Phenotypic and Functional Transformation in Smooth Muscle Cells Derived from a Superficial Thrombophlebitis-affected Vein Wall.

BACKGROUND: Superficial thrombophlebitis (ST) is a frequent pathology, but its exact incidence remains to be determined. This study tested the hypothesis whether relationships exist among smooth muscle cells (SMCs) derived from ST, varicose great saphenous veins (VGSVs), and normal great saphenous veins (GSVs). METHODS: Forty-one samples of ST, VGSVs, and GSVs were collected. SMCs were isolated and cultured. Proliferation, migration, adhesion, and senescence in SMCs from the three vein walls were compared by various methods. Bax, Bcl-2, caspase-3, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 messenger RNA (mRNA) and protein expressions were detected by fluorescence quantitative PCR and Western blot. RESULTS: An obvious decrease in cytoskeletal filaments was observed in thrombophlebitic vascular smooth muscle cells (TVSMCs). The quantity of proliferation, migration, adhesion, and senescence in TVSMCs was significantly higher than in varicose vascular smooth muscle cells and normal vascular smooth muscle cells (NVSMCs) (all P < 0.05). Bax and caspase-3 mRNA and protein expression were decreased, while Bcl-2 mRNA and protein expression were increased in the TVSMCs compared with the varicose vascular smooth muscle cells and the NVSMCs (all P < 0.05). MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA and protein expression were significantly increased in the TVSMCs compared with the VVGSVs and the NVSMCs (all P < 0.05). CONCLUSION: SMCs derived from ST are more dedifferentiated and demonstrate increased cell proliferation, migration, adhesion, and senescence, as well as obviously decreased cytoskeletal filaments. These results suggest that the phenotypic and functional differences could be related to the presence of atrophic and hypertrophic vein segments during the disease course among SMCs derived from ST, VGSVs, and GSVs.

COVID-19 susceptibility variants associate with blood clots, thrombophlebitis and circulatory diseases.

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung, inflammatory and vascular disease, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes. PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR = 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10). Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.

Recurrent superficial venous thrombophlebitis because of mutations in the protein C and fibrinogen genes in a young Argentinian female.

: Hypodysfibrinogenemia and protein C deficiency are coagulopathies and in this report, we describe a young patient with both defects confirmed by molecular genetic tests. The patient was a 24-year-old woman referred for recurrent thrombophlebitis and finally deep venous thrombosis. Routine coagulation studies revealed mild decrease of protein C (0.49 IU, reference values 0.7-1.40 IU) and hypodysfibrinogenemia (0.88 g/l and 1.83 g/l for activity and antigen, respectively, reference values 2.0-4.0 g/l). Direct sequencing analyses were performed on FGA, FGB, and FGG genes to confirm hypodysfibrinogenemia and on the protein C gene to confirm protein C deficiency. As a result, the patient was shown to be heterozygous p.Ala82Gly in the FGG gene (Fibrinogen Dunedin) and for compound heterozygous missense mutation in protein C gene. To our knowledge, this is the first report on a case of combined dysfibrinogenemia and protein C deficiency confirmed by molecular genetic tests.

Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden.

OBJECTIVE: This is the first nationwide study to determine familial risks of unusual forms of venous thrombosis amongst offspring of affected parents and amongst siblings. DESIGN AND SETTINGS: The Swedish Multigeneration Register of 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the period 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for venous thromboembolism (VTE), as determined by the International Classification of Diseases, compared to those whose relatives were not affected by VTE. RESULTS: The total number of hospitalized patients with VTE was 45 362, of which 1824 (4.0%) were affected by a rare thrombotic condition. The familial SIRs in cases with a history of VTE in parents or siblings were significantly increased for migrating thrombophlebitis (1.81; 95% confidence interval (CI) 1.40-2.31), portal vein thrombosis (2.35; 95% CI 1.77-3.06), vena cava thrombosis (1.96; 95% CI 1.42-2.64) and cerebral venous thrombosis (1.74; 95% CI 1.30-2.28). Budd-Chiari syndrome (SIR, 0.92; 95% CI 0.24-2.38) and renal vein thrombosis (SIR, 1.72; 95% CI 0.62-3.77) were not significantly associated with parental or sibling history of VTE; however, these two conditions were very rare, and therefore, we cannot draw any definite conclusions from this finding. CONCLUSIONS: Family history is an important risk factor for most unusual forms of VTE. Moreover, even the paraneoplastic phenomenon, migrating thrombophlebitis (Trousseau's syndrome), is associated with a family history of VTE. Thus, our data suggest that most rare forms of VTE have a familial background.

Superficial thrombophlebitis in varicose vein disease: the particular role of methylenetetrahydrofolate reductase.

BACKGROUND: The purpose of this study was to compare the genetic background of superficial (SVT) and deep vein thrombosis (DVT). METHODS: Factor V (FV)-Leiden (G16891A)-, factor II(G20210A)-mutations, protein C- and S, as well as methylenetetrahydrofolate reductase (MTHFR) polymorphisms at C677T and A1298C, and serum homocysteine levels (hcy) were determined in 29 patients with SVT and 26 with DVT. Findings FV- and -II-mutations were less frequent in patients with SVT (2/3) compared with DVT (9/5), respectively (P < 0.002 in case of FV). However, the frequency of the MTHFR C677T polymorphism was significantly higher in patients with SVT compared with DVT (CT 12 versus 10, and TT 7 versus 1, respectively, P << 0.001). The distribution of the MTHFR A1298C genotype and serum hcy levels was similar in both patient groups. Protein S-deficiency was recorded once (SVT). Interpretation These results suggest that the MTHFR C677T-mutant genetically predisposes its carriers to SVT which may contribute to hypercoagulation in pre-existing varicose vein disease.

Hereditary coagulopathies: practical diagnosis and management for the plastic surgeon.

BACKGROUND: Venous thromboembolism is a devastating complication representing one of the major causes of postoperative death in plastic surgery. Within the scope of plastic surgery, body-contouring procedures are often considered to carry a higher risk of venous thromboembolism. Hereditary thrombophilias comprise a group of conditions defined by a genetic predisposition to thrombosis development. Collectively, hereditary thrombophilias are present in at least 15 percent of Western populations and underlie approximately half of thromboembolic events. Although the topic of venous thromboembolism is discussed widely throughout the literature, there is little published on the diagnosis and management of hereditary thrombophilias in the plastic surgery literature. The goals of this study were to present a review of the major inherited thrombophilias, to delineate the risk of these disorders, and to recommend a practical algorithm for patient screening and management before major plastic surgery. METHODS: A MEDLINE search was performed from 1965 to the present to review the literature on inherited thrombophilia disorders. RESULTS: Based on the English language literature and clinical experience, the authors suggest practical guidelines for screening and management of hereditary thrombophilias. A thorough medical history and preoperative evaluation are key to reducing venous thromboembolism complications. CONCLUSIONS: Hereditary thrombophilias are present in a significant number of thromboembolic events. Preoperative vigilance on the part of the plastic surgeon may help to identify patients with undiagnosed hereditary thrombophilias and thereby decrease the incidence of venous thromboembolism.

A male adolescent with left iliac thrombophlebitis and heterozygosity for factor V Leiden mutation.

The epidemiology of deep vein thrombosis in adolescents has 2 potential associations. First, there is a demonstrated association with a congenital anomaly of the inferior vena cava (Dean SM, Tytle TL. Vas Med. 2006;11:165-169; Schnieider JG, Eynatten MV, Dugi KA, et al. J Intern Med. 2002;252:276-280). Secondly, resistance to activated protein C as a result of factor V Leiden is associated with thromboembolic disease at an early age (Price DT, Ridker PM. Ann Intern Med. 1997;127:895-903). Imaging modalities, central venous catheters, and improved life expectancy for critically and chronically ill children have resulted in an increased diagnosis of thromboembolic disease in the pediatric population (Journeycake MM, Manco-Johnson MJ. Hematol Oncol Clin N Am. 2004;18;1315-1338), and evaluation for thrombophilia should be performed for any child with thromboembolic disease.

Integrating genomic based information into clinical warfarin (Coumadin) management: an illustrative case report.

Warfarin is a well established oral anticoagulant for the treatment of thromboembolic disorders. Warfarin therapy is complicated by a narrow therapeutic index and marked inter-individual dose variability with therapeutic doses ranging from 1 mg to 10 mg/day. Recently genetic variation and resultant drug metabolizing polymorphisms have been found to contribute to warfarin dose variability with resultant hemorrhagic or thromboembolic complications. Cytochrome P4502C9 alters the rate of warfarin metabolism and clearance. A second enzyme, Vitamin K Epoxide Reductase Complex (VKORC) binds and reduces Vitamin K which is necessary for activation of clotting Factors II, VII, IX and X. The VKORC1 gene encodes for Vitamin K Epoxide Reductase Complex subunit 1, a key component of VKORC. The combination of physiologic factors (30%), CYP2C9 variations (20%) and VKORC1 variants (25%) accounts for approximately 75% of warfarin dose variability. This illustrative case report demonstrates the clinical importance of this new information. Clinicians need to incorporate these new genomic findings into appropriate management of warfarin dose anticoagulation.

A case of hereditary protein S deficiency presenting with cerebral sinus venous thrombosis and deep vein thrombosis at high altitude.

A 35-year-old healthy male with no history of any past medical illness developed severe headache, vomiting and drowsiness while at high altitude (4,572 m) in the eastern Himalayan ranges. He was evacuated to a tertiary-care hospital where he was diagnosed to have cerebral sinus venous thrombosis (CSVT) on magnetic resonance imaging, with deep vein thrombosis (DVT) of his right popliteo-femoral vein on color Doppler study. Investigation for thrombophilia revealed protein S (PS) deficiency in this patient. Family screening revealed low levels of PS in two elder brothers. One brother had a history of 'stroke in young' at the age of 20 years with the other being asymptomatic. This established the hereditary nature of PS deficiency. We are not aware of any previously published report on hereditary PS deficiency combined with CSVT and DVT occurring at high altitude. However, 1 case of protein C deficiency with CSVT has been reported previously.

Lemierre's syndrome and genetic polymorphisms: a case report.

BACKGROUND: Lemierre's syndrome presents a classic clinical picture, the pathophysiology of which remains obscure. Attempts have been made to trace genetic predispositions that modify the host detection of pathogen or the resultant systemic reaction. CASE PRESENTATION: A 17-year old female, with no previous medical history, was admitted to the intensive care unit for septic shock, acute respiratory distress syndrome and Lemierre's syndrome. Her DNA was assayed for single nucleotide polymorphisms previously incriminated in the detection of the pathogen, the inflammatory response and the coagulation cascade. We observed functional variations in her Toll like 5 receptor (TLR 5) gene and two coagulation variations (Tissue Factor (TF) 603 and Plasminogen-Activator-Inhibitor-1 (PAI-1) 4G-4G homozygosity) associated with thrombotic events. CONCLUSION: The innate immune response and the prothrombogenic mutations could explain, at least in part, the symptoms of Lemierre's syndrome. Genomic study of several patients with Lemierre's syndrome may reveal its pathophysiology.

Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? A systematic review.

Because use of combined oral contraceptives (COCs) confers some risk of venous thromboembolism (VTE), there is concern that this effect may be greater among women with thrombogenic mutations. We searched the MEDLINE and EMBASE databases for all articles published from January 1966 through September 2004 for evidence relevant to hormonal contraception and thrombogenic mutations. Of 301 articles identified by the search strategy, 16 evaluated COCs, and no studies were found for other hormonal methods. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. A total of 10 studies together provided "good" evidence of a greater risk of VTE (risk ratios of 1.3-25.1) and cerebral vein or cerebral sinus thrombosis among COC users with factor V Leiden mutation when compared with nonusers who have the mutation. The evidence for prothrombin and other thrombogenic mutations was not as strong as for factor V Leiden mutation. It is unclear whether the type of COC or duration of use modifies the risk of VTE among women with thrombogenic mutations.

Paradoxical coronary embolism causing non-ST segment elevation myocardial infarction in a case of pulmonary embolism.

We describe the case of a 61-year-old woman who simultaneously suffered a pulmonary embolism and a myocardial infarction due to paradoxical coronary artery embolism. Transesophageal echocardiography with injection of agitated hydroxyethyl starch revealed a patent foramen ovale. Thrombophlebistis of the left saphenous vein with extension of thrombus into the femoral vein could be identified as the source of embolism. Paradoxical coronary embolism is an underrecognized cause of MI. Diagnosis is particularly difficult, when MI and PE coincide, because of the similarity in clinical signs and symptoms of both entities. A high level of clinical suspicion and echocardiography, especially if performed soon after presentation, can be the clue to early diagnosis of PDE.

[Genetic risk factors of thrombosis]. / Facteurs génétiques de risque de thrombose.

Genetic risk factors became a frequent predisposing cause of venous thromboembolism (VTE) since the discovery of two mutations: factor V Leiden and G20210A mutation of prothrombin gene. One of these both mutations is associated with around 25% of VTE events. Interaction of genetic risk factors, such as interaction of FV Leiden or G20210A mutation of prothrombin with antithrombin, protein C or protein S deficiencies, as well as interaction with acquired risk factors, have demonstrated that venous thrombosis is a multifactorial disease. The search for thrombophilia must be done in VTE occurring before the age of 45, in case of recurrencies and in case of familial history of VTE.

Association of class I HLA antigens with the clinical manifestations of Turkish patients with Behçet's disease.

Genetic factors appear to be important in the pathogenesis of Behçet's disease. Although it is known to be strongly associated with HLA-B 51, the association of HLA class I antigens with specific clinical findings of the disease has not been studied extensively and the few studies are conflicting. The aim of this study was to investigate the association of HLA class I alleles with the manifestations of Behçet's disease in Turkish patients. Eighty-five patients with Behçet's disease were typed for HLA-A, B, and C antigens with the serologic, standard microlymphocytotoxicity technique. Possible associations of the HLA complex with clinical findings of Behçet's disease were examined. Statistically significant findings are as follows (P < 0.05): increased HLA-B 51 and decreased HLA-B35 frequency in patients with thrombophlebitis, increased HLA-A29 and decreased HLA-Bw6 frequency in patients with ocular involvement, decreased HLA-Cw2 frequency in patients with erythema nodosum, and decreased HLA-Cw 7 frequency in patients with genital ulceration. Of particular note, the results of this study suggest that the presence of HLA-B 51 and the absence of HLA-B35 can be regarded as laboratory risk factors of venous thrombosis in patients with Behçet's disease.

Prevalence of a 23bp insertion in exon 3 of the endothelial cell protein C receptor gene in venous thrombophilia.

BACKGROUND: The endothelial cell protein C receptor (EPCR) enhances protein C activation by the thrombin-thrombomodulin complex. As evidence is accumulating that EPCR is an important component of the protein C anticoagulant pathway, polymorphisms in the EPCR gene might be candidate risk factors predisposing to venous thromboembolism (VTE). Recently, a 23bp insertion in exon 3 of the EPCR gene has been identified, which duplicates the preceding 23 bases and results in a STOP codon downstream from the insertion point. However, the clinical significance of this mutation in VTE remains to be clarified. METHODS AND RESULTS: In this study we evaluated the EPCR 23bp insertion in 889 patients with documented VTE and in 500 healthy controls. The prevalence of the EPCR insertion among patients was 0.1%, which was not significantly different compared to controls (0.6%, p = 0.1). CONCLUSIONS: Our findings showed that the EPCR 23bp insertion is very rare in both patients with VTE and the general population and failed to support an association between the EPCR 23bp insertion and an increased risk of VTE.

Low level of circulating activated protein C is a risk factor for venous thromboembolism.

The levels of circulating activated protein C (APC) reflect in vivo protein C activation. The aim of this study was to determine whether a low APC level is an independent risk factor for venous thromboembolism (VTE). We measured APC in 160 patients with a history of VTE and without recognized thrombophilic defects, and in 199 healthy individuals. The mean (+/- SD) APC level was lower in patients (0.99 +/- 0.44 ng/ml) than in controls (1.19 +/- 0.41 ng/ml) (p < 0.0001), and showed a different distribution in the two groups. Thirty-eight patients (23.7%) had APC levels below the 5th percentile of the control group (<0.69 ng/ml) and 57 patients (35.6%) had APC levels below the 10th percentile (<0.77 ng/ml). APC levels <0.69 ng/ml increased the risk of a single or recurrent episode of VTE 4.2-fold (95% confidence interval, 2.0-9.0) or 6.9-fold (2.6-17.9). respectively, and APC levels <0.77 ng/ml increased these risks 3.4-fold (1.9-6.2) or 5.1-fold (2.3-11.2), respectively, compared with controls. Familial studies revealed that in some cases the low APC phenotype seems to be hereditary. We conclude that a low level of circulating APC in individuals without any of the most recognized thrombophilic defects is a prevalent, independent risk factor for VTE, and that it predisposes to recurrent VTE.