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INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

INTRODUCTION: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important. AREAS COVERED: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e. factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed. EXPERT OPINION: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

Since current treatments for both acute and chronic lung diseases are less than ideal, there has been recent interest in the use of cell-based therapies for inflammatory lung disease. Specifically, human amnion epithelial cells (hAECs) have been shown to reduce bleomycin-induced lung injury and prevent subsequent loss of respiratory function, primarily through modulation of the host immune response. The precise mechanisms of this effect remain unclear. We aimed to investigate the potential of hAECs to mitigate bleomycin-induced lung injury in surfactant protein C deficient (Sftpc-/-) mice, which are highly susceptible to pulmonary injury as a result of impairment of macrophage function. Primary hAECs were administered to wild-type (Sftpc+/+) and Sftpc-/- mice 24 h after exposure to bleomycin. Compared to Sftpc+/+ mice receiving bleomycin alone, Sftpc+/+ mice administered hAECs 24 h after bleomycin exposure had decreased expression of proinflammatory genes, decreased macrophage and neutrophil infiltration, fibrosis, collagen content, and alpha-smooth muscle actin as well as a significant improvement in lung function. Compared to Sftpc-/- mice given bleomycin alone, Sftpc-/- mice administered hAECs 24 h after bleomycin did not have a decrease in inflammatory gene expression or a reduction in macrophage pulmonary infiltration. Subsequently, Sftpc-/- mice did not show any decrease in pulmonary fibrosis or improvement of lung function after hAEC administration. The ability of hAECs to mitigate bleomycin-induced lung injury is abolished in Sftpc-/- mice, suggesting that hAECs require normal host macrophage function to exert their reparative effects. © 2012 Cognizant Comm. Corp.

Since current treatments for both acute and chronic lung diseases are less than ideal, there has been recent interest in the use of cell-based therapies for inflammatory lung disease. Specifically, human amnion epithelial cells (hAECs) have been shown to reduce bleomycin-induced lung injury and prevent subsequent loss of respiratory function, primarily through modulation of the host immune response. The precise mechanisms of this effect remain unclear. We aimed to investigate the potential of hAECs to mitigate bleomycin-induced lung injury in surfactant protein C deficient (Sftpc-/-) mice, which are highly susceptible to pulmonary injury as a result of impairment of macrophage function. Primary hAECs were administered to wild-type (Sftpc+/+) and Sftpc-/- mice 24 h after exposure to bleomycin. Compared to Sftpc+/+ mice receiving bleomycin alone, Sftpc+/+ mice administered hAECs 24 h after bleomycin exposure had decreased expression of proinflammatory genes, decreased macrophage and neutrophil infiltration, fibrosis, collagen content, and alpha-smooth muscle actin as well as a significant improvement in lung function. Compared to Sftpc-/- mice given bleomycin alone, Sftpc-/- mice administered hAECs 24 h after bleomycin did not have a decrease in inflammatory gene expression or a reduction in macrophage pulmonary infiltration. Subsequently, Sftpc-/- mice did not show any decrease in pulmonary fibrosis or improvement of lung function after hAEC administration. The ability of hAECs to mitigate bleomycin-induced lung injury is abolished in Sftpc-/- mice, suggesting that hAECs require normal host macrophage function to exert their reparative effects. © 2012 Cognizant Comm. Corp.

The prevalence of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiencies in portal vein system thrombosis (PVST) and Budd-Chiari syndrome (BCS) are substantially varied in different studies. No quantitative syntheses of these studies have been performed. A systematic review and meta-analysis were conducted to examine the prevalence of inherited AT, PC, and PS deficiencies in these patients and to compare the prevalence with healthy subjects.

Venous disease was evaluated in relation to post-thrombotic syndrome 5 years after deep venous thrombosis (DVT) in patients treated with a regimen of low-molecular-weight heparin (LMWH) and warfarin in a Hospital-in-the-Home program. The presence of flow, reflux and compressibility in 51 patients (102 limbs, 54 with DVT and 48 without DVT) was assessed by duplex ultrasound scanning. Blood tests were carried out for prothrombotic screening. Venous disease was related to pathologic severity of post-thrombotic syndrome, characterized by the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification on a scale of 0 to 6. In the 102 limbs studied, 30 patients (59%) had an underlying thrombophilic disorder. The most common cause of DVT was postoperation and prolonged immobilization not related to postoperation. The most common thrombophilic abnormalities were anticardiolipin antibody and a deficiency of protein C or S, or both. Twenty-six limbs (48%) had proximal involvement (proximal and proximal plus distal DVT); resolution (recanalization or normal vein) in these limbs was seen in 85% at 6 months and 96% at 5 years. After 5 years, 25 of these proximal DVT limbs (96%) developed reflux and there were 4 limbs in CEAP class 0, 8 in classes 1 to 3, and 14 in classes 4 to 6. All of the 28 limbs (52%) with distal DVT showed DVT resolution by 6 months. After 5 years, 10 limbs (36%) developed reflux, and 13 limbs were in class 0, 12 in classes 1 to 3, and 3 limbs in classes 4 to 6. No DVT was detected in the 48 contralateral limbs, but reflux was detected in 25 limbs (52%), predominately in the superficial veins (16 limbs, 64%). The resolution of thrombus was more rapid and complete in patients with distal DVT than in those with proximal DVT. Patients with proximal DVT developed a more severe form of post-thrombotic syndrome that was likely related to the development of deep venous reflux. An important finding of this study was an unexpectedly high incidence of venou

During pregnancy, the risk of venous thromboembolism (VTE) increases 2-5 fold and pulmonary embolism (PE) remains a leading cause of maternal mortality in developed countries. For pregnant women with suspected deep vein thrombosis (DVT) or PE, the use of serial compression leg ultrasound (CUS) should be considered to exclude DVT whereas a normal ventilation perfusion lung scan likely excludes PE. A computer tomographic pulmonary angiogram (CTPA) could assist in ruling out PE in women who present with an abnormal chest radiograph. Low molecular weight heparins (LMWH) are the agents of choice for treatment and thromboprophylaxis of pregnant patients with VTE but appropriate dosing changes throughout pregnancy remain uncertain. Women with previously unprovoked VTE and those in whom VTE are provoked by previous pregnancies or use of oral contraceptive are at highest risk of VTE recurrence during pregnancy, and should be offered antepartum and postpartum thromboprophylaxis. On the other hand, women with prior VTE related to a transient risk factor would benefit from postpartum thromboprophylaxis. More research is needed to identify the absolute risk of VTE during pregnancy associated with more prevalent risk factors such as maternal age, obesity, and mode of delivery. © 2011 Bentham Science Publishers Ltd.

Venous disease was evaluated in relation to post-thrombotic syndrome 5 years after deep venous thrombosis (DVT) in patients treated with a regimen of low-molecular-weight heparin (LMWH) and warfarin in a Hospital-in-the-Home program. The presence of flow, reflux and compressibility in 51 patients (102 limbs, 54 with DVT and 48 without DVT) was assessed by duplex ultrasound scanning. Blood tests were carried out for prothrombotic screening. Venous disease was related to pathologic severity of post-thrombotic syndrome, characterized by the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification on a scale of 0 to 6. In the 102 limbs studied, 30 patients (59%) had an underlying thrombophilic disorder. The most common cause of DVT was postoperation and prolonged immobilization not related to postoperation. The most common thrombophilic abnormalities were anticardiolipin antibody and a deficiency of protein C or S, or both. Twenty-six limbs (48%) had proximal involvement (proximal and proximal plus distal DVT); resolution (recanalization or normal vein) in these limbs was seen in 85% at 6 months and 96% at 5 years. After 5 years, 25 of these proximal DVT limbs (96%) developed reflux and there were 4 limbs in CEAP class 0, 8 in classes 1 to 3, and 14 in classes 4 to 6. All of the 28 limbs (52%) with distal DVT showed DVT resolution by 6 months. After 5 years, 10 limbs (36%) developed reflux, and 13 limbs were in class 0, 12 in classes 1 to 3, and 3 limbs in classes 4 to 6. No DVT was detected in the 48 contralateral limbs, but reflux was detected in 25 limbs (52%), predominately in the superficial veins (16 limbs, 64%). The resolution of thrombus was more rapid and complete in patients with distal DVT than in those with proximal DVT. Patients with proximal DVT developed a more severe form of post-thrombotic syndrome that was likely related to the development of deep venous reflux. An important finding of this study was an unexpectedly high incidence of venou

During pregnancy, the risk of venous thromboembolism (VTE) increases 2-5 fold and pulmonary embolism (PE) remains a leading cause of maternal mortality in developed countries. For pregnant women with suspected deep vein thrombosis (DVT) or PE, the use of serial compression leg ultrasound (CUS) should be considered to exclude DVT whereas a normal ventilation perfusion lung scan likely excludes PE. A computer tomographic pulmonary angiogram (CTPA) could assist in ruling out PE in women who present with an abnormal chest radiograph. Low molecular weight heparins (LMWH) are the agents of choice for treatment and thromboprophylaxis of pregnant patients with VTE but appropriate dosing changes throughout pregnancy remain uncertain. Women with previously unprovoked VTE and those in whom VTE are provoked by previous pregnancies or use of oral contraceptive are at highest risk of VTE recurrence during pregnancy, and should be offered antepartum and postpartum thromboprophylaxis. On the other hand, women with prior VTE related to a transient risk factor would benefit from postpartum thromboprophylaxis. More research is needed to identify the absolute risk of VTE during pregnancy associated with more prevalent risk factors such as maternal age, obesity, and mode of delivery. © 2011 Bentham Science Publishers Ltd.

Background: The Budd-Chiari syndrome (BCS) is hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. Objective: To characterize the causes and treatment of incident BCS. Design: Consecutive case series of patients with incident BCS, enrolled from October 2003 to October 2005 and followed until May 2006. Setting: Academic and nonacademic hospitals in France, Spain, Italy, Great Britain, Germany, Belgium, the Netherlands, Portugal, and Switzerland. Patients: Persons older than 16 years with definite hepatic outflow obstruction diagnosed by imaging. Persons with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. Measurements: Signs and symptoms; laboratory and imaging findings; diagnosis; treatment; and overall, transplantation-free, and intervention-free survival. Results: 163 incident cases of BCS were identified. Median follow-up was 17 months (range, 0.1 to 31 months). Most patients (84%) had at least 1 thrombotic risk factor, and many (46%) had more than 1; the most common was myeloproliferative disorders (49% of 103 tested patients). Patients were mainly treated with anticoagulation (140 patients [86%]), transjugular intrahepatic portosystemic shunting (56 patients [34%]), or liver transplantation (20 patients [12%]), and 80 patients (49%) were managed noninvasively. Only 3 patients underwent surgical shunting. The survival rate was 87% (95% CI, 82% to 93%) at 1 year and 82% (CI, 75% to 88%) at 2 years. Limitation: Treatment was not standardized across all centers, and data on important clinical variables were missing for some patients. Conclusion: Most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and inv

Fasting plasma homocysteine level and the related clinical findings were analysed in 240 consecutive patients with venous thromboembolism. Hyperhomocysteinemia, defined as a plasma level above 20 micromol/l (corresponding to the percentile 95th in the controls), was present in 11.2% of the patients. Plasma homocysteine level was similar in patients presenting with either deep venous thrombosis, pulmonary embolism or both conditions. It was significantly higher in patients with primary (unprovoked) VTE than in patients with secondary disease (associated with at least one risk factor): 12.3 vs. 9.55 micromol/l (p < 0.005). Mean homocysteine was higher in male than in female patients (14.51 vs. 12.9 micromol/l, p < 0.05) and increased significantly with age. Hyperhomocysteinemia was more frequent in patients with relapsing disease (14 of 76, 18.4%) than in those presenting with a single episode (13 of 164, 7.9%) (p = 0.034). Furthermore, hyperhomocysteinemia was correlated with reduced protein C level (p = 0.013). In a multivariate analysis, two factors were significantly associated with hyperhomocysteinemia: older age (p < 0.0001) and idiopathic occurrence (p < 0.02). Since the frequency of homozygous MTHFR thermolabile variant was rather similar in patients and controls, testing for C677T mutation was not helpful in screening VTE patients. However, the homozygous mutation was significantly more prevalent among hyperhomocysteinemia patients, confirming its role in the genesis of hyperhomocysteinemia. According to its prevalence, to the putative role in venous and arterial disease and the availability of an effective and low-cost corrective therapy, hyperhomocysteinemia deserves interest, especially in the elderly and in the patients with idiopathic VTE disease.

The inclusion of a mutation in a pathology-based database such as the Human Gene Mutation Database (HGMD) is a two-stage process: first, the mutation must occur at the DNA level, then it must cause a clinically detectable disease state. The likelihood of the latter step, termed the relative clinical observation likelihood (RCOL), can be regarded as a function of the structural/functional consequences of a mutation at the protein level. Following this paradigm, we modeled in silico all amino acid replacements that could potentially have arisen from an inherited single base pair substitution in five human genes encoding arylsulphatase A (ARSA), antithrombin III (SERPINC1), protein C (PROC), phenylalanine hydroxylase (PAH), and transthyretin (TTR). These proteins were chosen on the basis of 1) the availability of a crystallographic structure, and 2) a sufficiently large number of amino acid replacements being logged in HGMD. A total of 9,795 possible mutant structures were modeled and 20 different biophysical parameters assessed. Together with the HGMD-derived spectra of clinically detected mutations, these data allowed maximum likelihood estimation of RCOL profiles for the 20 parameters studied. Nine parameters (including energy difference between wild-type and mutant structures, accessibility of the mutated residue, and distance from the binding/active site) exhibited statistically significant variability in their RCOL profiles, indicating that mutation-associated changes affected protein function. As yet, however, a biological meaning could only be attributed to the RCOL profiles of solvent accessibility and, for three proteins, local energy change, disturbed geometry, and distance from the active center. The limited ability of the biophysical properties of mutations to explain clinical consequences is probably due to our current lack of understanding as to which amino acid residues are critical for protein folding. However, since the proteins examined here were unr

The inclusion of a mutation in a pathology-based database such as the Human Gene Mutation Database (HGMD) is a two-stage process: first, the mutation must occur at the DNA level, then it must cause a clinically detectable disease state. The likelihood of the latter step, termed the relative clinical observation likelihood (RCOL), can be regarded as a function of the structural/functional consequences of a mutation at the protein level. Following this paradigm, we modeled in silico all amino acid replacements that could potentially have arisen from an inherited single base pair substitution in five human genes encoding arylsulphatase A (ARSA), antithrombin III (SERPINC1), protein C (PROC), phenylalanine hydroxylase (PAH), and transthyretin (TTR). These proteins were chosen on the basis of 1) the availability of a crystallographic structure, and 2) a sufficiently large number of amino acid replacements being logged in HGMD. A total of 9,795 possible mutant structures were modeled and 20 different biophysical parameters assessed. Together with the HGMD-derived spectra of clinically detected mutations, these data allowed maximum likelihood estimation of RCOL profiles for the 20 parameters studied. Nine parameters (including energy difference between wild-type and mutant structures, accessibility of the mutated residue, and distance from the binding/active site) exhibited statistically significant variability in their RCOL profiles, indicating that mutation-associated changes affected protein function. As yet, however, a biological meaning could only be attributed to the RCOL profiles of solvent accessibility and, for three proteins, local energy change, disturbed geometry, and distance from the active center. The limited ability of the biophysical properties of mutations to explain clinical consequences is probably due to our current lack of understanding as to which amino acid residues are critical for protein folding. However, since the proteins examined here were unr

Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals affected by protein C deficiency are at risk for venous thrombosis. One such affected individual was shown earlier to carry a -14 T --> C mutation in the promoter region of the protein C gene. It is shown here that the region around this mutation corresponds to a binding site for the transcription factor hepatocyte nuclear factor (HNF)-6 and that this site completely overlaps an HNF-1 binding site. HNF-6 and HNF-1 bound in a mutually exclusive manner. The -14 T --> C mutation reduced HNF-6 binding. In transient transfection experiments, HNF-6 transactivated the wild-type protein C promoter and introduction of the mutation abolished transactivation by HNF-6. Similar experiments showed that wild-type protein C promoter activity was reduced by cotransfection of an HNF-1 expression vector. This inhibiting effect of HNF-1 was reversed to a stimulatory effect when promoter sequences either upstream or downstream of the HNF-6/HNF-1 site were deleted. It is concluded that HNF-6 is a major determinant of protein C gene activity. Moreover, this is the first report describing the putative involvement of HNF-6 and of an HNF-6 binding site in human pathology.

With the introduction of transesophageal echocardiography, atheromatosis of the thoracic aorta is now well recognized as an occult source of systemic embolism in the elderly. In the absence of macroscopic atheromatosis, the presence of thrombi in the thoracic aorta identified by transesophageal echocardiography is an unexpected finding in a middle-aged patient with arterial embolism. Risk factors were investigated and hypercoagulable state with protein C deficiency was demonstrated., SCOPUS: ar.j, info:eu-repo/semantics/published

short communications, the abstract is not necessary