Thrombophilia and hypofibrinolysis:
Pathoetiologies for Retinal Artery Thrombosis
A free, new (9/12/00) clinical research study at the Jewish Hospital Cholesterol Center, 3200 Burnet Avenue, Cincinnati,
OH, 45229. Phone 513-585-7800, Fax 513-585-7950, Email at glueckch@healthall.com
Contact us by email or by phone if you are interested in participating.
1. Purpose:
Our specific aim is to assess major thrombophilic and hypofibrinolytic pathoetiologies for nonarteritic ischemic optic
neuropathy (NAION). We postulate that when exogenous thrombophilic factors (estrogen-containing oral contraceptives, estrogens, corticosteroids) are
superimposed on heritable thrombophilic and/or hypofibrinolytic coagulation disorders, blood clots can form in the small arteries which serve the optic
nerve and the optic disc.
2. Significance in Relationship to Human Health
Nonarteritic ischemic optic neuropathy (NAION) is a common and serious ophthalmologic health problem. It can lead to
serious visual impairment and even loss of vision itself. It appears that there are three primary mechanisms involved: degenerative changes in the
vessel wall, thrombophilia, and an abnormal perivascular status (i.e. adjacent sclerotic vessels sharing a common adventitia). The final presentation is
likely due to a combination of these factors, and in different patient groups, the extent to which each factor is involved may vary. The subject of our
study will be the role of thrombophilia.
In the body, there is a delicate, constantly changing, opposing balance between blood clotting (thrombosis) and lysis of
blood clots (fibrinolysis). Either through inheritance, or through acquired exogenous factors, there may be an increased likelihood of thrombi formation
(thrombophilia), a decreased likelihood of fibrinolysis (hypofibrinolysis), or both. Major inherited factors which produce thrombophilia include the
following (by assay type):
THROMBOPHILIA
PCR-DNA assays
- Factor V Leiden mutation
- Prothrombin gene mutation
- MTHFR
- Platelet glycoprotein IIIa PlA1/A2 polymorphism
Serologic assays
- Homocysteine
- Deficiency of proteins C, S, or antithrombin III
- Anticardiolipin antibody IgG, IgM
- Lupus anticoagulant
- Factor VIII
- Factor XI
Acquired factors which promote thrombophilia include estrogen-containing oral contraceptives, estrogen replacement
therapy, Evista, pregnancy, immobilization, recent surgery (particularly abdominal or orthopedic), and certain cancers.
Major inherited factors which produce hypofibrinolysis include the following:
PCR-DNA assays
- 4G4G polymorphism of the PAI-1 gene
Serologic assays
- Plasminogen activator inhibitor activity (PAI-Fx)
- Lipoprotein (a) [Lp(a)]
A general rule is that younger patients require more thrombophilic and/or hypofibrinolytic conditions in order to
sustain a thrombotic event than do older patients. Often heritable thrombophilias or hypofibrinolyses do not manifest until another acquired
thrombophilic factor is superimposed (i.e. starting oral contraceptives).
Studies completed 1999-2000 funding year:
Glueck CJ, Fontaine RN, Wang P. Interaction of estrogen-mediated and heritable thrombophilias: pathoetiologies for
ischemic optic neuropathy and ischemic stroke. Journal of Investigative Med 2000; 48:189A. Presented, Biology 2000, National Meeting of the AFMR, San
Diego, 4/16-18, San Diego, California.
Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang J. The thrombophilic Factor V Leiden mutation (resistance
to activated protein C) and estrogen replacement therapy as risk factors for atherothrombotic cardiovascular disease in 423 women. Circulation 1999;
100 (Supplement I): I-331. Presented, National AHA, Atlanta, November, 1999.
Glueck CJ, Fontaine RN, Wang P. Interaction of heritable and estrogen-induced thrombophilia: Possible pathoetiologies
for ischemic optic neuropathy. J Invest Med, In Press, September 2000. Presented, CSCR/AFMR, Chicago, September 2000.
Glueck CJ, Bell H, Vadlamani L, Gupta A, Fontaine RN, Wang P, Tracy T, Stropp D, Gruppo D. Heritable thrombophilia and
hypofibrinolysis. Arch Opthalmology 1999; 117:43-49.
Glueck CJ, Fontaine RN, Wang P. Interaction of heritable thrombophilia (prothrombin gene, MTHFT, platelet glycoprotein
IIIa gene A1/A2 polymorphism) and acquired thrombophilia (estrogen replacement therapy): Possible pathoetiologies for nonarteritic ischemic optic
neuropathy. Thrombosis and Haemostasis, In press, 2000.
3. Method of Study
Patients:
We plan to study 30 new patients with NAION, with particular focus on women whose NAION occurred while on estrogen
replacement therapy or on oral contraceptive therapy.
Exclusions:
Patients whose retinal artery thrombosis is secondary to cholesterol crystal emboli after coronary or carotid
angiography or bypass will not be included in the study, since these represent mechanical inductions of thrombosis, less directly related to underlying
pathoetiologies. Other patients to be excluded from the study are those on Coumadin, low molecular weight heparin, or agents that would interfere with
the measurement of coagulation factors.
Protocol:
Each patient will be seen at the Jewish Hospital Cholesterol center by Dr. Glueck and/or one of the Jewish Hospital
resident co-investigators. A detailed medical history will be taken along with a history of exogenous oral contraceptive, estrogen replacement therapy,
or corticosteroid use.
A detailed family history will be done, focusing on ischemic stroke, stroke of any type, venous thrombosis, arterial
thrombosis, and/or myocardial infarction.
A brief physical examination will be carried out. Measures of height, weight, and blood pressure will be obtained.
The medical history, physical examination, and blood draw should total to approximately 1 hour.
Each participating patient will have the following coagulation measures drawn in the morning in a seated position:
cDNA-PCR:
Factor V Leiden gene, MTHFR gene, Prothrombin Gene, PAI-1 gene, IIb/IIIa polymorphism of the platelet glycoprotein gene.
Serologic tests for thrombophilia:
Protein C, Protein S, Antithrombin III, anticardiolipin antibodies (IgG, IgM), lupus anticoagulant, homocysteine.
Serologic tests for hypofibrinolysis:
Plasminogen activator inhibitor activity (PAI-Fx), lipoprotein (a).
Atherosclerotic risk factors:
Low, very low, and high density lipoprotein cholesterol (LDLC, VLDLC, HDLC).
Normal Controls:
The patients will be compared to 234 normal controls in whom we have already measured all the DNA polymorphisms and all
of the coagulation tests.
Risks and benefits:
Benefits:
Should include the potential to prevent blindness by prophylactic
anticoagulation to prevent retinal vein or artery thrombosis in the contralateral eye to the original thrombosis. Also, knowledge of heritable
coagulation disorders should facilitate prevention of thrombotic events in other arterial and venous beds.
Risks:
Documentation of coagulation disorders of a heritable nature, might, were
they known to medical insurance companies, be identified as a pre-existing risk for thrombosis. However, the information for the current study will be
processed following strict confidentiality rules and will be released only with signed patient consent.
Payment:
There will be no financial remuneration. Parking will be free in the
Alliance ABC garage.
Subject Costs:
There are no anticipated costs for the patients. Third party payers
have covered diagnostic tests in the past.
References:
E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-585-7950
