Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease.

Venous disease is a term that broadly covers both venous thromboembolic disease and chronic venous disease. The basic pathophysiology of venous thromboembolism and chronic venous disease differ as venous thromboembolism results from an imbalance of hemostasis and thrombosis while chronic venous disease occurs in the setting of tissue damage because of prolonged venous hypertension. Both diseases are common and account for significant mortality and morbidity, respectively, and collectively make up a large health care burden. Despite both diseases having well-characterized environmental components, it has been known for decades that family history is an important risk factor, implicating a genetic element to a patient's risk. Our understanding of the pathogenesis of these diseases has greatly benefited from an expansion of population genetic studies from pioneering familial studies to large genome-wide association studies; we now have multiple risk loci for each venous disease. In this review, we will highlight the current state of knowledge on the epidemiology and genetics of venous thromboembolism and chronic venous disease and directions for future research.

Pregnancy-associated venous insufficiency course with placental and systemic oxidative stress.

The development of lower extremity venous insufficiency (VI) during pregnancy has been associated with placental damage. VI is associated with increased oxidative stress in venous wall. We have investigated potential disturbance/dysregulation of the production of reactive oxygen species (ROS) in placenta and its eventual systemic effects through the measurement of malondialdehyde (MDA) plasma levels in women with VI. A total of 62 women with VI and 52 healthy controls (HCs) were studied. Levels of nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), 2 (NOX2), inducible nitric oxide synthase (iNOS), endothelial (eNOS), poly(ADP-ribose) polymerase PARP (PARP) and ERK were measured in placental tissue with immunohistochemistry and RT-qPCR. Plasma and placental levels of MDA were determined by colorimetry at the two study times of 32 weeks of gestation and post-partum. Protein and gene expression levels of NOX1, NOX2, iNOS, PARP and ERK were significantly increased in placentas of VI. eNOS activity was low in both study groups, and there were no significant differences in gene or protein expression levels. Women with VI showed a significant elevation of plasma MDA levels at 32 weeks of gestation, and these levels remained elevated at 32 weeks post-partum. The MDA levels were significantly higher in placentas of women with VI. Placental damage that was found in the women with VI was characterized by overexpression of oxidative stress markers NOX1, NOX2, and iNOS, as well as PARP and ERK. Pregnant women with VI showed systemic increases in oxidative stress markers such as plasma MDA levels. The foetuses of women with VI had a significant decrease in their venous pH as compared to those from HC women. The situation of oxidative stress and cellular damage created in the placenta is in coexpression with the production of a pH acidification.

Genetic biases related to chronic venous ulceration.

Chronic wounds represent a major socioeconomic problem. Chronic venous ulceration is one of the least well-understood types of chronic wounds. A chronic venous ulcer arises as a result of chronic venous insufficiency (CVI), which affects approximately 10-35% of people in the developed world, yet not all people with CVI develop ulceration. The question of why some patients with CVI develop chronic ulceration and others do not, still remains unanswered. Risk factors for the development of chronic ulceration are poorly understood and include age, residual iliofemoral vein obstruction, residual deep incompetence, persistent venous hypertension, obesity and genetics. The genetic aspects of CVI have only been vaguely evaluated. This paper reports on a literature review of the variation in genetic polymorphisms and gene expression associated with the development of a chronic venous ulceration.

Genetic predisposition for chronic venous insufficiency in several genes for matrix metalloproteinases (MMP-2, MMP-9, MMP-12) and their inhibitor TIMP-2.

OBJECTIVE: The project was scheduled as a case-control study to investigate the correlation between MMP-2 (rs243864), MMP-9 (3918242), MMP-12 (rs7123600) and TIMP-2 (rs8176329) polymorphisms and chronic venous disease (CVD) risk. The genotype and phenotype research envisages the testing of possible associations between MMP and TIMP-2 genotypes and phenotypes of CVD. MATERIAL AND METHODS: 150 patients with CVD and 227 controls were enrolled into the study. The MMPs and TIMP-2 genotypes were identified by the PCR method and restriction analysis according to standard protocols. RESULTS: The G allele of MMP-2 -790 T/G was 1.85 times more frequent in men with CVD than in the control group (P = 0.008). The T allele of MMP-9 -1562 C/T was observed 2.571 times more frequently in patients with CVD than in the control individuals (both in men and women) with clinically significant specificity (P = 0.0000009). The G allele of MMP-12 rs7123600 was determined 2.082 times more frequently in female patients with CVD than in the control group with clinically significant specificity (P = 0.02). No significant result in TIMP-2 rs8176329 polymorphism in the case-control study was observed. CVD women with G allele in MMP-2 -790 T/G in the genotype-phenotype study are seen to develop ulceration 2.539 times more frequently (P = 0.003). The G allele of MMP-12 rs7123600 was detected 3.167 times more frequently in CVD women with ulceration compared with CVD women without ulceration (P = 0.007). In CVD men in C6 stage, the incidence of AG genotype in rs7123600 MMP-12 polymorphism was found to be 4.675 times higher compared to CVD women with C6 staging (P = 0.005). The AG genotype in TIMP 2 rs8176329 polymorphism was found to be associated with higher risk of tumour (P = 0.01). CONCLUSION: Studying these polymorphisms can contribute to better identification of patients at higher risk of developing CVD, while providing the most appropriate prevention and treatment strategies for limiting the progression and complications of CVD.

Mycology - an update. Part 1: Dermatomycoses: causative agents, epidemiology and pathogenesis.

Dermatomycoses are caused most commonly by dermatophytes. The anthropophilic dermatophyte Trichophyton rubrum is still the most frequent causative agent worldwide. Keratinolytic enzymes, e.g. hydrolases and keratinases, are important virulence factors of T. rubrum. Recently, the cysteine dioxygenase was found as new virulence factor. Predisposing host factors play a similarly important role for the development of dermatophytosis of the skin and nails. Chronic venous insufficiency, diabetes mellitus, disorders of cellular immunity, and genetic predisposition should be considered as risk factors for onychomycosis. A new alarming trend is the increasing number of cases of onychomycosis - mostly due to T. rubrum - in infancy. In Germany, tinea capitis is mostly caused by zoophilic dermatophytes, in particular Microsporum canis. New zoophilic fungi, primarily Trichophyton species of Arthroderma benhamiae, should be taken into differential diagnostic considerations of tinea capitis, tinea faciei, and tinea corporis. Source of infection are small household pets, particularly rodents, like guinea pigs. Anthropophilic dermatophytes may be introduced by families which immigrate from Africa or Asia to Europe. The anthropophilic dermatophytes T. violaceum, T. tonsurans (infections occurring in fighting sports clubs as "tinea gladiatorum capitis et corporis") and M. audouinii are causing outbreaks of small epidemics of tinea corporis and tinea capitis in kindergartens and schools. Superficial infections of the skin and mucous membranes due to yeasts are caused by Candida species. Also common are infections due to the lipophilic yeast fungus Malassezia. Today, within the genus Malassezia more than 10 different species are known. Malassezia globosa seems to play the crucial role in pityriasis versicolor. Molds (also designated non-dermatophyte molds, NDM) are increasingly found as causative agents in onychomycosis. Besides Scopulariopsis brevicaulis, several species of Fusarium and Aspergillus are found.

The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants.

The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

Analysis of the association between an insertion/deletion polymorphism within the 3' untranslated region of COL1A2 and chronic venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common cause of leg pain and swelling and is commonly associated with varicose veins. It has significant socioeconomic consequences and is among the most common problems encountered in surgical practice. Although our current understanding of the pathogenesis of CVI is far from clear, there is a growing body of evidence suggesting a genetic contribution to the etiology of CVI. METHODS: By analyzing 254 CVI cases and 508 healthy controls in a Chinese population, we used a candidate gene approach to evaluate the association between a 7-base pair insertion/deletion (indel) polymorphism (rs3917) in the 3' untranslated region (3'UTR) of the alpha-2 type I collagen gene (COL1A2) and CVI susceptibility. Logistic regression was used to analyze the association between rs3917 and CVI risk, adjusted for sex and age. Computational modeling was used to predict potential molecular mechanisms underlying the association. RESULTS: Logistic regression analysis revealed that subjects carrying indel or deletion/deletion genotypes had a significantly increased risk for CVI than individuals carrying insertion/insertion genotypes (adjusted odds ratio, 1.64; 95% confidence interval [CI], 1.10-2.45; P = 0.010). Carrying the 7-base pair deletion allele was associated with a 1.60-fold risk for CVI (95% CI, 1.11-2.31; P = 0.008). Computational modeling suggests that the rs3917 insertion allele lies within a predicted binding site (seed region) for microRNA-382 and that the deletion allele alters the affinity of microRNA-mRNA binding by disrupting the local structure of COL1A2 mRNA, presumably allowing for upregulated COL1A2 expression. CONCLUSIONS: Taken together, our data suggest that common genetic variations in COL1A2 may influence CVI risk, possibly through microRNA-382-mediated regulation. Replication of our studies in other populations will strengthen our understanding of this association.

The role of alpha-1-antitrypsin in the etiopathogenesis of chronic venous disease: A prospective clinical trial.

OBJECTIVE: The study aimed to examine whether alpha-1-antitrypsin (AAT), an inhibitor of leukocyte esterase(LE), which damages the venous vessel wall, has a protective effect against chronic venous disease(CVD), and to examine the relationship between AAT levels and disease severity. METHODS: Patients admitted with varicose vein disease and having reflux flow lasting longer than 0.5 s as determined by Doppler ultrasound were included. The informed consents were taken, and blood samples were obtained for complete blood count, C-reactive protein (CRP) level, and AAT level following anamnesis and physical examination. Clinical Etiologic Anatomic Pathologic (CEAP) classification was used to assess disease severity, and patients were divided into CEAP 1-5 groups accordingly. RESULTS: A total of 87 patients were included in the study. There was no statistically significant difference between the groups in body weight, red blood cell counts, platelet counts, or neutrophil counts (p = 0.117, p = 0.932, p = 0.177, and p = 0.177, respectively).CRP and AAT levels were higher in patients with a CEAP clinical score of 5 compared to the other groups (p = 0.018, and p = 0.020, respectively). AAT levels were similar in the CEAP 1-3 group and decreased in the CEAP-4 group but increased again in the CEAP-5 group. The AAT level was 1.62 ± 0.3 g/L in the CEAP-1 group, 1.61 ± 0.21 g/L in the CEAP-2 group, 1.61 ± 0.27 g/L in the CEAP-3 group, 1.48 ± 0.28 g/L in the CEAP-4 group, and 1.94 ± 0.39 g/L in the CEAP-5 group. CRP levels and platelet counts were observed to affect AAT levels (p = 0.10, p = 0.017, respectively). CONCLUSION: We believe that our hypothesis that low AAT levels play a role in the etiopathogenesis of CVD has been partially validated, at least in the CEAP-4 group. However, we believe that increased AAT levels in the CEAP-5 group may be a reactive increase in increased LE levels due to higher CRP levels of this group.

A genetic study of chronic venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is an important cause of morbidity in Western countries. The aim of this study is to demonstrate the heredity of CVI, focusing on molecular and genetic aspects of the disease. METHODS: The study depended on the recruitment of informative families, accurate determination of the phenotype of each family member, and blood sample for DNA extraction for genetic analysis. Each family member was invited to attend a vascular consultation. A genealogical tree for each recruited family was composed. Then, a peripheral blood sample for DNA extraction from each member of the recruited families was obtained for genetic evaluation. RESULTS: By the evaluation of genealogical trees, it was evident that CVI segregates, in all families studied, in an autosomal dominant mode with incomplete penetrance. In nine families studied, varicose veins were linked to the candidate marker D16S520 on chromosome 16q24, which may account for the linkage to FOXC2. CONCLUSION: In our study, in families with affected patients with the D16S520 marker, there was evidence of saphenofemoral junction reflux. The fact that there is linkage to a candidate marker for the FOXC2 gene suggests there is a functional variant within, or in the vicinity of, which predisposes to varicose veins. Further studies are necessary to identify genes and mechanism so as to achieve better understanding of the genetic basis of CVI.

Acroangiodermatitis of Mali in protein C deficiency due to a novel PROC gene mutation.

Acroangiodermatitis of Mali is a dermatologic condition of kaposiform skin lesions that has been associated with chronic venous insufficiency. Here we report a case of a 28-year-old Chinese man with acroangiodermatitis which co-existed with chronic lower limb deep vein thrombosis. Investigations revealed protein C deficiency and a frame shift mutation, c246_247dupCT, of the PROC gene. Our report lengthens the list of male acroangiodermatitis of Mali cases with a Chinese patient harboring a novel PROC mutation with manifest protein C deficiency.

Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence.

Chronic venous disease is a condition globally widespread, resulting in a disabling pathological disorder. The CD4 + Th17+ (Cluster Differentiation 4) lymphocytes represent a regulative factor for innate immunity related to the development of complex diseases. Recently, these mechanisms have been associated with vascular disease. The aim of this work is to validate whether the Th17 response correlates with the development of CVI (Chronic venous insufficiency)and CVLUs (chronic venous limbs ulcers) and whether Th17 markers can be used, both as intrinsic risk factors and diagnostic markers, for disease development. PBL derived from peripheral blood samples of patients and controls were subjected to gene expression analysis for IL23R, IL17, SGK1, TGFß, RORγ, FOXO1, and RANBP1 by qRT-PCR and immunoblot. A post hoc correlation, the diagnostic performance of the target genes, and multivariable analyses were properly conducted. The main expression markers of the CD4 + Th17+ switch were strongly activated in chronic venous insufficiency and in advanced ulceration. The correlation analysis demonstrated the inter-dependence on Th17's signature modulation. ROC (Receiver Operating Characteristic) analysis defined, for the examined genes, a clinical value as the potential diagnostic markers. Multi-logistic regression studies showed that Th17 markers behave as empirical risk factors for CVD (chronic venous disease) development. Taken together, the present data provide a new hypothesis for the TH17-dependent pathogenesis of CVD, favoring the possibility for the development of new diagnostic, preventive, and therapeutic approaches.

Type I plasminogen activator inhibitor 4G allele frequency is associated with chronic venous insufficiency.

Chronic venous insufficiency (CVI) is a common disease associated with poor quality of life. Genetic polymorphisms causing coagulation abnormalities may account for some of the CVI pathogenesis. Type I plasminogen activator inhibitor (PAI-1) is responsible for fibrinolytic system regulation, and plasma levels of PAI-1 are strongly correlated with PAI-1 4G/5G gene polymorphism. The association between PAI-1 4G/5G gene polymorphism and CVI was investigated. In 34 consecutive patients with clinically overt CVI, the PAI-1 4G/4G polymorphism was detected in three cases (8.8%); the 4G/5G polymorphism was detected in 28 (82.4%). In 34 age- and sex-matched controls, the PAI-1 4G/4G polymorphism was detected in one case (2.9%) and the 4G/5G polymorphism was detected in 14 cases (41.2%). The PAI-1 4G allele was found significantly more frequently in CVI patients than in controls. The 4G allele was associated with a 3.25-fold increase in CVI risk. Thus, a relationship between CVI and the PAI-1 4G allele is apparent.

Evaluation and management of the lateral marginal vein in Klippel-Trénaunay and other PIK3CA-related overgrowth syndromes.

The lateral marginal vein is an anomalous clinical entity found in association with Klippel-Trénaunay and other PIK3CA-related overgrowth syndromes. Although it is reported to affect <20% of patients with Klippel-Trénaunay syndrome, this venous anomaly has been associated with significant morbidity and mortality attributable to venous hypertension and potentially lethal thromboembolic events. Limited literature exists on the diagnosis and management of this rare anomaly, with most of the reports focusing on retrospective clinical experience at a few centers of excellence. Despite these limitations, a systematic approach to diagnosis and treatment of this anomaly is warranted and expounded on herein. When plausible, clinical recommendations based on best available literature are made.

Tight junctions and compression therapy in chronic venous insufficiency.

Tight junctions (TJs) provide a barrier function, inhibiting solute and water flow through the paracellular space. There had been no analysis until now as to how tight junction molecules could be involved in the pathology of patients with chronic venous insufficiency. The aim of the study was to analyse the expression pattern of TJ-molecules occludin (OCLN), claudin-1 (CLDN-1), claudin-3 (CLDN-3) and claudin-5 (CLDN-5) on mRNA and protein level in patients with edema, venous leg ulcers and healthy controls. Biopsy specimens were taken in healthy individuals and in patients before, and four weeks after compression therapy. mRNA-expression was determined by using reverse-transcriptase and polymerase chain reaction (RT-PCR) and the protein-expression was determined by Western blotting from tissue specimens. Quantification performed determining the expression for TJ-molecules displayed diminished expression for CLDN-1 (p<0.01) and CLDN-5 (p<0.01) in patients with chronic venous insufficiency in comparison with healthy controls on mRNA as well as protein level. No statistical differences were detected for OCLN and CLDN-3 between the edema group and healthy controls. There was a significantly elevated expression (p<0.01) on mRNA and protein level between the leg ulcer group and healthy controls for OCLN and CLDN-3. Densitometric evaluation revealed a more significantly elevated expression (p<0.01) for CLDN-1 and CLDN-5 on mRNA and protein level after four weeks of compression therapy in comparison with prior to treatment for the edema as well as the leg ulcer group. Compression therapy tightens the paracellular barrier via elevated expression of specific TJs and prevents thereby the progression of chronic venous insufficiency due to inhibited permeability of fluid into the perivascular tissue.

Cross-sectional study on heredity and venous disorders: the end of the dominant maternal heredity dogma?

OBJECTIVE: To evaluate the heredity factor of the chronic venous disorders and odds ratio linked to maternal or paternal heredity. METHODS: Cross-sectional epidemiological study conducted in daily practice of medical practitioners on all patients consulting them. The practitioners described the venous status of all patients consulting them and recorded the familial past history of venous disease. RESULTS: Among 21319 patients, 60.4% have a familial history of chronic venous disorder: unilateral paternal 7.5%, unilateral maternal 40.9% and bilateral: 12.0%. Chronic venous disorder prevalence is 58.8% in the global population, 38.2% in the absence of parental history, 67.0% for unilateral paternal, 71.3% for unilateral maternal and 79.2% for bilateral (p < 0.0001). After adjustment on age and sex, results show significant (p < 0.0001) odds ratio of 3.2 for unilateral paternal, of 3.4 for unilateral maternal and of 5.6 for a history in both parents. In the context of a history in both parents, the odds ratio increased to 5.6 for women and 8.4 for men. CONCLUSION: This large cross-sectional study confirms the association between heredity and venous disease, but its results could call into question the maternal predominant character of the chronic venous disorder heredity.

Distichiasis, congenital heart defects and mixed peripheral vascular anomalies.

We report on a previously apparently unreported syndrome of distichiasis with congenital heart defects and with mixed peripheral vascular anomalies in a mother and her four children. The mother had a ventricular septal defect; both daughters had surgery for patent ductus arteriosus. Sinus bradycardia alone (elder son), with stress induced asystole (younger son), and with wandering atrial pacemaker (both daughters) are documented electrocardiographically. Three of the five have edema, two have visible varicosities, three have symptoms consistent with chronic venous disease of the legs, and the older daughter has complaints consistent with arterial disease in the legs. Doppler flow studies demonstrated post-phlebitic syndrome in all but the younger daughter, and vasospastic disease in the mother, older daughter, and second son.

Inflammation in stasis dermatitis upregulates MMP-1, MMP-2 and MMP-13 expression.

Stasis dermatitis is a common disorder, which is a consequence of impaired venous drainage of the legs. It is characterized histologically by proliferation of small blood vessels in the papillary dermis. This neovascularization may lead occasionally to the formation of discrete papules due to inflammatory processes. In order to evaluate the role of matrix metalloproteinases (MMPs) in the acute phase of chronic venous insufficiency, we examined the production of MMP-1, -2, -13 and tissue inhibitors of metalloproteinase (TIMP)-1 and -2 in lesional skin of stasis dermatitis. A total of 19 patients affected by stasis dermatitis were included in this experimental study. Polymerase chain reaction, western blot and immunohistochemical studies on tissue specimen were performed. In lesional skin of stasis dermatitis, there was elevated gene expression and immunoreactivity for MMP-1, -2 and -13 in comparison to healthy controls. In contrast, genexpression and immunoreactivity for TIMP-1 and -2 were diminished in stasis dermatitis in comparison with healthy controls. Overexpression and production of MMP-1, -2 and -13 without inhibitory effects could be the result of cytokine mediated induction. Matrix metalloproteinases (MMPs) may play an important role in the remodeling of lesional skin in stasis dermatitis.

The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency.

OBJECTIVES: To study the prevalence of factor V Leiden mutation in patients with chronic venous insufficiency and venous leg ulcers, compared with a control group, and to find out whether factor V Leiden mutation is more frequent in patients with chronic venous insufficiency and a history of deep venous thrombosis. DESIGN: A case control study. SETTING: Three outpatient dermatological clinics. PATIENTS: Ninety-two patients (37 men, 55 women) with venous leg ulcers and 53 control patients (23 men, 30 women). MAIN OUTCOME MEASURE: Factor V Leiden mutation. RESULTS: Factor V Leiden mutation was significantly more frequent in patients with chronic venous insufficiency and venous leg ulcers than in the control group (23% vs 7.5%; P=.03), and the patients with factor V Leiden mutation were more likely to have a history of venous thromboembolism (91% vs 48%, P=.002). Also, recurrent deep venous thrombosis (38% vs 14%) and recurrent leg ulcerations (9 episodes or more) occurred more frequently in the patients with factor V Leiden mutation (43% vs 19%, P=.01). No difference was observed in venous refill time or in the presence of dermatoliposclerosis and atrophie blanche. CONCLUSIONS: Factor V Leiden mutation is more frequent in patients with venous leg ulceration than in the control group and the general population. Patients with factor V Leiden mutation have an increased risk of developing deep venous thrombosis and recurrent leg ulceration.