Vascular access thrombosis is one of the major causes of morbidity in patients maintained on chronic hemodialysis. Thrombophilia has been recognized as a risk factor of vascular access thrombosis. The authors report a case of inherited protein S deficiency associated with vascular access thrombotic events. DNA sequence analysis of the PROS1 gene identified a novel heterozygous nonsense mutation in exon 10 by transition of AAG (lysine) to TAG (stop codon) at codon 473 (c.1417A>T, p.K473X). Results from the study suggest that the inherited protein S deficiency due to a PROS1 gene mutation may cause vascular access thrombosis in hemodialysis patients.
Codon ; Codon, Nonsense ; Exons ; Humans ; Protein S ; Protein S Deficiency ; Renal Dialysis ; Risk Factors ; Sequence Analysis, DNA ; Thrombophilia ; Thrombosis

BACKGROUND/AIMS: This study aimed to investigate the risk factors associated with provoked pulmonary embolism (PE). METHODS: This retrospective cohort study included 237 patients with PE. Patients that had transient risk factors at diagnosis were classified as having provoked PE, with the remaining patients being classified as having unprovoked PE. The baseline clinical characteristics and factors associated with coagulation were compared. We evaluated the risk factors associated with provoked PE. RESULTS: Of the 237 PE patients, 73 (30.8%) had provoked PE. The rate of respiratory failure and infection, as well as the disseminated intravascular coagulation score and ratio of right ventricular diameter to left ventricular diameter were significantly higher in patients with provoked PE than in those with unprovoked PE. The protein and activity levels associated with coagulation, including protein C antigen, protein S antigen, protein S activity, anti-thrombin III antigen, and factor VIII, were significantly lower in patients with provoked PE than in those with unprovoked PE. Multivariate analysis showed that infection (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 7.4) and protein S activity (OR, 0.97; 95% CI, 0.95 to 0.99) were significantly associated with provoked PE. CONCLUSIONS: Protein S activity and presence of infection were important factors associated with provoked PE. We should pay attention to the presence of infection in patients with provoked PE.
Cohort Studies ; Diagnosis ; Disseminated Intravascular Coagulation ; Factor VIII ; Humans ; Multivariate Analysis ; Protein C ; Protein S ; Pulmonary Embolism* ; Respiratory Insufficiency ; Retrospective Studies ; Risk Factors*

PURPOSE: Hyperhomocysteinemia is accepted as an independent risk factor for peripheral arterial disease (PAD). The purpose of this study is to evaluate the correlation between the preoperative plasma homocysteine concentration and restenosis after therapeutic revascularization. METHODS: We retrospectively analyzed the clinical records of 58 consecutive patients (they were confined to Trans Atlantic Inter-Society Consensus [TASC] type C & D) among 103 patients who were diagnosed as having infrainguinal PAD and who were treated with bypass surgery or endovascular surgery from July 2003 to July 2009. We analyzed the effect of several factors such as gender, age, the plasma lipid profile and the protein C, protein S, fibrinogen, C-reactive protein, diabetes mellitus, hypertension, ankle-brachial index (ABI), and homocysteine levels, which are all considered to be risk factors for restenosis. Multivariate and univariate analyses were performed to assess the effect of possible confounders. RESULTS: The subjects were 50 men and 8 women (mean age: 63.8+/-10.9). There were 33 (56.9%) cases of bypass surgery and 25 (43.1%) cases of endovascular surgery. Of them, 19 cases (32.8%) showed restenosis after revascularization. In the patients with restenosis, 18 cases (94.7%) showed a preoperative high plasma homocysteine level and 1 case (5.2%) showed a normal level. A lower ABI and hyperhomocysteinemia were significantly more common in the patients with restenosis (P=0.025, P<0.001). There were no significant differences of the other factors, except for the plasma homocysteine level on multivariate analysis (P=0.001). CONCLUSION: We can regard the preoperative hyperhomocysteinemia level as a predictive marker of restenosis after revascularization. Special attention may need to be given to the patients who have a lower preoperative ABI and hyperhomocysteinemia after revascularization.
Ankle Brachial Index ; C-Reactive Protein ; Consensus ; Diabetes Mellitus ; Female ; Fibrinogen ; Homocysteine ; Humans ; Hyperhomocysteinemia ; Hypertension ; Male ; Multivariate Analysis ; Peripheral Arterial Disease ; Plasma ; Protein C ; Protein S ; Retrospective Studies ; Risk Factors

Deranged expression of cell cycle modulators has been reported to contribute to the development and progression of hepatocellular carcinoma (HCC). However, their expression patterns remain poorly understood in hepatitis B virus (HBV)-related HCC, which constitutes about 65-70% of HCC in Korea. The aims of this study were to evaluate the expressions of G1-S modulators in HBV-related HCCs and dysplastic nodules (DNs), and to correlate with the histopathologic features of HCCs. Immunohistochemical expressions of cyclin D1, cyclin E, p53, p27, p21, p16, Rb, and PCNA proteins were investigated in 80 HCCs and 22 DNs. Cyclin D1 overexpression showed positive relationships with advanced tumor stage, poor differentiation, larger tumor size, microvascular invasion, intrahepatic meta-stasis, no tumor capsule formation, infiltrative growth, aberrant p53 expression, and high PCNA labeling index (LI) of HCC (p<0.05). Aberrant p53 expression showed positive relationship with poor differentiation of HCC (p<0.01). Expression of cyclin D1 or p53 was not observed in DNs. The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05). Cyclin D1 overexpression and aberrant p53 expression could be associated with the progression of HBV-related HCC, and might have a less crucial role in the DN-HCC sequence. In addition, elevated expression of p27 and p16 proteins might have inhibitory action to the intrahepatic metastasis of HBV-related HCC.
Adult ; Aged ; Carcinoma, Hepatocellular/chemistry/etiology/*pathology ; Cyclin D1/*analysis ; Female ; G1 Phase ; Hepatitis B/*complications ; Human ; Immunohistochemistry ; Liver Neoplasms/chemistry/etiology/*pathology ; Male ; Microfilament Proteins/analysis ; Middle Age ; Precancerous Conditions/*virology ; Proliferating Cell Nuclear Antigen/analysis ; Protein p16/analysis ; Protein p53/*analysis ; Retinoblastoma Protein/analysis ; S Phase

BACKGROUND: Pulmonary embolism (PE) is a common clinical problem in the West that is associated with substantial morbidity and mortality. The diagnostic modality has been changed since 2001. This study retrospectively reviewed the PE mortality with the aim of identifying the risk factors associated with mortality since the multidetector computed tomography (MDCT) was introduced. METHODS: We analyzed 105 patients with acute PE proven by multidetector CT or ventilation perfusion scan. The primary outcome measure was the all-cause mortality at 3 months. The prognostic effect of the baseline factors on survival was assessed by multivariate analysis. RESULTS: The main risk factors were prolonged immobilization, stroke, cancer and obesity. Forty nine percent of patients had 3 or more risk factors. The overall mortality at 3 months was 18.1%. Multivariate analysis revealed low diastolic blood pressure and the existence of cancer to be independent factors significantly associated with mortality. Forty two PE patients were examined for the coagulation inhibitors. Four of these patients had a protein C deficiency (9.5%), and 11 had a protein S deficiency (26%). CONCLUSION: PE is an important clinical problem with a high mortality rate. Close monitoring may be necessary in patients with the risk factors.
Blood Pressure ; Hospitals, Teaching ; Humans ; Immobilization ; Multidetector Computed Tomography ; Multivariate Analysis ; Obesity ; Outcome Assessment (Health Care) ; Perfusion ; Prognosis ; Protein C Deficiency ; Protein S Deficiency ; Pulmonary Embolism ; Retrospective Studies ; Risk Factors ; Stroke ; Thrombophilia ; Venous Thrombosis ; Ventilation

OBJECTIVETo assess the value of thrombotic biomarkers in estimation of venous thromboembolism (VTE) risk in cancer patients.

METHODSA total of 1473 cancer patients treated in the Tianjin Medical University General Hospital from 2009 to 201 were selected, including 845 males and 628 females in the age of 56 ± 17 years. The activities of von Willebrand factor antigen (vWF:Ag), factor VII (F VII:A), factor VIII (F VIII:A), antithrombin (AT:A), protein C (PC:A) and protein S (PS:A) were assayed using an ACL TOP 700 blood coagulation analyzer. The level of D-dimer (D-D) was assayed using the Biomerieux Mini Vidas Automated Immunoassay Analyzer. Receiver operating characteristic curve (ROC) was used to analyze the diagnostic performance of the parameters. Cox regression analysis model was applied to evaluate the effect on prognosis, and Kaplan-Meier curve was used to implement the survival analysis.

RESULTSThe levels of vWF:Ag, D-D, and F VIII:A were significantly higher in all the specified tumor groups ( except the other tumor group ) than that of the control groups (P < 0.05). F VIII:A was significantly higher than that in the control group in all tumor groups except the renal carcinoma, prostatic cancer, lymphoma groups and the other tumor group (P < 0.05). The PC:A level was significantly lower in all tumor patients groups than in the control group, except glioma, breast cancer, gastric carcinoma, renal carcinoma and the other tumors groups (P < 0.05). The PS: A level was significantly lower in all tumor groups than in the control group, except the glioma, breast cancer, prostatic cancer, lymphoma and the other tumors groups (P<0.05). The AT: A level was significantly lower in all tumor groups than in the control group (P<0.05). When the optimum cut-off point of vWF:Ag for VTE diagnosis was 192% in the cancer group, the area under ROC curve = 0.828 (95% CI: 0.716 to 0.939). When the optimum cut-off point of D-dimer for VTE diagnosis was 1484 ng/ml in the cancer group, the area under ROC curve = 0.915 (95% confidence interval: 0. 840 to 0.988). When the optimum cut-off point of PC: A for VTE diagnosis was 75.2% in the cancer group, the area under ROC curve = 0.764 (95% confidence interval: 0.630 to 0.898). The Cox analysis showed that age, surgery, chemotherapy and D-dimer were independent risk factors for VTE event within three months in cancer patients. The cumulative probability of VTE was increased significantly in the cancer patients if whose plasma D-dimer level was over the cut-off value.

CONCLUSIONSThe plasma D-dimer level is obviously increased in cancer patients, and there is a relevance to thrombosis risk stratification and VTE cumulative probability. It is with good diagnostic performance, and may be used as an effective marker in estimation of VTE risk within 3 months in cancer patients.

Aged ; Antithrombins ; blood ; Biomarkers ; blood ; Factor VII ; analysis ; Factor VIII ; analysis ; Female ; Fibrin Fibrinogen Degradation Products ; Humans ; Male ; Middle Aged ; Neoplasms ; blood ; Prognosis ; Protein C ; analysis ; Protein S ; analysis ; ROC Curve ; Regression Analysis ; Risk Assessment ; Risk Factors ; Venous Thromboembolism ; etiology ; von Willebrand Factor ; analysis

BACKGROUND: Dysfunctional natural anticoagulant systems enhance intravascular fibrin for mation in disseminated intravascular coagulation (DIC), and plasma levels of natural anti coagulants can be used in the diagnosis and prognosis of DIC. Herein, the diagnostic value of 4 natural anticoagulants was assessed, and the prognostic value of antithrombin and protein C were validated in a large population. METHODS: Part 1 study included 126 patients with clinically suspected DIC and estimated plasma levels of 4 candidate anticoagulant proteins: antithrombin, protein C, protein S, and protein Z. Part 2 comprised 1,846 patients, in whom plasma antithrombin and protein C levels were compared with other well-known DIC markers according to the underlying dis eases. The 28-day mortality rate was used to assess prognostic outcome. RESULTS: Antithrombin and protein C showed higher areas under the ROC curve than pro tein S and protein Z. In part 2 of the study, antithrombin and protein C levels significantly correlated with DIC score, suggesting that these factors are good indicators of DIC severity. Antithrombin and protein C showed significant prognostic power in Kaplan-Meier analyses. In patients with sepsis/severe infection, antithrombin and protein C showed higher hazard ratios than D-dimer. Platelet count showed the highest hazard ratio in patients with hemato logic malignancy. In patients with liver disease, the hazard ratio for antithrombin levels was significantly high. CONCLUSIONS: Decreased plasma anticoagulant levels reflect florid consumption of the phys iologic defense system against DIC-induced hypercoagulation. Plasma antithrombin and protein C levels are powerful prognostic markers of DIC, especially in patients with sepsis/severe infection.
Adult ; Aged ; Anticoagulants/*blood ; Antithrombins/*blood ; Blood Platelets/cytology ; Blood Proteins/analysis ; Disseminated Intravascular Coagulation/complications/*diagnosis/mortality ; Female ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Male ; Middle Aged ; Platelet Count ; Prognosis ; Protein C/*analysis ; Protein S/analysis ; Prothrombin Time ; Regression Analysis ; Sepsis/complications/*diagnosis ; Severity of Illness Index

The retinoblastoma protein (pRb)/cyclin D1/ p16 pathway plays a critical role in controlling the progression from G1 to S phase of the cell cycle. Abnormal expression of the individual components of the pathway has been reported in many human cancers, including the breast. Our aim was to investigate the role of this pathway in tumorigenesis and tumor progression, and to evaluate the value of these oncoproteins as potential prognostic factors in breast cancer. MATERIALS AND METHODS: We examined the significance of the p16, pRb, and cyclin D1 expression in 128 cases of invasive breast carcinomas using immunohistochemistry on formalin fixed, paraffin sections. The results correlated with the survival rate and clinicopathologic variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER) and progesterone receptor (PR) content. The negative finding for nuclear staining for pRb and p16 were defined as abnormal. RESULTS: Abnormal expression of the p16 and pRb were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between the p16 and pRb expressions. There was no association between the p16 staining and any other parameters, including survival rate, cyclin D1, or clinicopathologic variables. Surprisingly, there was a trend for pRb positive tumors to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grades, and with higher ER and PR expressions. CONCLUSION: These findings suggest the p16 may be negatively regulated by the pRb, and that cyclin D1 is involved in the tumor progression in well-differentiated tumors and could be an ER and PR related protein. In a Cox multivariate analysis, the p16, pRb, and cyclin D1 were not independent predictors of patient outcome.
Breast Neoplasms* ; Breast* ; Carcinogenesis ; Carcinoma, Ductal ; Cell Cycle ; Cyclin D1 ; Estrogens ; Formaldehyde ; Humans ; Immunohistochemistry ; Lymph Nodes ; Multivariate Analysis ; Oncogene Proteins ; Paraffin ; Receptors, Progesterone ; Retinoblastoma Protein ; S Phase ; Survival Rate

A 56-yr-old man with lung adenocarcinoma presented with subsegmental pulmonary thrombosis. Platelet count on presentation was 531x10(9)/L. The patient was anticoagulated with subcutaneous low molecular weight heparin (LMWH). Next day, oral anticoagulation was initiated with 5 mg of warfarin once daily with LMWH and LMWH was discontinued at third hospital day. On the third day of oral anticoagulation therapy, he complained of left leg swelling and prolonged painful penile erection of 24 hr-duration. His platelet count reached a nadir 164x10(9)/L at that time, and the patient had a deficiency of protein C and S, with an activity level of 16% and 20% of normal value. Warfarin was stopped and he underwent penile aspiration. The next day, left leg edema and penile erection was disappeared, but penile and glans penis necrosis was started. This case illustrates that processes underlying heparin-induced thrombocytopenia (HIT) may also underlie warfarin-induced skin necrosis.
Adenocarcinoma/complications/diagnosis ; Anticoagulants/*adverse effects ; Heparin/*adverse effects ; Humans ; Lung Neoplasms/complications/diagnosis ; Male ; Middle Aged ; Necrosis ; Penile Erection/drug effects ; Penis/*pathology ; Platelet Count ; Protein C/analysis ; Protein S/analysis ; Pulmonary Artery ; Thrombocytopenia/*chemically induced ; Thrombosis/complications/diagnosis/drug therapy ; Warfarin/*adverse effects

OBJECTIVETo study the enhancing effect of isoflavonoid genistein in irradiation (IR) on prostate DU145 cancer cells.

METHODSProstate cancer cell line DU145 was used in this experiment. Clonogenic assay was applied to compare the survival fractions of DU145 cells after treatments with genistein alone and/or graded IR. DNA electrophoresis and TUNEL method were applied to detect cell apoptosis. Cell cycle was observed using flow cytometry and related protein expressions by immunoblotting.

RESULTClonogenic assay demonstrated that genistein, even at low to medium concentrations, enhanced the radiosensitivity of DU145 cells. After treatments with IR and/or genistein for 24 h, apoptosis was mainly seen with genistein at high concentration and was minimally dependent on IR. Apoptosis also occurred after treatments for 72 h with lower concentrations of genistein, especially when combined with IR. While IR or genistein led to a G2/M cell cycle arrest, combination of them could further increase DU145 cells at G2/M phase. This G2/M arrest was largely maintained at 72 h, and accompanied by increasing apoptosis and hyperdiploid cell populations. Cell-cycle related protein analysis disclosed biphasic changes in cyclin B1, less markedly increased cdc-2 and stably elevated p21(cip1) levels with increasing genistein concentrations.

CONCLUSIONGenistein could enhance the radiosensitivity of DU145 prostate cancer cells. The mechanisms might be involved in the increased apoptosis, prolonged cell cycle arrest and impaired damage repair induced by the combined treatment.

Apoptosis ; drug effects ; radiation effects ; CDC2 Protein Kinase ; analysis ; Cell Line, Tumor ; Cell Survival ; drug effects ; radiation effects ; Cyclin B ; analysis ; Cyclin B1 ; G2 Phase ; drug effects ; radiation effects ; Genistein ; pharmacology ; Humans ; Male ; Prostatic Neoplasms ; pathology ; radiotherapy ; Radiation-Sensitizing Agents ; pharmacology ; S Phase ; drug effects ; radiation effects