Histopathological Features of Cancer-Associated Venous Thromboembolism: Presence of Intrathrombus Cancer Cells and Prothrombotic Factors.

BACKGROUND: Cancer-associated venous thromboembolism (VTE) is a critical complication in patients with cancer. However, the pathological findings of VTE are limited. Here, we investigated the histopathological features of cancer-associated VTE in human autopsy cases. METHODS: We clinically examined the autopsy cases of VTE with (n=114) and without cancer (n=66) and immunohistochemically analyzed the expression of prothrombotic factors in intrathrombus cancer cells, the thrombus contents of erythrocytes, fibrin, platelets, citrullinated histone H3, and degree of organization. RESULTS: Vascular wall invasion or small cell clusters of cancer cells was observed in thrombi in 27.5% of deep vein thrombosis and 25.9% of pulmonary embolism cases. The majority of the cancer cells in deep vein thrombi appeared to be invading the vessel wall, whereas the majority of pulmonary thrombi had cancer cell clusters, consistent with embolization via blood flow. These cancer cells were immunohistochemically positive for TF (tissue factors) or podoplanin in up to 88% of VTE cases. The frequency of TF-positive monocyte/macrophages in thrombi was higher in cancer-associated VTE than that in VTE without cancer. Citrullinated histone H3 was predominantly observed in the early stages of organizing thrombi. There was no significant difference in thrombus components between VTE with cancer and without cancer groups. CONCLUSIONS: Vascular wall invasion or cancer cell clusters in thrombi might influence thrombogenesis of cancer-associated VTE. TF and podoplanin in cancer cells and in monocyte/macrophages may induce coagulation reactions and platelet aggregation. Neutrophil extracellular traps may play a role in the early stages of VTE, regardless of cancer status.

Human coronary thrombus formation is associated with degree of plaque disruption and expression of tissue factor and hexokinase II.

BACKGROUND: Atherosclerotic plaque thrombogenicity is a critical factor that affects thrombus formation and the onset of acute myocardial infarction (AMI). The aim of this study was to identify the vascular factors involved in thrombus formation and AMI onset. METHODS AND RESULTS: Culprit lesions in 40 coronary arteries with thrombi at autopsy after lethal AMI and non-cardiac death (asymptomatic plaque disruption) were analyzed on histology. Thrombus size, ratio of thrombus to lumen area, length of plaque disruption, and immunopositive areas for tissue factor (TF) and hexokinase (HK)-II were significantly larger in coronary arteries with AMI than with asymptomatic plaque disruption. The size of coronary thrombus positively correlated with the length of plaque disruption (r=0.80) and with immunopositive areas for TF (r=0.38) and HK-II (r=0.40). Because both M1 and M2 macrophages express TF and HK-II in symptomatic plaques, we assessed TF and HK-II expression in M1- and M2-polarized macrophages. The expression of TF was increased and that of HK-II was decreased in M2-, compared with M1-polarized THP-1 macrophages. Inhibiting glycolysis enhanced TF expression in the macrophages partly via hypoxia inducible factor-1α. CONCLUSIONS: The degree of plaque disruption and expression of TF and HK-II appear to be important vascular factors for AMI onset, and polarized macrophages make a distinct contribution to thrombogenicity and glucose metabolism.

Hemangioma of the umbilical cord with pseudocyst.

A case of umbilical cord hemangioma with a large cystic mass, diagnosed by ultrasound at 18 weeks of gestation, is reported. A normal female infant was born at 39 weeks of gestation. The umbilical cord was 32 cm long with a cystic mass (10 × 10 × 8 cm). Histopathologic examination of the umbilical cord revealed a hemangioma with myxomatous degeneration, presenting as a large cyst with thinning of the umbilical venous wall. A total of 33 umbilical cord hemangioma cases have been reported in detail, and only seven cases had a pseudocystic degeneration. The associated pathologic findings of umbilical cord hemangioma are reviewed.

A case of acute cerebral infarction with a favorable prognosis after rt-PA administration by a general physician with telestroke support.

Objective: Herein, we report a patient with acute cerebral infarction with a favorable prognosis after being managed by a general physician with support from the telestroke program. Patient and Methods: An 85-year-old man was transferred to a regional hospital due to sudden onset of dysarthria and left hemiparesis. As no neurosurgeons or neurologists were available in that hospital or area, the patient was examined by a general physician who diagnosed him with cardioembolic stroke on the left middle cerebral artery territory. The physician consulted a stroke specialist using the telestroke system; with the support from the telestroke program, the physician administered thrombolytic therapy 4 hours and 10 minutes after the onset of symptoms. Results: The patient's National Institutes of Health Stroke Scale score improved from 9 to 3 and he was subsequently transferred to the stroke center. However, the occluded left middle cerebral artery had already re-canalized. His hemiparesis completely improved one week after the onset. Conclusion: A telemedicine system for general physicians is indispensable in areas without accessible stroke specialists as it provides access to a standard of care for hyper-acute stroke patient assessment and management, and helps improve neuroprognosis.

Implementation of a telestroke system for general physicians without a nearby stroke center to shorten the time to intravenous thrombolysis for acute cerebral infarction.

AIM: We aimed to establish a telestroke system for general physicians in areas without a nearby stroke center and investigate its usefulness for recombinant tissue plasminogen activator (rt-PA) therapy for patients with acute cerebral infarction. METHODS: We used a hub and spoke model, in which a hub hospital provided telestroke support to the spoke hospitals in rural areas that were not nearby a stroke center. The telestroke support device enabled the sharing of images and real-time face-to-face discussion with a stroke specialist for diagnosis and treatment. We evaluated the effect of this telestroke system on shortening time to start rt-PA therapy. RESULT: One hub and three spoke hospitals were selected. From May 2017 to November 2018, seven patients (77.2 ± 6.3 years old) suspected to have acute cerebral infarction were treated at the spoke hospitals via this system, three of whom received intravenous rt-PA administration by a general physician under telestroke support. If these patients would have been sent via ground ambulance to the nearby stroke center, it would have taken approximately 48 min more to administer rt-PA. CONCLUSION: Establishment of a telestroke support system for general physicians in areas without a nearby stroke center was useful for promptly performing rt-PA therapy.

[A case of advanced gastric cancer with liver metastases successfully treated by combination therapy of TS-1 and docetaxel].

The patient was a 70-year-old man who was diagnosed inoperable because of liver metastases of advanced gastric cancer and his respiratory dysfunction. He received docetaxel at the starting dose of 40 mg/m(2) by iv infusion over 1 hour on day 1 and TS-1 at the full dose of 80 mg/m(2) daily for two weeks every three weeks. After 6 cycles of this combination therapy, gastric cancer with liver metastases entirely disappeared. No re-growth of gastric cancer has been seen for three years with chemotherapy of TS-1. This chemotherapy shows a high degree of safety and efficacy in this patient.

The values of wall shear stress, turbulence kinetic energy and blood pressure gradient are associated with atherosclerotic plaque erosion in rabbits.

AIM: To clarify the contribution of hemodynamic factors to the onset of plaque erosion in smooth muscle cell (SMC)-rich atherosclerotic plaque. METHODS: We developed a rabbit model of SMC-rich atherosclerotic plaque with various degree of stenosis induced by incomplete ligation and generated three-dimensional models of five rabbit femoral arteries based on 130-162 serial histological cross-sections at 100-µm intervals per artery. We performed a computational blood flow simulation using the Reynolds-averaged Navier-Stokes model and calculated the wall shear stress (WSS), turbulence kinetic energy (TKE), blood pressure (BP) and blood pressure gradients (BPG) in eight sections (the inlet, the stenotic portion and areas 1, 2 and 5mm from the stenotic portion) in each rabbit. We also investigated whether the magnitude of WSS or TKE was related to the presence or absence of erosive injury by evaluating six points (the locally highest, median and lowest of WSS or TKE) in each section. RESULTS: The magnitudes of WSS, TKE and BPG, but not BP, correlated significantly with the extent of histologically-defined plaque erosion (WSS, r=0.55, p＜0.001; TKE, r=0.53, p＜0.001; BPG, r=0.61, p＜0.0001, n=40). The values for WSS and TKE were significantly larger at sites with, compared to without, erosive injury (n=107 and n=119 points, respectively; both p＜0.0001). CONCLUSIONS: These results suggest that increased values of WSS, TKE and BPG considerably contribute to the onset of plaque erosion.

Circulating des-acyl ghrelin improves cardiovascular risk prediction in older hypertensive patients.

BACKGROUND: We aimed to assess the predictive value of circulating levels of des-acyl ghrelin, an abundant form of ghrelin in humans, for the risk of cardiovascular disease (CVD) in older hypertensive patients. We simultaneously evaluated other biomarkers, such as high-molecular-weight (HMW) adiponectin, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor 1 (PAI-1), for their usefulness in risk prediction. METHODS: We enrolled 590 older hypertensive patients (mean age = 72.9 years; 41.0% men). The incidences of CVD, including coronary artery disease, stroke, congestive heart failure, and sudden death, were prospectively ascertained. RESULTS: During an average duration of 2.8 (SD = 0.7) years (1,653 person-years), there were 42 CVD events. Patients with CVD events had lower levels of des-acyl ghrelin at baseline than those without CVD events (median = 78.2 vs. 114.7 fmol/ml; P < 0.001). No difference was found among other biomarkers between the patients with CVD events and those without such events. The Cox proportional hazards model adjusted by covariables revealed that the hazard ratio for CVD events in patients with a 1-SD decrease of log des-acyl ghrelin was 1.8 (95% confidence interval = 1.3-2.4). Incorporation of des-acyl ghrelin in the risk model (including age, current smoking, 24-hour systolic blood pressure, preexisting CVD, and carotid intima-media thickness) improved the C statistics (from 0.683 to 0.721; P = 0.22) and resulted in a net reclassification improvement of 20.5% (P = 0.02). In contrast, HMW adiponectin, hs-CRP, and PAI-1 provided no improvement in risk prediction. CONCLUSIONS: Des-acyl ghrelin improved the prediction of CVD events in older hypertensive patients.

Elevated plasma factor VIII enhances venous thrombus formation in rabbits: contribution of factor XI, von Willebrand factor and tissue factor.

Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.

Regional differences in hypertensive cardiovascular remodeling between fishing and farming communities in Japan.

BACKGROUND: Effects of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) intake on the cardiovascular system have been reported, and thus we hypothesized that the prevalence of hypertensive cardiovascular remodeling would be lower in a fishing than a farming community. METHODS: We recruited 263 essential hypertensives from a fishing and 333 from a farming village; all subjects were ≥40 years (mean 73 years; 42% men). They were cross-sectionally examined for serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), asymmetric dimethylarginine (ADMA) levels, left ventricular mass index (LVMI), and common-carotid artery (CCA) and internal-carotid artery (ICA) intima-media thickness (IMT). RESULTS: Compared to the patients in the farming village, those in the fishing village had higher serum EPA and DHA levels (63.3 vs.70.9 µg/ml, 137.2 vs.157.8 µg/ml) and lower ADMA levels (0.49 vs.0.47 nmol/ml; all P < 0.05). LVMI and both CCA-IMT and ICA-IMT levels were lower in the fishing than the farming village (113.2 vs.121.6 g/m(2), 0.88 vs.0.94 mm, 1.10 vs.1.17 mm: all P < 0.01) even after adjustment for age, sex, body mass index (BMI), duration of hypertensive medication, number of antihypertensive medications, and 24-h systolic blood pressure (SBP) level. The differences in LVMI and IMT levels between these communities also remained unchanged (all P < 0.01) after additional adjustment for the regional differences in EPA, DHA, and ADMA levels. A multivariable linear regression analysis showed that the difference in place of residence was independently associated with LVMI as well as with both CCA-IMT and ICA-IMT levels (all P < 0.01). CONCLUSION: The prevalence of cardiovascular remodeling was significantly lower in patients in the fishing community than in those in the farming community. Further investigations are required to explain the mechanisms underlying this association.

Plasma Pentraxin 3, but not high-sensitivity C-reactive protein, is a useful inflammatory biomarker for predicting cognitive impairment in elderly hypertensive patients.

BACKGROUND: Due to the increasing longevity of human populations worldwide, there is need of a useful biomarker for the early detection of cognitive impairment in elderly persons. Both high blood pressure (BP) and inflammatory processes have been reported to be involved in cognitive impairment via cerebrovascular atherosclerosis or neuronal cell damage. METHODS: In this cross-sectional study of 210 ambulatory elderly hypertensive patients without clinically evident dementia (mean age: 74 years; 44% men), we measured 24-hour BP, circulatory pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) levels, and cognitive function (Mini-Mental State Examination [MMSE]). RESULTS: A high plasma PTX3 level was observed in lean subjects, especially in those whose current body weight was lower than that measured 5 years earlier, whereas a high hs-CRP level was associated with obesity (all p < .05). Both PTX3 and hs-CRP levels were significantly associated with the MMSE score (r = -.248, p<0.001 and r = -.153, p<0.05, respectively); however, in multiple regression analysis, the PTX3 level, but not the hs-CRP level, was inversely associated with the MMSE score independently of patient demographics, glucose and lipid metabolic parameters, 24-hour systolic BP (SBP) level, and the atherosclerotic burden (all p < .05). Moreover, there was a significant interaction between the PTX3 and 24-hour SBP levels in the determinants of MMSE score (p < .05). CONCLUSIONS: A high plasma PTX3 level in elderly hypertensive patients, particularly in those with a high 24-hour BP level, could be a significant predictor of cognitive impairment. A high PTX3 level may be a marker of frailty in elderly hypertensive patients.

Inhibition of factor XI reduces thrombus formation in rabbit jugular vein under endothelial denudation and/or blood stasis.

INTRODUCTION: In addition to acquired and inherited risk factors, the growth of venous thrombus under static conditions and endothelial injury play important roles in the development of deep venous thrombosis (DVT), for which risk factors include increased plasma levels of coagulation factor XI (FXI). The aim of this study is to understand the role of FXI in venous thrombus formation under conditions of endothelial denudation and/or blood stasis. MATERIALS AND METHODS: The contribution of FXI to venous thrombus formation was investigated in a rabbit model and a flow chamber system. Thrombi were induced in the rabbit jugular veins by (1) endothelial denudation, (2) vessel ligation (blood stasis) or (3) by combined endothelial denudation and vessel ligation. Blood samples were perfused on immobilized type III collagen at a wall shear rate of 70/s and then the surface area covered by platelets and fibrin was morphometrically evaluated. Prothrombin fragment 1+2 (F1+2) generation was also measured before and after perfusion. RESULTS: All thrombi induced in rabbit jugular veins were composed of platelets, fibrin and erythrocytes. Anti-FXI antibody significantly reduced ex vivo plasma thrombin generation initiated by ellagic acid but not by tissue factor, and in vivo thrombus formation under endothelial denudation and/or vessel ligation. The antibody significantly reduced surface areas covered by platelets and fibrin, as well as F1+2 generation at a wall shear rate of 70/s in flow chambers. CONCLUSION: These results suggest that FXI contributes to venous thrombus growth under conditions of endothelial denudation and/or blood stasis, and that thrombin generation by FXI interaction promotes further platelet aggregation and fibrin formation at low shear rates.

Thrombin generation by intimal tissue factor contributes to thrombus formation on macrophage-rich neointima but not normal intima of hyperlipidemic rabbits.

Arterial thrombosis occurs in atherosclerotic, but rarely in non-atherosclerotic arteries. The present study investigates how hyperlipidemic condition affects thrombus formation on macrophage-rich neointima or normal intima in rabbits. Rabbits were fed with a 0.5% cholesterol diet, and then the femoral artery on one side of each rabbit was injured with a balloon catheter. Three weeks later, bilateral femoral arteries were similarly injured with a balloon catheter to produce thrombi on neointima and normal intima. We compared the expression and activity of intimal tissue factor (TF) as well as thrombus size and composition between these femoral arteries. 0.5% cholesterol diet combined with a balloon injury induced macrophage-rich neointima in injured arteries. The whole blood coagulation activity or plasma thrombin generation activity did not differ after consuming the 0.5% cholesterol diet for 4 weeks, and an anti-TF antibody did not affect the measured parameters. TF activities were increased in the neointima/media compared with normal intima/media. Balloon injury induced large platelet-fibrin thrombi on macrophage-rich neointima, whereas small platelet thrombi were produced in normal arteries even under hyperlipidemic conditions. Recombinant human tissue factor pathway inhibitor (25microg/(kgmin)) and argatroban (100microg/(kgmin)), a specific thrombin inhibitor, significantly reduced thrombus formation on induced neointima, but not on normal intima. Thrombin generation mediated by TF in intima contributes to thrombus formation on macrophage-rich neointima, but not on normal intima. The TF content in disrupted atherosclerotic plaques might play a more important role than hyperlipidemia in the development of atherothrombosis.