Papillophlebitis versus paediatric venous thrombosis. A case with 46C/T polymorphism in the F12 coagulation gene. / Papiloflebitis versus trombosis venosa pediátrica. Un caso con polimorfismo C46T del gen F12 de la coagulación.

CLINICAL CASE: An 8 year-old boy with no known diseases, with sudden loss of visual acuity (VA) in the left eye (LE). EXAMINATION: VA 1 in right eye, and 0.1 in LE, discrete left relative afferent pupil defect (RAPD). Normal biomicroscopy. Funduscopy: congestive papilla, venous tortuosity, peripapillary haemorrhages with macular oedema in LE. The systemic study only revealed A C46Tpolymorphism in the F12 coagulation gene. He had a VA of 1 and normal funduscopy 8 months later. DISCUSSION: Papillophlebitis is an inflammatory and non-ischaemic central retinal vein occlusion, ophthalmoscopically similar to central retinal vein thrombosis. The systemic study is essential to rule out underlying diseases.

Pathogenic mechanisms in varicose vein disease: the role of hypoxia and inflammation.

AIMS: Although the aetiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function. Among the regulatory factors of vessel tone, synthesises, pro- and anti-inflammatory, adhesion molecules and the transcription factor hypoxia inducible factor-1 alpha (HIF-1alpha), which are responsible for recruiting leukocytes, are very important. METHODS: Investigation in this study focused on the expression of ICAM-1, E-selectin and HIF-1alpha on endothelial cells using immunostaining and RT-PCR in varicose vein specimens compared with controls. RESULTS: Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium in varicose veins. Based on data derived from immunostaining and RT-PCR, no major differences were identified between ICAM-1 and E-selectin expression in varicose vein specimens compared with controls. In contrast, immunostaining results identified HIF-1alpha expression in five (5/20) varicose vein specimens, whereas no control saphenous vein specimens expressed HIF-1alpha. CONCLUSIONS: These findings could explain other evidence of hypoxia in varicose veins. Finally, results already obtained in this investigation suggest that the process of pathogenesis of varicose veins is not restricted to the role of adhesion molecules.

Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1.

Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPARalpha) ligands (fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARalpha-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARalpha wild-type, but not of PPARalpha-null mice, demonstrating a role for PPARalpha in this fibrate action. In human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARalpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARalpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARalpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARalpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARalpha-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARalpha physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPARalpha by interfering with the NF-kappaB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.

[Prevalence of Factor V Leiden and the G20210A mutation of the prothrombin gene in a random group of patients with thrombotic episodes]. / Prevalencia del factor V Leiden y de la mutación G20210A del gen de la protrombina en un grupo no seleccionado de pacientes con episodios trombóticos.

UNLABELLED: Factor V Leiden and G20210A mutation of the prothrombin gene have been described as risk factors in thrombophilic pathologies. Our objective has been to know the prevalence of these two mutations in a group of patients with thrombophilic pathology and to compare it with its prevalence in a control group of Spanish population. PATIENTS AND METHODS: 64 patients were divided in two groups. First, 39 patients with deep venous thrombosis (DVT): 24 with an unique episode of DVT; 11 with more than one episode; 3 with DVT and pulmonary thromboembolism, and one with DVT and more than one episode of cerebral thrombosis. Second, 25 patients with other pathologies, such as pulmonary thromboembolism (9 patients), acute cerebrovascular accident (10 patients) and 6 who came to our Department because there were some carrier in their families. The 20210A allele was analyzed in 37 of the 64 patients. Some of the 64 patients had haematological determinations of the activated protein C resistance (APC resistance). As well, 103 unrelated subjects with unknown thrombotic pathologies were analyzed. RESULTS: We have found a prevalence of factor V Leiden in the group of patients of 14.1% (9 carriers in 64 patients, all of them in the first group of 39 patients with DVT) versus 1% in the control group (1 carrier in 103 controls). On the other hand, the difference between the prevalence of the 20210A allele was not statistically significant between the group of patients and the control group (2.7% vs 2.9%). In 75% of the patients no haematological results of APC resistance were obtained, generally because they were with anticoagulant treatment, and in 11.1% of the carriers the result of the determination was considered as ambiguous or false negative. CONCLUSION: Factor V Leiden is well established as risk factor in the thrombophilic pathology, but more studies are needed to know the meaning of the G20210A mutation of the prothrombin gene.

[20210A mutation of the prothrombin and venous thromboembolism gene]. / Mutacion 20210A del gen de la protrombina y tromboembolismo venoso.

PURPOSE: Various genetic disorders interact with environmental factors to cause thrombotic diseases. Recently, a G to A transition at nucleotide 20210 in the prothrombin gene, has been described in association with venous thromboembolism, in Dutch population. Currently, several reports want to know the frequence of this mutation in other ethnic groups and populations. The aim of this work was to assess the prevalence rates of prothrombin mutation in both, thrombotic and healthy Spanish populations, and to estimate the associated relative risks. We described the clinical features in our series of thrombotic carriers and moreover, we compared a routine clotting test versus DNA analysis in the diagnosis of this anomaly. POPULATION, MATERIAL AND METHODS: The design was a non-matched case-control study. The involved populations were: 187 patients of venous thromboembolic diseases and 200 healthy controls. Patients and controls were genotyped and both, carriers and non-carrier patients, were analyzed by a routine prothrombin clotting assay, to determine the sensibility and specificity and optimal cut off level of the test. RESULTS: The 20210 A allele was identified in 17 patients (9.1%) and in 7 controls (3.5%), with a 2.76-fold increased risk (OR 2.76, 95% CI = 1.12-6.81), in carriers. One patient and none of the controls were homozygous. The clinical characteristics (first manifestation age or thrombotic recurrence) are similar in both, carriers and non-carriers, patient groups. The prothrombin level by a routine coagulometric method was 1.31 +/- 0.14 U/ml (95% CI = 1.24-1.38) for the 20210 A carriers, whereas for the non carrier-patients was significantly lower, 1.06 (95% CI = 1.03-1.08) (p < 0.00001). With a cut off level of 1.25 U/ml, 12/16 (75%) carriers and 14/132 (10.6%) non-carriers were positive. Therefore, the sensibility was 75% and the specificity 89.4%. With a cut off level of 1.40 U/ml the diagnostic efficiency was even worse. CONCLUSIONS: 3.5% of healthy subjects and 9.1% of thromboembolic patients carried this prothrombin mutation with a relative risk of 2.76 (95% CI = 1.12-6.81). The relevant clinical features are similar to the rest of the series. The mean prothrombin level was higher (1.31 U/ml) than in the normal patients (1.06 U/ml), but the clotting test seems inappropriate for a diagnostic purpose.

Different forms of AT-III congenital defect: a study by crossed immunoelectrofocusing.

Antithrombin III (AT-III) deficiency may be due to quantitative or qualitative AT-III reduction. The diagnosis of qualitative disorder is suspected when a discrepancy is found between immunological and functional levels of AT-III. Heterogeneity has been hypothesized in both quantitative and qualitative deficiency of AT-III. A technique based on crossed immunoelectrofocusing (CIEF) was applied to investigate molecular variants of AT-III. 3 families with low functional and immunological levels of AT-III and 1 family with only a low functional AT-III level were investigated. An abnormal AT-III pattern was found with CIEF in the family with suspected qualitative disorder and in 1 of the families with quantitative disorder. The 2 abnormal patterns were different. Thus the use of CIEF AT-III patterns could help to define congenital AT-III deficiencies and could serve as a basis for classification of different forms of AT-III deficiency.

[Familial recurrent phlebitis due to deficiency of antithrombin III. Apropos of a case]. / Phlébites récidivantes familiales par déficit en antithrombine III. A propos d'un cas.

The authors report the case of a young woman aged 29, mother of 2 children, presenting a post-phlebitic syndrome with hyperalgic capillaritic ulcer, a 10 year history of serious thrombophlebitic episodes with repeated pulmonary embolism despite heparin therapy, and reports of similar episodes in the family, some of which proved fatal. Haematological study showed a clear diminution in progressive antithrombin activity. A discussion follows on the clinical and haematological aspects of this constitutional and familial deficiency, which has been known since 1965 (Egelberg). The relative rarity of this condition should not prevent the routine search (by combined functional, immunological and chromogenic estimation) in the presence of repeated thrombosis, and when the thrombosis is biologically resistant to heparin : in such cases, the indication for long term treatment with vitamin K antagonists is undeniable.