The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62-3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.     

Significantly increased prevalence of factor V Leiden in patients with dural arteriovenous fistulas

Resistance to activated protein C (APCR) is the most common genetic risk factor for venous thrombosis and is generally caused by a mutation in the factor V (FV) gene leading to FV Leiden. The recent finding of FV Leiden in three of seven patients with dural arteriovenous fistulas (DAVFs) prompted us to evaluate systematically the role of APCR due to FV Leiden in the pathogenesis of DAVFs in 22 patients and age- and sex-matched controls. We found a significantly higher frequency of APCR and FV Leiden in the patient group than among controls (5/22 vs. 0/22, P=0.048, Fisher's exact test). We conclude that APCR due to FV Leiden is of pathogenetic significance in a subgroup of DAVFs. Received: 10 December 1999, Received in revised form: 12 January 2000, Accepted: 16 February 2000     

Increased rate of factor V Leiden mutation in patients with cerebral venous thrombosis

We investigated the association between cerebral venous thrombosis and hereditary resistance to activated protein C (APC) in 12 consecutive German patients with non-fatal cerebral venous thrombosis and in 187 controls without a history of thrombotic disorder. Three patients (25%) had a mutation in the factor V Leiden gene against only one subject in the control group. This difference was significant (P<0.05), with an odds ratio of 11.7 (1.5–87 ; 95% confidence interval). Two patients carrying the mutation had additional common risk factors for thrombosis, and 2 had a positive family history of thromboembolism. We conclude that inherited APC resistance by a mutation in factor V Leiden is an important risk factor in non-fatal cerebral venous thrombosis. We recommend testing for APC resistance and, if abnormal for factor V Leiden mutation in patients with cerebral venous thrombosis. Received: 27 February 1997 Received in revised form: 14 August 1997 Accepted: 17 November 1997     

High prevalence of factor V Leiden in healthy Jordanian Arabs

The prevalence of APC resistance in healthy Jordanian Arabs was studied. Between October 1996 through September 1997 a total of 400 healthy subjects were studied. There were 212 males and 188 females. APC resistance was studied by functional and DNA methods. There were a total of 52 subjects (13%) who were APC resistant by the functional test. There were 49 subjects (12.25%) who had FV Q506 by DNA test. Of these there were 42 heterozygous and 7 homozygous (allele frequency 0.07). None of the subjects had clinical thrombosis. It is concluded that the prevalence of APC resistance due to FV Q506 is high in Jordanian Arabs.     

Role of haemorheological factors in patients with retinal vein occlusion

Retinal vein occlusion (RVO) is an important cause of permanent visual loss. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of RVO. Aim of this case-control study was to evaluate the possible association between haemorheology and RVO. In 180 RVO patients and in 180 healthy subjects comparable for age and gender we analysed the whole haemorheological profile: [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV), and fibrinogen]. WBV and PLV were measured using a rotational viscosimeter, whereas DI was measured by a microcomputer-assisted filtrometer. WBV at 0.512 sec(-1) and 94.5 sec(-1) shear rates as well as DI, but not PLV, were found to be significantly different in patients as compared to healthy subjects. At the logistic univariate analysis, a significant association between the highest tertiles of WBV at 94.5 sec(-1) shear rate (OR: 4.91, 95% CI 2.95-8.17; p < 0.0001), WBV at 0.512 sec(-1) shear rate (OR: 2.31, 95% CI 1.42-3.77; p < 0.0001), and the lowest tertile of DI (OR: 0.18, 95% CI 0.10-0.32; p < 0.0001) and RVO was found. After adjustment for potential confounders, the highest tertiles of WBV at 0.512 sec(-1) shear rate (OR: 3.23, 95% CI 1.39-7.48; p = 0.006), WBV at 94.5 sec(-1) shear rate (OR: 6.74, 95% CI 3.06-14.86; p < 0.0001) and the lowest tertile of DI (OR: 0.20,95% CI 0.09-0.44, p < 0.0001) remained significantly associated with the disease. In conclusion, our data indicate that an alteration of haemorheological parameters may modulate the susceptibility to the RVO, by possibly helping to identify patients who may benefit from haemodilution.     

Thrombophilic risk factors in patients with central retinal vein occlusion

Few and contrasting data are available on the prevalence of hemostatic risk factors in patients with central retinal vein occlusion (CRVO). Aim of this study was to investigate the metabolic and inherited risk factors for venous thrombosis in 100 CRVO patients (age: 59 yrs; range 18-77) and in 100 controls (age: 56 yrs; range 18-84). In patients homocysteine (Hcy) levels were significantly higher than in controls and were affected by the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (p < 0.001). The prevalences of activated protein C resistance (APCR), factor V Leiden positivity, elevated PAI-1 and Lp(a) levels were significantly higher in patients with respect to controls. At multivariate analysis, only hyperhomocysteinemia (OR 11, 95% CI 3.6-36.2; p < 0.0001) and elevated PAI-1 levels (OR 8.9, 95% CI 3.5-41.3; p < 0.01), in addition to hypertension (OR 40.5, 95% CI 8.6-188.8; p < 0.00001) and hypercholesterolemia (OR 3.1, 95% CI 1.6-20.5; p < 0.05), were independent risk factors for CRVO. These data demonstrate a potential role of hemostatic risk factors in the pathophysiology of CRVO.     

Carotid artery disease in patients with retinal vein and artery occlusion]

To evaluate carotid artery disease in patients with retinal vein occlusion (RVO) and with retinal artery occlusion (RAO), 41 RVO patients (male 21, female 20, mean age 63 +/- 12 years) and 59 RAO patients (male 39, female 20, mean age 66 +/- 12 years) were investigated. All patients were examined neurologically and underwent carotid ultrasound examination. Using carotid ultrasound, carotid artery disease was evaluated in terms of presence of plaque, echogenicity of the plaque, degree of stenosis, or presence of ulceration. Carotid plaque or occlusion of the carotid artery was observed more frequently in RAO patients than in RVO patients (ipsilateral side: p < 0.01, contralateral side: p < 0.001; Fisher's exact test). Heterogeneous plaque was found more frequently in RAO patients compared to RVO patients (ipsilateral side: p < 0.01, contralateral side: p < 0.02; Fisher's exact test). Ulcerated plaque was found only in patients with RAO. In conclusion, carotid artery disease was more frequently found in patients with RAO than in patients with RVO.     

Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion

INTRODUCTION: Moderate hyperhomocysteinemia is considered a risk factor for both venous and arterial thrombosis. A prevalence of up to 30% of fasting hyperhomocysteinemia has been recently reported in patients with retinal vein occlusion (RVO) whereas conflicting data exist on the role of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as a risk factor for RVO. No report has been published on cystathionine beta-synthase (CBS) 844ins68 polymorphism (another genetic determinant of blood Hcy levels) in RVO patients. Moreover, scarce information is available on the usefulness of measuring homocysteine also after methionine loading to increase the diagnostic efficacy of hyperhomocysteinemia in RVO patients. MATERIALS AND METHODS: In 55 consecutive patients with diagnosis of RVO and 65 matched controls, plasma fasting total homocysteine (Hcy) levels and CBS and MTHFR polymorphisms were evaluated. In patients with normal fasting Hcy levels, post-methionine Hcy levels were determined. RESULTS: Moderate fasting hyperhomocysteinemia was detected in 18/55 patients (32.7%). In the remaining 37 patients, Hcy was measured again post-methionine loading (PML). Only 3/37 (8.1%) patients had PML hyperhomocysteinemia. Thus, the total prevalence of moderate hyperhomocysteinemia in this cohort of RVO patients was 21/55 (38.2%). The prevalence of homozygosity for C677T MTHFR genotype, but not that of heterozygosity for CBS844ins68, was significantly higher in RVO patients than in controls. CONCLUSIONS: Differently from what has been reported for arterial and/or venous thrombosis, a single fasting Hcy measurement is able to detect most of RVO patients (85.7%) with moderate hyperhomocysteinemia. C677T MTHFR, but not CBS 844ins68, genotype may play a role as risk factor for RVO.     

Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography

Factor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography. We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls. Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95: 1.18-7.31 ) and 2.63 (CI95: 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis. In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.     

Tardive dyskinesia in schizophrenics under 60 years of age

Ninety-one schizophrenics (mean age 34 years) were examined for tardive dyskinesia (TD) during chronic neuroleptic treatment. Dyskinesia was found in 23 (25.3%). The only variable that showed an association with TD was the current doses of neuroleptics: in none of the TD patients did the dose of fluphenazine decanoate (or equivalent) exceed 45 mg/week, whereas it was higher in 23 of the 68 without TD (p less than 0.01). When these 23 "high-dose" patients were disregarded, the TD group differed significantly from the 45 dose-matched non-TD subjects in that it had more common anticholinergic drugs, more common parkinsonian symptoms, and less instances of good remission (p less than 0.05 in each case). There was no association between TD and other considered variables (drug history, age, sex, clinical characteristics, size of the lateral brain ventricles, neurological "soft" signs, cognitive impairment). The results illustrate a relationship between TD prevalence and current doses of neuroleptics and indicate that differences in doses between the groups with and without TD may obscure associations between dyskinesia and other factors.     

Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis

BACKGROUND: Idiopathic cerebral vein thrombosis (iCVT) represents approximately 30% of the cases of cerebral vein thrombosis (CVT). New, inherited - factor V Leiden (FVL) and prothrombin gene mutation (PTHRA20210) - and inherited/acquired - hyperhomocysteinemia (HHcy) - prothrombotic conditions have been detected recently. METHODS: We assessed fasting plasma homocysteine (Hcy) levels and main Hcy determinants, FVL and PTHRA(20210) in 30 patients with documented iCVT and 40 age- and sex-matched healthy subjects. RESULTS: A strong and significant association of PTHRA(20210) [30% (9/30) vs. 2.5% (1/40) iCVT vs. controls, respectively, p = 0.001; OR = 16.174, p = 0.002] and HHcy [13/30 (43.3%) vs. 4/40 (10%) iCVT vs. controls, respectively; p = 0.002, OR = 6.88, p = 0.002] with iCVT was found. CONCLUSIONS: PTHRA(20210) and HHcy should be considered when screening for thrombophilia and should be assessed in patients with a family or personal history of CVT.     

High frequency of factor V Leiden in surgical patients with symptomatic venous thromboembolism despite prophylaxis

Among candidate risk factors associated with postoperative venous thromboembolism (VTE), the role of factorV Leiden (FVL) mutation remains unclear. We performed a case-control study to assess the potential significance of FVL mutation in postoperative VTE cases despite prophylaxis. We used data from the ongoing case-control "EDITH" study. We extracted 133VTE cases and 144 controls who had undergone either surgery or had plaster cast in the previous three months. Prophylaxis adequacy with regard to the recommendations published by the American College of Chest Physicians was retrospectively assessed. FVL mutation was present in 20VTE cases and four controls (OR 5.9, 95% CI 2-18). Prophylaxis was judged as adequate in 116 cases (88.5%) and in 129 controls (87.2%) (p=0.66). The frequency of FVL mutation was not different in VTE cases occurring while on adequate prophylaxis and in VTE cases occurring after the end of adequate prophylaxis (p=0.27). FVL mutation was closely associated with postoperative VTE in patients classified as having received an adequate prophylaxis (8.4; 95% CI, 2.4 to 29). This study shows a close association between the presence of factorV Leiden mutation in symptomatic VTE occurring after surgery despite prophylaxis.