Expression of fibroblast activation protein-α in human deep vein thrombosis.

BACKGROUND: Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is associated with wound healing, cancer-associated fibroblasts, and chronic fibrosing diseases. However, its expression in deep vein thrombosis (DVT) remains unclear. Therefore, this study investigated FAP expression and localization in DVT. METHODS: We performed pathological analyses of the aspirated thrombi of patients with DVT (n = 14), classifying thrombotic areas in terms of fresh, cellular lysis, and organizing reaction components. The organizing reaction included endothelialization and fibroblastic reaction. We immunohistochemically examined FAP-expressed areas and cells, and finally analyzed FAP expression in cultured dermal fibroblasts. RESULTS: All the aspirated thrombi showed a heterogeneous mixture of at least two of the three thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reaction components. Immunohistochemical expression of FAP was restricted to the organizing area. Double immunofluorescence staining showed that FAP in the thrombi was mainly expressed in vimentin-positive or α-smooth muscle actin-positive fibroblasts. Some CD163-positive macrophages expressed FAP. FAP mRNA and protein levels were higher in fibroblasts with low-proliferative activity cultured under 0.1 % fetal bovine serum (FBS) than that under 10 % FBS. Fibroblasts cultured in 10 % FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin. CONCLUSIONS: The heterogeneous composition of venous thrombi suggests a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP during the organizing process. FAP expression may be higher in fibroblasts with low proliferative activity.

Elevated plasma levels of factor VIII enhance arterial thrombus formation on erosive smooth muscle cell-rich neointima but not normal intima in rabbits.

BACKGROUND: Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques. AIMS: We aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits. METHODS AND RESULTS: We assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5'-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group. CONCLUSIONS: Increased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis.

A 48-Year-Old Man Presenting as an Emergency with Severe Back Pain, a Large Anterior Paravertebral Hematoma, and Spontaneous Rupture of the Right 9th Intercostal Artery Successfully Managed by Transcatheter Arterial Embolization: A Case Report.

BACKGROUND The rupture of an intercostal artery is rare and is usually associated with trauma, neurofibromatosis type 1, or coarctation of the aorta. Transcatheter arterial embolization is a minimally invasive vascular surgical procedure used to control hemorrhage of an intercostal artery. This report describes a case of a 48-year-old man who presented with severe back pain. This was due to a large anterior paravertebral hematoma following the spontaneous rupture of the right 9th intercostal artery. The rupture was successfully managed by transcatheter arterial embolization. CASE REPORT A 48-year-old man suddenly felt severe back pain while walking. He had no previous medical history and he had not experienced any external injury. On arrival, he was tachycardic and hypertensive. He did not have abnormal physical findings. His chest radiograph, 12-lead electrocardiogram, ultrasonography, and blood test findings were unremarkable. A chest computed tomography scan with contrast media was performed, which revealed a 4.3×2.7×7.0 cm mass, enhanced with contrast media, anterior to the 9th vertebral body. The patient was diagnosed with spontaneous rupture of the right ninth intercostal artery. The lesion was embolized with 8 microcoils. The patient was discharged on the 8th hospital day without complications. CONCLUSIONS This report presents a rare case of the rupture of an intercostal artery in which no cause was identified. It highlights the role of imaging as an important diagnostic tool. Furthermore, this report shows the benefits of the timely use of emergency transcatheter arterial embolization, which in this instance resulted in a successful outcome.

Successful covered stent-graft treatment of superficial femoral arterial injury due to blunt trauma.

BACKGROUND: Endovascular treatment is used for traumatic arterial injuries in the torso. However, the effectiveness of endovascular covered stent-graft treatment for peripheral artery injury is unclear. We present a case of superficial femoral artery (SFA) injury successfully treated with a covered stent-graft. CASE REPORT: A 68-year-old man presented with traumatic lower limb injury and shock. Computed tomography angiography revealed left subtrochanteric fracture and hematoma with extravasation. Digital subtraction angiography revealed extravasation from a left SFA branch, and a pseudoaneurysm at the SFA trunk. We coil embolized the SFA branch, and treated the pseudoaneurysm with a covered stent-graft. Computed tomography carried out 22 days later showed complete pseudoaneurysm exclusion and sufficient stent patency. CONCLUSION: We successfully used a covered stent-graft to treat SFA injury due to blunt trauma. A covered stent-graft could be effective for peripheral artery injury.

Improving Thermodynamic Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Incorporation of 8-trifluoromethyl-2'-deoxyguanosine.

In this study, we incorporated 8-trifluoromethyl-2'-deoxyguanosine (FG) into a thrombin binding aptamer (TBA). Circular dichroism, nuclear magnetic resonance (NMR), electrophoresis, and prothrombin time (PT) assay were performed to investigate the structure, thermodynamic stability, biological stability, and anticoagulant activity of the FG-modified TBA sequences. We found that the replacement of FG into TBA sequences led to a remarkable improvement in the melting temperature up to 30 °C compared with the native sequence. The trifluoromethyl group allowed us to investigate the TBA G-quadruplex structure by 19F NMR spectroscopy. Furthermore, PT assays showed that the modified sequences can significantly improve the anticoagulant activity in comparison with the native TBA. Finally, we demonstrated that the trifluoromethyl-modified TBA sequence could function as an anticoagulant reagent in live rats. Our results strongly suggested that FG is a powerful nucleoside derivative to increase the thermodynamic stability and anticoagulant activity of TBA.

Therapeutic response of immunoglobulin 4-related aortitis and pancreatitis demonstrated by diffusion-weighted MRI.

Immunoglobulin (IgG) 4-related disease is a systemic inflammatory disease, and it affects vascular system as aortitis, periaortitis, or aneurysm. However, due to a lack of serum biomarker on aortic damage and the multiorgan involvement, it is difficult to assess aortic inflammatory activity of IgG4-related disease. We described a case of IgG4-related pancreatitis and aortitis, which was visualized with magnetic resonance merged image of diffusion weighted and T1 weighted images. The aortic signal intensity or apparent diffusion coefficient value reduced or increased after oral prednisone administration, respectively. Magnetic resonance diffusion weighted image and apparent diffusion coefficient may be a useful imaging tool for assessment of vascular inflammation in IgG4-related aortitis.

Higher lactate and purine metabolite levels in erythrocyte-rich fresh venous thrombus: Potential markers for early deep vein thrombosis.

BACKGROUND: Thrombolytic therapy is effective in fresh deep vein thrombosis (DVT) although the benefit may fall below the risk of bleeding in non-fresh thrombosis. Markers reflecting fresh DVT have not been established. The present study aims to identify metabolites reflecting fresh venous thrombus and their role in thrombus formation. METHODS: Metabolites of rabbit venous blood and jugular venous thrombus 4 h after thrombus induction were analysed using electrophoresis-time of flight mass spectrometry. The effects of the altered metabolites on blood coagulation and platelet aggregation were assessed by using rotation thromboelastometry and platelet aggregometer. Cellular contents and glucose transporter (Glut)-1 expression in aspirated human DVT samples were pathologically analysed. RESULTS: Metabolome analysis identified 226 metabolites (133 cationic and 93 anionic metabolites). Largely altered 18 metabolites (thrombus/blood ratio: >5 or <0.5) included glycolytic metabolites, redox-related metabolites, purine nucleotides and tryptophan metabolites. Among the metabolites with >5-fold increase, lactic acid was most abundant and guanine modestly enhanced whole blood clotting with thromboelastometry. Lactic acid and adenosine monophosphate inhibited collagen-induced platelet aggregation. Human DVTs were rich in erythrocytes expressing Glut-1. The erythrocyte content and Glut-1 expression were negatively correlated with the time after onset of DVT. CONCLUSIONS: Glycolysis-, purine-, and redox-related metabolites may reflect fresh erythrocyte-rich venous thrombus, and altered metabolites may affect venous thrombus formation. An increased level of lactate may reflect active glycolysis of thrombus cellular components, predominantly erythrocytes.

Efficient screening of patients with aldosterone-producing adenoma using the ACTH stimulation test.

Adrenal venous sampling (AVS) is the gold standard test for distinguishing between unilateral and bilateral primary aldosteronism (PA); however, AVS requires advanced and time consuming technique. The needs for AVS have been increasing due to the increased utilization of screening for PA. An efficient selection of unilateral PA, such as aldosterone-producing adenoma (APA), before AVS is useful to avoid undesirable AVS in bilateral PA, such as idiopathic hyperaldosteronism. In this study, 40 patients who received all three confirmatory tests, including the captopril challenge test, furosemide upright test and adrenocorticotropin (ACTH) stimulation test (AST), and who were diagnosed as having PA by AVS were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n = 22) or bilateral aldosterone excess (n = 18) by AVS. All patients with unilateral PA underwent an operation and were finally diagnosed with APA. Major differences were detected in serum potassium level, basal plasma aldosterone concentration (PAC), presence of adrenal tumor, and AST results between the two groups. The PAC/cortisol ratio at 120 min in the AST showed the highest diagnostic capability for distinguishing the subtypes of PA according to a receiver operating characteristic (ROC) curve analysis (area under the ROC curve was 0.956). At a cutoff value of 1.20 for the PAC/cortisol ratio at 120 min on the AST, the sensitivity was 95.5%, and the specificity was 88.9%. This sufficiently high sensitivity suggests that the PAC/cortisol ratio at 120 min in the AST could be useful for the screening of patients with PA who are suitable for AVS.

Safe Resection of Renal Cell Carcinoma with Liver Invasion Using Liver Hanging Technique Supported by Preoperative Portal Vein Embolization.

In cases of RCC with liver involvement, partial hepatectomy is known to provide a better chance of survival for patients. For this reason, complete resection with clear surgical margin is thought to be necessary to achieve favorable outcome. Anterior liver hanging maneuver was extremely useful during hemihepatectomy in this rare type of RCC. A 63-year-old male was diagnosed with a large right renal cell carcinoma. The tumor measured 10 cm in diameter with tumor thrombus toward the inferior vena cava (IVC). In addition, we observed direct infiltration to the liver. We attempted a preoperative portal vein embolization (PVE) to preserve residual liver volume and function after right lobectomy. After PVE the resected volume decreased from 921 cm3 (71%) to 599 cm3 (53.4%). During the procedure, a nasogastric tube was placed in the retrohepatic space for liver hanging maneuver according to the original Belghiti's maneuver after dissection of the renal artery and vein. After hepatic parenchymal transection exposing vena cava, the right hepatic veins were safely transected using vascular stapler; right nephrectomy and hemihepatectomy were performed. The patient recovered without postoperative hepatic or urinary complications and has remained free of local recurrence and any de novo metastasis for 18 months.