks of gestation). In the second phase, denominated "angiogenesis phase", the superficial and deep capillary plexus are formed (15,20). The Retinopathy of Prematurity (ROP) was described for the first time in 1942 (4), at the present moment it is a public health problem in the developing countries. The International Classification of ROP classifies it in 5 stages, dividing it in 3 anatomical zones. It is a public health problem that continuous without having an effective prophylaxis. The early diagnosis and treatment in thresholds stages have changed the prognosis of this disease (11,12).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in epithelial and tumor cells (1). In conditions of hypoxia it is secreted by the pericytes, the Retina Pigmented epithelium (RPE)and glial cells, including a the Müller cells (1,2,4,5) favoring the formation of new abnormal vessels (1). Its activity is mediated by two high affinity receptors: the receptor VEGF 1 (FLT-1) and VEGF 2 (FLT-2) (1,9). The FLT-1 promotes cellular proliferation whereas FLT-2 the migration and cell- extracellular matrix interaction (9). The VEGF is essential as much for the normal retinal vascularization as for pathological (5,14).

Normal Retinal vascularization has two phases: In the first fase, cells of mesenquimatous origin form the first superficial plexus (14-21 weeks of gestation). In the second phase, denominated "angiogenesis phase", the superficial and deep capillary plexus are formed (15,20). The second phase is highly dependent of VEGF induced by hypoxia (15,20). In the normal retina the growth occurs from the optical nerve to the periphery (17).

The scientific progress in the neonatal intensive care units in the last years has allowed the survival of a larger number of premature newborns(15).

The Retinopathy of Prematurity (ROP)(ROP) was described for the first time in 1942 (4), at the present moment it is a public health problem in the developing countries. Of each 100.000 blind child in Latin America, 24.000 are due to ROP (240/1000 blind child) (17). It is the main cause of blindness in premature new born (1,4,5). It is of multifactorial etiology (17) but it has been related to a short gestational age (smaller to 32 weeks of gestation) (4), to low birth weight (less of 1500gr) or very low birth weight (less 1250gr)(1,4,5,17,18,20), to the administration of high oxygen concentration immediately after birth (1,3,18), low levels of the Insulin-like growth factor(IGF-I) and excessive production of VEGF (3,17).

All this, combined with large periods of hyperoxia-hypoxia, Produces that the normal vascularization of the retina stops. This also produces vascular-occlusive changes, arteriovenous anastomoses in the edge of the vascularized with the none-vascularized retina (18), begins the formation of abnormal vessels towards the vitreous, finally lead to retina detachment in the most severe cases (2,3,4,5).

The International Classification of ROP classifies it in 5 stages, dividing it in 3 anatomical zones. A threshold stage is considered when we have the presence of stage 3, in zone 1 or 2 in 5 continuous hour uses or 8 discontinuous with plus disease (15,16,17). The pre-threshold stage is divided in two types: type 1 is any stage of the disease in zone 1 with plus disease, stage 3, without plus disease in zone 1 or stage 2 or 3 with plus in zone 2. Type 2 is stage 1 or 2 without plus disease in zone 1 or stage 3 without plus disease in zone 2 (17,19). The threshold stage happens approximately in 5% of the patients with very low weight to the birth, of which the 10-15% develop blindness (6,8)

It is a public health problem that continuous without having an effective prophylaxis (5), nevertheless the use of constant oxygen concentrations, avoiding the periods of hyperoxia-hypoxia, has demonstrated to produce a decrease of the presentation of advanced stages of the disease and the necessity of ophthalmological surgery (5). The early diagnosis and treatment in thresholds stages have changed the prognosis of this disease (11,12). The use of the laser as treatment in the threshold and prethreshold stages is successful in the 91-95% of the cases(10), the ablative effect on the neurons, probably diminishes the VEGF production (15). The use of the vitrectomy in the early cases of retinal detachment also has good results (13).

For the determination and the quantification of VEGF several laboratory techniques have been used, as they are the Westernblot (1), the flow cytometry (7), CBA (7). Nevertheless, the Enzyme-linked immunoabsorbent assay (ELISA) remains the gold standard for the measurement of interleukins, growth factors and other cytokines in corporal fluids, including the vitreous, aqueous and subretinal fluid (1,5,7).

It has been demonstrated in humans that there are high vitreous concentrations of VEGF in eyes with active neovascularization (6,14). In the same way, the animal models of ROP report high levels of VEGF (2,21). The levels of this growth factor are altered in both stages, with a more marked increase during the first stage (2). Some clinical studies in patients with ROP in stage 4 and 5 have reported an increase of up to 90 times greater of the concentration of VEGF in the subretinal liquid in comparison with the found in patients with retinal detachment of any other cause (1). Finally, when it has been possible to examine retinas immediately after the treatment (due to death of the patient) have been found a low expression of mRNA of VEGF in the treated cells (6).

Study Type

Interventional

Enrollment (Anticipated)

15

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
    • DF
      • Mexico, DF, Mexico, 04030
        • Asociación Para Evitar la Ceguera en México

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 months to 10 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Premature newborns with less than 32 weeks of gestation.
  • Low birth weight (less than 1500gr) Stage V ROP.
  • The parents has signed the informed consent.

Exclusion Criteria:

  • Previous treatment of ROP.
  • Surgery or another ocular pathology of any type.
  • Systemic diseases, including diabetes mellitus, congestive heart failure acute renal insufficiency, Chronic renal insufficiency, high blood pressure.
  • Lack of Informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine the degree of VEGF in aqueous, vitreous and SRF in patients with ROP in stage V. Verifying that it is greater to that found in healthy newborn patients with different ocular pathology
Time Frame: 4 months
4 months

Secondary Outcome Measures

Outcome Measure
Time Frame
To establish a relation between the low and very low birth weight with the VEGF levels.
Time Frame: 4 months
4 months
To prove that the VEGF level found in ROP patients is greater than in other pathologies that normally produce neovessels (like in DM).
Time Frame: 4 months
4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Asociación para Evitar la Ceguera en México

Investigators

  • Principal Investigator: Hugo Quiroz-Mercado, MD, Asociación Para Evitar la Ceguera en México
  • Principal Investigator: Raul Velez-Montoya, MD, Asociación Para Evitar la Ceguera en México

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2007

Study Completion (Actual)

June 1, 2007

Study Registration Dates

First Submitted

July 10, 2007

First Submitted That Met QC Criteria

July 10, 2007

First Posted (Estimate)

July 12, 2007

Study Record Updates

Last Update Posted (Estimate)

November 26, 2007

Last Update Submitted That Met QC Criteria

November 21, 2007

Last Verified

November 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VEGFROP

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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