Retinal vascular occlusion and deficiencies in the protein C pathway

doi:10.1016/S0002-9394(99)00074-4

American Journal of Ophthalmology

Volume 128, Issue 1, July 1999, Pages 69-74

https://doi.org/10.1016/S0002-9394(99)00074-4 Get rights and content

Abstract

PURPOSE: To report abnormalities in the protein C pathway and other vascular occlusion risk factors in patients with retinal vascular occlusion.

METHODS: In a study, we investigated 76 consecutive patients who had in-patient evaluation of venous or arterial retinal vascular occlusion. All patients underwent comprehensive tests for coagulation disorders including determinations of protein C, protein S, lupus anticoagulants, and resistance to activated protein C and were screened for vascular disease risk factors. Resistance to activated protein C was confirmed by a polymerase chain reaction method to detect the specific factor V R506Q mutation. For comparative purposes, we also screened 209 consecutive inpatients with deep vein thrombosis from the same geographic region for resistance to activated protein C as well as protein C and protein S deficiencies.

RESULTS: Ten (29%) of 35 patients with central retinal vein occlusion (CRVO) had factor V R506Q mutation. The factor V R506Q mutation was detected in four (19%) of 21 patients with branch retinal vein occlusion. The higher frequency in factor V R506Q mutation compared with the expected 9% mutation prevalence in a white population was highly significant for the central retinal vein occlusion group but not for the branch retinal vein occlusion group. In all patients with resistance to activated protein C, the factor V R506Q mutation was detected; 16 were heterozygous, one homozygous. No cases of lupus anticoagulants, protein C, or protein S deficiencies were detected. Forty (19%) of 209 patients with deep vein thrombosis were carriers of the factor V R506Q mutation.

CONCLUSIONS: The prevalence of the factor V R506Q mutation is similar in patients with central retinal vein occlusion and patients with deep vein thrombosis and represents a relevant risk factor. Screening for this mutation is therefore recommended in all patients with central retinal vein occlusion.

Section snippets

Patients and methods

In our study, 76 consecutive patients admitted to the Mainz University Hospital for evaluation of retinal vascular occlusive disease (central retinal vein occlusion in 35 patients, branch retinal vein occlusion in 21 patients, central retinal artery occlusion in 13 patients, and branch retinal artery occlusion in seven patients) were evaluated. The hospital serves as a referral center for approximately 4.4 million people. Within this area, referral practice is similar.

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Results

This series of 76 patients with retinal vascular disease consisted of 35 (46%) patients with central retinal vein occlusion, 21 (28%) with branch retinal vein occlusion, 13 (17%) with central retinal artery occlusion, and seven patients with branch retinal artery occlusion. All patients in the retinal vascular occlusion group and in the group with deep vein thrombosis were white. TABLE 1, TABLE 2 summarize the demographic data for the patient population with retinal vascular occlusion and the

Discussion

Much attention has been drawn to the protein C pathway since a new thrombophilic defect, resistance to activated protein C, was described by Dahlbäck.9, 34, 35 Until then, defects in other pathway components (for example, protein C and protein S) were detected rarely, even in patients with spontaneous venous thrombosis.8, 17, 36, 37 The Leiden Thrombophilia Study determined the prevalence of protein C and protein S deficiency in patients with an objectively confirmed diagnosis of thrombosis to

References (40)

B.J. Keyser et al.
Color Doppler imaging of arterial blood flow in central retinal vein occlusion
Ophthalmology
(1994)
H. Zegarra et al.
The natural course of central retinal vein occlusion
Ophthalmology
(1979)
A.K. Vine et al.
Screening for resistence to activated protein C and the mutant gene for factor V506 in patients with central retinal vein occlusion
Am J Ophthalmol
(1997)
A.K. Vine et al.
The role of abnormalities in the anticoagulant and fibrinolytic systems in retinal vascular occlusions
Surv Ophthalmol
(1993)
R.D. Appleby et al.
The inherited basis of venous thrombosis
Pathology
(1997)
B. Zöller et al.
Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis
Lancet
(1994)
D.C. Rees et al.
World distribution of factor V Leiden
Lancet
(1995)
T. Koster et al.
Venous thrombosis due to poor anticoagulant response to activated protein CLeiden Thrombophilia Study
Lancet
(1993)
C.M. Greven et al.
Peripheral retinal neovascularization and retinal vascular occlusion associated with activated protein C resistence
Am J Ophthalmol
(1997)
T. Talmon et al.
Retinal arterial occlusion in a child with factor V Leiden and thermolabile methylene tetrahydrofolate reductase mutations
Am J Ophthalmol
(1997)

J. Holm et al.

Myocardial infarction associated with homozygous resistance to activated protein C

Lancet

(1994)

J.I. Jorquera et al.

Modified test for activated protein C resistance

Lancet

(1994)

B.P. Koeleman et al.

Activated protein C resistance as an additional risk factor for thrombosis in protein C–deficient families

Blood

(1994)

B. Zoller et al.

Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S

Blood

(1995)

W.R. Green et al.

Central retinal vein occlusionsa prospective histopathologic study of 29 eyes in 28 cases

Retina

(1981)

Davie ED, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance and regulation. Biochemistry...

M. Makris et al.

Familial thrombophiliagenetic risk factors and management

J Intern Med

(1997)

B. Dahlbäck et al.

Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C

Proc Natl Acad Sci U S A

(1993)

B. Dahlbäck

Resistance to activated protein C caused by the R⁵⁰⁶Q mutation in the gene for factor V is a common risk factor for venous thrombosis

J Intern Med

(1997)

R.M. Bertina et al.

Venous thrombosisthe interaction of genes and environment

N Engl J Med

(1998)

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Update on Retinal Vein Occlusion
2023, Asia-Pacific Journal of Ophthalmology
Retinal vein occlusion represents the second leading cause of retinal vascular disorders, with a uniform sex distribution worldwide. A thorough evaluation of cardiovascular risk factors is required to correct possible comorbidities. The diagnosis and management of retinal vein occlusion have changed tremendously in the last 30 years, but the assessment of retinal ischemia at baseline and during follow-up examinations remains crucial. New imaging techniques have shed light on the pathophysiology of the disease and laser treatment, once the only therapeutic option, is now only one of the possible approaches with antivascular endothelial growth factors and steroid injections being preferred in most cases. Nowadays long-term outcomes are better than those achievable 20 years ago and yet, many new therapeutic options are under development, including new intravitreal drugs and gene therapy. Despite this, some cases still develop sight-threatening complications deserving a more aggressive (sometimes surgical) approach. The purpose of this comprehensive review is to reappraise some old but still valid concepts and to integrate them with new research and clinical data. The work will provide an overview of the disease's pathophysiology, natural history, and clinical features along with a detailed discussion on the advantages of multimodal imaging and of the different treatment strategies with the aim of providing retina specialists with the most updated knowledge in the field.
Central retinal artery occlusion in a young child secondary to resistance to activated protein C
2018, Journal Francais d'Ophtalmologie
Thrombophilic and cardiovascular risk factors for retinal vein occlusion
2017, European Journal of Internal Medicine
The role of thrombophilic and cardiovascular risk factors in different manifestations of retinal vein occlusion (RVO), i.e., central or branch RVO, and at different ages is still debated.
To evaluate the association between thrombophilic and cardiovascular risk factors and the risk of RVO (overall, separately for central and branch RVO, and at different ages).
Case-control study on 313 patients with a first objectively-confirmed RVO (216 central and 97 branch RVO) and 415 healthy individuals.
Antithrombin, protein C or protein S deficiency (adjusted odds ratio [95%CI]: 15.60 [2.01–121]; p = 0.009), hyperhomocysteinemia (HHCy; 3.22 [1.38–7.49]; p = 0.007), high factor VIII (FVIII) levels (3.08 [1.20–7.89]; p = 0.019), factor V Leiden (2.93 [0.97–8.86]; p = 0.058) and the presence of at least one cardiovascular risk factor (1.79 [1.00–3.23]; p = 0.050) were associated with an increased risk of branch RVO. The association was weaker for central RVO, and limited to HHCy (2.15 [1.09–4.24]; p = 0.027) and high FVIII (1.99 [0.90–4.42]; p = 0.091). For HHCy, high FVIII and cardiovascular risk factors the association with the risk of RVO was stronger at an age > 50 years (3.41[1.29–8.99], p = 0.013; 2.57[1.00–6.68], p = 0.050; and 2.03[1.16–3.56], p = 0.013, respectively) than ≤ 50 years (1.93[0.85–4.36], p = 0.114; 1.67[0.54–5.12], p = 0.371; and 1.22[0.73–2.03], p = 0.454, respectively), whereas classic inherited thrombophilia (antithrombin, protein C or protein S deficiencies, factor V Leiden and prothrombin G20210A mutation) was slightly more prevalent at an age ≤ 50 years (1.62 [0.76–3.45], p = 0.210) than > 50 years (1.11[0.44–2.79], p = 0.833).
Thrombophilic and cardiovascular risk factors are associated with RVO, particularly branch RVO. The risk of RVO associated with HHCy, high FVIII and cardiovascular risk factors is higher at an older age.
Neutrophil/lymphocyte ratio and mean platelet volume in branch retinal vein occlusion
2016, Saudi Journal of Ophthalmology
To evaluate the mean platelet volume (MPV) and the neutrophil/lymphocyte ratio (NLR) in patients with branch retinal vein occlusion (BRVO).
Thirty patients with branch retinal vein occlusion (BRVO group) and 27 age and sex matched subjects (control group) were included in the study. MPV and NLR parameters obtained from peripheral blood were recorded.
The mean age was 62.6 ± 12.3 years in BRVO and 63.5 ± 8.2 years in control group. The BRVO group consisted of 13 males and 17 females and the control group included 12 male and 15 female subjects. The mean MPV values were 8.64 ± 2.01 fL in BRVO group and 8.5 ± 1.26 fL in control group. NLR was 2.24 ± 0.79 and 1.89 ± 0.64 in BRVO and control groups respectively. The difference between two groups in terms of MPV and NLR was not statistically significant.
MPV and NLR were found to be not affected in branch retinal vein occlusion patients.
Seeing through thick and through thin: Retinal manifestations of thrombophilic and hyperviscosity syndromes
2016, Survey of Ophthalmology
Citation Excerpt :
Deficiencies of these 2 endogenous anticoagulant pathways are well-established in both systemic venous thrombosis and retinal venous occlusive disease.5,57,60,70,77 Prospective series have estimated the prevalence of protein C and protein S deficiencies of up to 20% in younger aged individuals with retinal vein occlusion: however most of these studies were small, and few included a control group.9,28,43,72 There are case reports of CRVO associated with thrombotic thrombocytopenic purpura and antiphospholipid antibodies.17,34,52,65
The presence of retinal vasculopathy in the absence of typical predisposing factors should suggest a possible underlying hematologic abnormality. In such cases, a systemic investigation may reveal a potentially fatal hypercoagulability or hyperviscosity syndrome. Retinal vein occlusion is the most commonly encountered ophthalmic finding in such syndromes; however, abnormalities of the arterial system, the choroid, and the macula are also possible. Visual symptoms may be the only manifestation of the underlying process, making timely diagnosis by the ophthalmologist critical for both treatment and thrombotic prophylaxis. Moreover, as newer ophthalmic diagnostic technologies arise, there is an increasingly important role for eye physicians in the management of such syndromes.
Association of methylenetetrahydrofolate reductase (A1298C and C677T) polymorphisms with retinal vein occlusion in Tunisian patients
2014, Transfusion and Apheresis Science
The role of two polymorphisms C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) gene in the etiology of retinal vein occlusion (RVO) has not been adequately clarified. The aim of this study was to examine the prevalence of these polymorphisms among RVO Tunisian patients with and without systemic risk factors. Seventy-two patients with retinal vein occlusion (RVO) were studied. The control group included 140 people matched for age, sex, and risk factors. Participants in the study were genotyped for the MTHFR C677T and A1298C polymorphisms. The genotyping was performed by PCR-RFLP. No significant differences were found in the frequencies of the three genotypes (AA, AC, CC) of the MTHFR A1298C polymorphism between RVO patients and healthy controls. However, the prevalence of the group of mutated genotypes (AC + CC) of the missense variant MTHFR A1298C was significantly different between patients and controls (16.67% vs. 6.42%, p = .01). Additionally, the frequency of the CT genotype as well as the group of combined mutated genotypes (CT + TT) for the C677T variant was significantly higher among RVO patients compared with controls (p < 10⁻³, p < 10⁻³). This suggests an association between this polymorphism and RVO. Large study populations would be required to understand more completely the contribution of these markers in the risk of RVO.

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Original ArticlesRetinal vascular occlusion and deficiencies in the protein C pathway

Abstract

Section snippets

Patients and methods

Results

Discussion

Ophthalmology

Ophthalmology

Am J Ophthalmol

Surv Ophthalmol

Pathology

Lancet

Lancet

Lancet

Am J Ophthalmol

Am J Ophthalmol

Lancet

Lancet

Blood

Blood

Central retinal vein occlusionsa prospective histopathologic study of 29 eyes in 28 cases

Retina

Familial thrombophiliagenetic risk factors and management

J Intern Med

Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C

Proc Natl Acad Sci U S A

Resistance to activated protein C caused by the R506Q mutation in the gene for factor V is a common risk factor for venous thrombosis

J Intern Med

Venous thrombosisthe interaction of genes and environment

N Engl J Med

Original Articles
Retinal vascular occlusion and deficiencies in the protein C pathway

Resistance to activated protein C caused by the R⁵⁰⁶Q mutation in the gene for factor V is a common risk factor for venous thrombosis