Prognostic significance of hemostatic parameters in patients with lung cancer

There is a subclinical activation of coagulation and fibrinolysis system in lung cancer. Alterations in hemostatic system are seen frequently in lung cancer correlated with the prognosis of disease. In this prospective study, our purpose was to investigate the prognostic significance of hemostatic markers in patients with lung cancer. The study comprised 58 patients (22 squamous cell carcinoma, 16 adenocarcinoma, 20 small cell carcinoma). There were 55 men (95%)and 3 women (5%) with a mean age of 61 years range (36-74). Plasma level of platelets (PLT), prothrombin time (PT), active partial thromboplastin time (aPTT), antithrombin III (AT III), fibrinogen (F) and D-dimer level were measured before the initiation of any therapy. Patients were followed up for 17 (12-20) months. The median survival was determined as 6.4 months. Three histopathologic groups; squamous cell carcinoma, adenocarcinoma and small cell carcinoma were compared for the hemostatic parameters. There were no statistically significant differences among the histopathologic types for any of the parameters (P > 0.05). Patients were divided into two groups as patients without distant metastasis (stages I,II,III) and with distant metastasis (stage IV). The group with distant metastasis had higher level of D-dimer than the other group (P < 0.05). However, there were no statistically significant differences for D-dimer level between stages IIIB and IV (P > 0.05). Patients having high D-dimer and low AT III level had poor survival in our study. Thus, high level of D-dimer and low AT III level were determined as correlated with short survival (P < 0.05). These results suggest that elevated plasma level of D-dimer and low AT III level might be a sign of poor prognosis in patients with lung cancer.     

非小细胞肺癌患者 D-二聚体、凝血指标和生存预后的相关研究

目的：探讨非小细胞肺癌患者的 D-二聚体、凝血指标与患者生存时间的关系。方法选择承德医学院附属医院2010年1月至2011年3月收治的初治的非小细胞肺癌患者共57例,记录患者治疗前 D-二聚体及凝血指标,对患者进行随访,总随访期限为36个月。对数据进行整理、汇总及统计分析,分别进行单因素生存分析和多因素生存分析。结果单因素生存分析显示 D-二聚体升高、纤维蛋白原升高、凝血酶原时间升高及疾病分期晚是使总生存期缩短的主要因素。采用 Cox 回归模型进行多因素生存分析显示 D-二聚体升高、凝血酶原时间升高及疾病分期晚是非小细胞肺癌患者生存期缩短的独立影响因素。结论 D-二聚体升高、凝血酶原时间升高、疾病分期晚是影响非小细胞肺癌患者总生存期的独立因素。     

老年脓毒症患者内皮及凝血功能的改变

目的 观察老年脓毒症患者内皮及凝血功能指标的变化及其对预后的影响. 方法选取120例老年脓毒症患者和50例健康者,将脓毒症患者按照预后分成生存组84例与死亡组36例.采用Sysmex CA-7000型血液凝固仪免疫法测定血管性血友病冈子(vWF)和D-二聚体水平,发色底物法测定抗凝血酶活性和蛋白C活性.凝固法测定纤维蛋白原(FIB)水平. 结果老年脓毒症患者vWF、D-二聚体水平治疗前、治疗后均高于对照组(P<0.01),抗凝血酶和蛋白C活性低于对照组,差异有统计学意义(P<0.05或0.01),FIB在3组中差异无统计学意义(P>0.05);治疗后死亡组vWF、D-二聚体水平高于生存组(P<0.01),抗凝血酶和蛋白C活性低于生存组(P<0.01),FIB差异无统计学意义(P>0.05);治疗后抗凝血酶和蛋白C活性降低、vWF增高12例,死亡10例(83.3%);上述指标恢复正常39例,死亡仅2例(5.1%),两组比较差异有统计学意义(X~2=26.99,P<0.01). 结论老年脓毒症患者存在内皮损伤和凝血功能异常,内皮及凝血功能指标可预测患者的预后.     

Haemostasis in ischaemic stroke and vascular dementia.

Abnormalities of coagulation and fibrinolysis may play an important role in the pathogenesis of ischaemic stroke and vascular dementia. We aimed to determine whether haemostatic function is altered in acute recent-onset or chronic ischaemic cerebrovascular disease. We studied consecutive patients with ischaemic stroke (n = 74) and vascular dementia (n = 42) compared with healthy controls (n = 40) in a case-control study. The ischaemic stroke group was assessed twice, 3-10 days after the acute stroke and at 1-3 months. Fibrinogen, fibrin D-dimer (marker of fibrin turnover) and von Willebrand factor (vWF) (marker of endothelial disturbance) were elevated acutely (P < 0.0001) and in the convalescent phase after ischaemic stroke (P < 0.0001, P < 0.0001, and P < 0.01 respectively, compared with controls). Similar results were seen in the vascular dementia group. Stepwise multivariate regression analyses showed that cerebrovascular disease correlated independently with fibrinogen (P < 0.001) and fibrin D-dimer levels (P < 0.001), while vWF correlated independently with electrocardiograph evidence of ischaemic heart disease (P = 0.004). Changes between acute and convalescent phases in ischaemic stroke were slightly inconsistent. However, in the acute stage there were tendencies for fibrinogen, D-dimer and vWF to be increased, and factor VIII was significantly higher. Abnormalities of haemostasis, including increased fibrin turnover and endothelial disturbance, are found in both acute and chronic cerebral ischaemia. Many of these patients have co-existent ischaemic heart disease and this may contribute to some of these changes. Acute ischaemic stroke is associated with transient changes in haemostatic factors; however, most abnormalities persist into the convalescent phase, and are also demonstrable in subjects with vascular dementia.     

High-dose busulfan, melphalan and thiotepa as consolidation for non-inflammatory high-risk breast cancer

The purpose of this study was to evaluate the toxicity and efficacy of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) in patients with high-risk non-inflammatory breast cancer defined as stage II disease > or =10 lymph nodes (n = 52) or stage III (n = 69), and prognostic factors for treatment outcome. One hundred and twenty-one patients (median age, 46 years) were treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) (HDC) followed by autologous stem cell infusion (ASCI). One hundred patients were initially treated with surgery followed by standard adjuvant chemotherapy prior to HDC/ASCI. Twenty-one patients with stage III disease had inoperable tumors at diagnosis and were treated with neoadjuvant chemotherapy and surgery before HDC/ASCI. Transplant-related mortality was 6%. The probabilities of event-free survival (EFS) at 3 and 5 years (median follow-up of 36 months) from transplant were, for all patients: 0.62-0.60; stage II: 0.71-0.67: stage III: 0.55-0.55 (for stage III adjuvant and neoadjuvant groups: 0.60-0.60 and 0.42-0.42, respectively). Multivariate analysis did not identify variables associated with poor outcome. The efficacy of Bu/Mel/TT is similar to other HDC regimens reported for patients with high-risk non-inflammatory breast cancer. Bu/Mel/TT has high activity in stage II disease and a moderate benefit in stage III operable tumors.     

Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment.

OBJECTIVE--To determine whether chronic atrial fibrillation is associated with abnormalities in plasma fibrinogen, von Willebrand factor (vWF) (a marker of endothelial disturbance), or fibrin D- dimer (a measure of fibrin turnover); and if so, whether such levels are related to haemodynamic disturbance (enlarged left atrium, poor left ventricular function) or existing treatment with warfarin or aspirin. To investigate the effects of introducing warfarin in patients with atrial fibrillation on fibrinogen and D- dimer levels. DESIGN--Cross sectional population sample controlled study and longitudinal study of patients undergoing anticoagulation. SETTING--District general hospital. SUBJECTS--87 patients (44 men and 43 women of mean (SEM) age 63.0 (1.0)) with chronic atrial fibrillation. At the time of the study, 37 were taking no antithrombotic medication (group 1), 31 were taking warfarin (including two on warfarin and aspirin) (group 2) and 19 were taking aspirin alone (group 3). They were compared with 158 population controls from a random population sample (the second Glasgow monitoring trends and determinants in cardiovascular disease study). As part of clinical treatment warfarin was introduced in 20 patients with chronic atrial fibrillation (14 men and six women of mean (SEM) (range) age 63.9 (2.35 (32-74) years). RESULTS--Plasma fibrinogen remained significantly increased in patients of group 1 (no antithrombotic medication) compared with that of the population controls (median difference 1.23 g/l; 95% confidence interval (CI) 0.88 to 1.62, P < 0.0001). There was also a significant increase in plasma D-dimer levels (median difference 77 ng/ml; 95% CI 38 to 122, P < 0.01) and vWF (median difference 63 IU/dl; 95% CI 38 to 89, P < 0.0001). There was no significant difference in plasma fibrinogen (median difference 0.14 g/l; 95% CI -0.44 to 0.77, P = 0.65) or vWF (median difference 3.5 IU/dl; 95% CI - 41 to 41, P = not significant in patients of group 2 (warfarin treatment) compared with that of patients in group 1. Levels of D-dimer were significantly lower in group 2 (median difference 90 ng/ml, 95% CI 39 to 150, P < 0.0001) than in group 1. There were no significant differences in plasma fibrinogen (median difference 0.08 g/l; 95% CI - 0.52 to 0.77, P = 0.73), D-dimer (median difference - 34 ng/ml; 95% CI - 114 to 21.0, P = 0.25), or vWF (median difference 2%; 95% CI - 35 to 41, P = not significant) levels between patients of groups 1 and 3. There were no significant correlations between the coagulation indices and left atrial volume or ventricular function. There was a significant positive correlation between plasma fibrin D-dimer and vWF levels in patients of groups 1 and 3 (r = 0.52, P < 0.001). There was a significant reduction in median plasma fibrin D-dimer levels at 2 months after the introduction of warfarin (181 ng/ml v 80 ng/ml, P < 0.001), but no effect on plasma fibrinogen. CONCLUSIONS--Increased median plasma fibrinogen and vWF levels were found in patients with chronic atrial fibrillation. Plasma D-dimer levels were also increased in patients with chronic atrial fibrillation not receiving warfarin, suggesting increased intravascular thrombogenesis in such patients. Introduction of warfarin normalised circulating fibrin D- dimer levels, suggesting that warfarin treatment was effective in preventing excessive fibrin turnover, consistent with the antithrombotic effects of warfarin. These results suggest three possible thrombotic markers to assess patients with atrial fibrillation who are at high risk of thrombogenesis; D-dimer also merits assessment as a measure of reduction in thrombotic risk in patients receiving warfarin.     

D-二聚体、纤维蛋白原与肺癌的分期及预后的关系研究

目的分析血浆D-二聚体、纤维蛋白原（fibrinogen,FIB）与肺癌的分期、体力状况评分及预后的关系。方法按分期、有无胸水及远处转移、卡氏及ECOG评分、死亡与否对肺癌患者进行分组,分别测定血浆D-二聚体、FIB水平,分析其在不同分组间的差异。结果 D-二聚体水平在以上不同分组间比较均差异显著。FIB水平在死亡组、存活组及不同卡氏及ECOG评分组间比较差异显著,而在其他分组间比较差异均无统计学意义。结论肺癌患者血浆D-二聚体、FIB水平均与预后相关。D-二聚体是比FIB更敏感的反映肺癌高凝状态的指标。     

Association between blood rheology, thrombosis and cancer survival in patients with gynecologic malignancy

In cancer patients impaired blood rheology in the presence of coagulation activation may reduce blood flow in the vascular microcirculation that favors thrombosis but may also support tumor progression and metastasis. In 451 patients with gynecological cancer and 177 patients with corresponding benign tumor disease preoperatively, during adjuvant treatment, when venous thrombosis (VT) or cancer progression was diagnosed hematocrit (micro centrifuge), hemoglobin, leukocytes, platelets (Coulter Counter); red blood cell (RBC) aggregation (aggr.) during stasis and low shear conditions (MA 1, Myrenne), plasma viscosity (viscosimeter KSPV 1 Fresenius), and fibrinogen (Multifibren Behring Dade) were investigated. One hundred and twelve healthy women served as controls. Preoperatively, mean plasma viscosity (pv) was significantly higher in cancer patients as compared to patients with the corresponding benign tumor disease (breast cancer: n = 261; pv = 1.32 vs. 1.27 mPa s; p = 0.023; ovarian cancer: n = 68; pv = 1.39 vs. 1.31 mPa s; p < 0.001; endometrial cancer: n = 70; pv = 1.37 vs. 1.25 mPa s; p < 0.001; cervical cancer: n = 52; pv = 1.33 vs. 1.26 mPa s; p = 0.004). RBC aggr. was significantly lower in controls compared to the preoperative values in cancer patients but mean (median) values (RBC aggr. stasis < 21) were within the normal range in all. Preoperatively, plasma viscosity was a significant risk factor for the overall survival in ovarian cancer patients (p = 0.02) and for subsequent thrombosis in ovarian (p = 0.02) and cervical cancer patients (p = 0.007). In the multivariate analysis plasma viscosity was an independent prognostic marker for the overall survival of breast cancer patients (r = 99.45; 95% CI: 7.32-980.2; p < 0.0001). An optimized preoperative cut-off value above 1.40 mPa s (Log-Rank-test) was significantly associated with poor outcome in the Kaplan-Mayer survival estimates, even in node-negative breast cancer. In gynecologic cancer patients the combination of an increase in RBC aggregation and plasma viscosity impairs blood-flow-properties and may induce hypoxia in the microcirculation that favors thrombosis, settlement of tumor-cells and thus metastasis. Improvement of blood fluidity and thus oxygen transfer in the tumor-vascular-microcirculation may increase susceptibility of systemic anti-cancer therapy.     

Angiogenic and coagulation-fibrinolysis factors in non Hodgkin's lymphoma

High serum VEGF and bFGF levels are independent prognostic factors of poor prognosis in NHL patients. There is growing evidence that both angiogenesis and haemostatic aberrancies are integral parts of the pathobiology of cancer growth and dissemination. The purpose of the study was: (a) to analyze relations of VEGF and bFGF serum levels, fibrinogen and D-dimer plasma levels with lymphoma Ann Arbor Staging System (AASS) and International Prognostic Index (IPI) and, (b) to evaluate correlations between serum levels of angiogenic cytokines and plasma levels of coagulation-fibrinolysis factors in 52 previously untreated NHL patients included to the study. The control group consisted of 23 healthy volunteers. Serum VEGF, bFGF and plasma D-dimer levels were measured by enzyme-linked immunosorbent assay (ELISA). Plasma levels of fibrinogen were determined on Behring Coagulation System (BCS) equipment. In lymphoma group serum VEGF and bFGF levels were significantly higher than in the control. Differences in concentrations of VEGF, bFGF between II, III and IV stage of disease acc. AASS were not statistically significant. Plasma levels of fibrinogen and D-dimer were elevated in lymphoma patients when compared with the control. Fibrinogen plasma levels were similar in all stages. The D-dimer level was significantly higher in patients with IV stage in comparison to stage II and III. Statistically significant differences of VEGF and bFGF serum levels were observed only between intermediate/high and high risk groups acc. IPI. Fibrinogen plasma levels were significantly higher in high risk group than in low risk group. D-dimer plasma levels were significantly higher in high risk group than in low risk group and low/intermediate group. We observed positive correlation between serum level of VEGF and plasma level of fibrinogen, and between serum level of bFGF and plasma level of fibrinogen. There was also negative correlation between serum level of VEGF and plasma level of D-dimer, and between serum level of bFGF and plasma level of D- dimer. Our study indicates that D-dimer level, but not VEGF, bFGF and fibrinogen correlates with AASS and IPI in NHL patients. Significant correlations between levels of VEGF/bFGF and fibrinogen/D-dimer suggest specific interactions between angiogenic and coagulation-fibrinolysis system.     

Haemostatic derangement in advanced peripheral occlusive arterial disease.

BACKGROUND: Dysbalance of the coagulation and fibrinolysis system was suspected to be a further risk factor for the progression of peripheral occlusive arterial disease (POAD). Reports on disturbed platelet function in advanced disease, however, were contradictory. Therefore, we studied haemostasis parameters and platelet function in symptomatic patients with peripheral arterial disease. METHODS: 60 peripheral arterial disease patients hospitalised for invasive diagnostic procedures were included into this comparative study. Patients were clinically stratified according to the criteria for chronic limb ischemia (grade I: n=36; grade II: n=11; grade III: n=13). Plasma fibrinogen, antithrombin III, von Willebrand factor, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) prothrombin time, and activated partial thromboplastin time were determined using standard methods. We measured flow cytometrically, the platelet activation marker P-selectin on nonstimulated, ADP- and TRAP-6-stimulated platelets. Angiographic data were assessed using the Bollinger score. RESULTS: Plasma levels of the procoagulant proteins fibrinogen (grade I: 3.7/grade II: 3.9/grade m: 4.0 g/l) and vWF (158/156/178%) increased and of antithrombin III (109/103/102%) and the PAI-1/tPA ratio (5.2/5.0/4.1) decreased with progressive disease. Highest platelet activation levels were observed in the CLI grade II subgroup. A significant correlation of disease severity was seen with the ankle-brachial pressure index (p=0.006; r=0.39) and with the Bollinger score (p=0.002; r=-0.41). CONCLUSIONS: Progressive peripheral obstructive arterial disease was associated with platelet hyper-reactivity, haemostatic dysbalance of pro- and anticoagulant proteins, and a counterregulatory increase of fibrinolytic activity. Therapeutic concepts should include these pathogenetic mechanisms.     

Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina

BACKGROUND: Although statin-treatment during the acute phase of unstable coronary syndromes improve the outcome their effects on thrombosis/fibrinolysis system in normocholesterolemic patients admitted with unstable angina remain obscure. We assessed the effects of short-term atorvastatin treatment on thrombotic/fibrinolysis markers in normocholesterolemic in patients with unstable angina. METHODS: Forty-five patients with unstable angina were allocated into two groups to receive atorvastatin 10 mg/day (n = 24) or no statin (n = 21) for 6 weeks. Circulating levels of von Willebrand Factor (vWF), factor V (fV), protein C (prC), tissue plasminogen activator (tPA) and antithrombin III (ATIII) were measured by enzyme linked immunosorbent assay, by the patients admission and at the 1st and 6th week of the study. RESULTS: After 1 week of treatment, a significant increase of ATIII (p < 0.05), fV (p < 0.01) and vWF (p < 0.05) was found in the control group, but not in atorvastatin-treated group. Similarly, at 6 weeks after admission, plasma levels of ATIII were still significantly higher than at baseline in controls (p < 0.05), but not in atorvastatin-treated group. Plasma levels of PrtC were significantly increased in both controls (p < 0.01) and atorvastatin-treated patients (p < 0.05) at 1 week, while remained unaffected in atorvastatin-treated group at 6th week. There was no significant difference in the variations of plasma levels of tPA, PrtS and fVII between the two groups at 1 and 6 weeks after admission. CONCLUSIONS: In normocholesterolemic patients admitted with unstable angina the early administration of atorvastatin, significantly affects von Willebrand factor levels and the expression of liver-derived components of both thrombosis and fibrinolysis system.     

Sequential alterations in haemorheology, endothelial dysfunction, platelet activation and thrombogenesis in relation to prognosis following acute stroke: The West Birmingham Stroke Project.

Abnormalities of haemorheology (plasma viscosity, fibrinogen), endothelial function [von Willebrand factor (vWf)], platelet activation (soluble P-selectin) and thrombogenesis [plasminogen activator inhibitor (PAI), and fibrin D-dimer] are common in cardiovascular disease. We investigated changes in these markers in 86 patients (58 males) presenting with acute stroke (all age < 75 years, with ictus < 12 h), and sequential changes at six time points (baseline on admission, 48 h, 1 week, 2 weeks, 3 months and 6 months following the onset of stroke). Baseline plasma viscosity, haematocrit, fibrinogen, vWf, PAI, soluble P-selectin and fibrin D-dimer levels were increased in the acute stroke patients compared with 35 age-matched and sex-matched controls. Following admission, there were significant increases in haematocrit at 2 weeks, vWf at 48 h and 1 week, fibrinogen at 1 week, PAI at 48 h and 1 and 2 weeks, soluble P-selectin at 48 h, and fibrin D-dimer at 48 h and 1 week following admission. Using univariate 'time to event' analysis, high (> median) mean age (log-rank test, P = 0.0262), diastolic blood pressure (P = 0.01), haematocrit (P = 0.0234), PAI-1 (P = 0.0066) and fibrin D-dimer levels (P = 0.0356) were associated with a shortened event-free survival. Using a multivariate Cox survival analysis, only PAI-1 levels remained an independent predictor of survival (P = 0.0349). We conclude that acute stroke patients have marked baseline abnormalities of haemorheology, endothelial disturbance, thrombogenesis, platelet activation and abnormal fibrinolysis, with further changes over the subsequent follow-up period. Abnormal thrombogenesis and fibrinolysis may significantly influence survival in patients with acute stroke. These changes may have potential implications for the pathogenesis of stroke and its complications, although the possibility remains that we are documenting an acute phase response that previous studies, which included stroke patients with a wide time range since ictus onset, have neglected to consider.     

Long-term behavior of endothelial and coagulation markers in Eisenmenger syndrome.

The long-term behavior of endothelial markers was studied in patients with Eisenmenger syndrome who were subjected to conventional therapy (no vasodilators) and observed for 18 months. Biochemical markers were analyzed comparatively in patients with class II or III symptoms (group 1, n=10) and patients with class IV symptoms (group 2, n=7). Plasma von Willebrand factor antigen (vWF:Ag), thrombomodulin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and D-dimer were determined by immunoenzymatic assay at baseline, and at 6, 12, and 18 months. At baseline, the main clinical difference between groups was a decreased peripheral oxygen saturation in group 2 versus group 1 (77+/-5% and 86+/-4%, respectively, p=0.001). Basal vWF:Ag and t-PA were increased and thrombomodulin was decreased in both groups in comparison with controls (p<0.0001), while D-dimer was increased in group 2 only (p=0.0003). In response to treatment, there was a decrease in vWF:Ag in both groups (19% and 23%, respectively in groups 1 and 2, at 18 months vs. baseline, p<0.0001) and t-PA in group 1 (38% vs. baseline, p=0.0485). Plasma vWF:Ag tended to be higher in group 2 in comparison with group 1 during the whole follow-up. Levels of PAI-1 greater than 38.4 ng/mL (upper 90% limit for normals) and D-dimer greater than 500 ng/mL were detected in individual patients (both groups) during the follow-up period. Thrombomodulin remained decreased in both groups. Thus, severity of symptoms in the Eisenmenger syndrome appears to correlate with low oxygen saturation and higher vWF:Ag levels. Improvement of endothelial dysfunction may occur in response to treatment, although increased risk for thrombosis persists, in view of residual abnormalities.     

Hypercoagulability, high tissue factor and low tissue factor pathway inhibitor levels in severe ovarian hyperstimulation syndrome: possible association with clinical outcome.

During ovarian gonadotrophin stimulation for ovulation induction or in vitro fertilization, a clinical severe ovarian hyperstimulation syndrome (OHSS) may occur. Only few studies have investigated the mechanism responsible for the alterations of the haemostatic system in women affected by severe OHSS. The aim of the present study was to investigate the correlation between the magnitude of ovarian stimulation and the increase in fibrin formation and degradation in severe OHSS. Twenty-five patients (age range 23-43 years) who were hospitalized for severe OHSS, 25 women undergoing in vitro fertilization who did not develop OHSS (case-control group) and 25 healthy age-matched women (healthy control group) were investigated. On the day of admission a number of haemostatic markers, including D-dimer, thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), plasmin-antiplasmin complexes (PAP), tissue factor (TF), tissue factor pathway inhibitor (TFPI) and von Willebrand factor antigen (vWF), were examined. In patients with severe OHSS, TF, D-dimer, TAT, F1 + 2, PAP and vWF antigen plasma levels were significantly higher than those observed both in the case-control group and in healthy controls, whereas TFPI levels were significantly lower (P < 0.005) with respect to both case-controls and healthy controls. D-Dimer levels were related with serum oestradiol levels and oocyte number recovered (r = 0.45, P < 0.001 and r = 0.47, P < 0.001, respectively). D-Dimer and TAT levels were significantly (P < 0.05 and P < 0.005, respectively) higher in OHSS patients with unsuccessful pregnancy outcome (D-dimer, 226.5, 56-1449 ng/ml; TAT, 19.8, 3.1-82.6 microg/l) with respect to those with successful outcome of pregnancy (D-dimer, 145, 29-330 ng/ml; TAT, 5.0, 1.0-19.6 microg/l). Our data indicate that a marked hypercoagulability with alterations of TF and TFPI levels is detectable in patients with severe OHSS and that it is related to the clinical outcome.     

von Willebrand factor independently predicts long-term survival in patients with pulmonary arterial hypertension

OBJECTIVES: We hypothesized that higher plasma levels of von Willebrand factor (vWF) and reduced ristocetin cofactor activity (RCA)/vWF ratios at baseline and follow-up would be associated with an increased risk of death in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Endothelial injury and dysfunction cause increased vWF levels in patients with cardiovascular disease. Increased vWF is associated with a higher risk of death in patients with coronary artery disease, congestive heart failure, and ARDS. In PAH, vWF is elevated and functions abnormally, resulting in reduced platelet binding. The ability of vWF to bind platelets is reflected by RCA. METHODS: We performed a retrospective cohort study of 66 PAH patients who underwent initial evaluation at our center from January 1994 to June 2002. The primary outcome was death or lung transplantation. RESULTS: vWF level was directly associated with Factor VIII activity, RCA, fibrinogen, and prothrombin time (p < or = 0.01). vWF levels at baseline and follow-up were associated with the risk of death (hazard ratio [HR] per 50% increase, 1.4; 95% confidence interval [CI], 1.1 to 1.8 [p = 0.02]; and HR per 50% increase, 1.5; 95% CI, 1.1 to 2.0 [p = 0.011]; n = 48, respectively). RCA/vWF ratios were not associated with outcome. These results were unaffected by adjustment for demographics, baseline hemodynamics, laboratory results, or PAH therapy in multivariate analyses. CONCLUSIONS: Increased vWF levels at baseline and follow-up are associated with worse survival in patients with PAH; however, RCA/vWF ratios are not. The hemostatic effects of vWF do not account for these findings. This suggests that endothelial injury and dysfunction may persist despite treatment and may impact on disease course. Therapies that target endothelial injury may therefore improve outcomes for patients with PAH.     

Plasma von Willebrand factor level as a prognostic indicator of patients with metastatic colorectal carcinoma

AIM: To evaluate the correlations of plasma von Willebrand factor (vWF) level with the distant metastasis and prognosis of patients with colorectal cancer. METHODS: A total of 86 patients with historically confirmed metastatic colorectal cancers receiving treatment at Taipei Veterans General Hospital were enrolled. All patients had measurable metastatic lesions and life expectancies of more than 3 mo. Plasma vWF levels were measured by immuno-turbidimetric assay and compared with results from 40 non-metastatic colorectal cancer patients and 22 healthy controls. Patients with metastatic colorectal cancer were divided into two groups according to serum vWF levels and the differences between these two groups were analyzed using X2 test. Data on age, gender, performance status, location of primary tumor, extent of metastasis, site of metastases, histological differentiation, serum CEA and plasma vWF levels were analyzed to determine association with survival. Survival curves were constructed by Kaplan-Meier product limit method and the data was analyzed using log-rank test on a microcomputer. Multivariate analysis using the Cox's proportional hazards regression model was then performed to determine the independent prognostic indicators among all of the possible variables. RESULTS: Colorectal cancer patients were identified as having significantly higher plasma vWF concentrations than healthy controls (P<0.05). Moreover, higher vWF plasma levels were associated with advanced tumor stage (P<0.05) and the presence of multiple metastases (P=0.014). Patients with lower vWF plasma levels (≤160%) survived significantly longer than those with a higher plasma vWF level (log-rank test, P= 0.0043). By multivariate analysis, plasma vWF levels (P<0.001), the extent of metastasis (P= 0.012), and the performance status (P=0.014) were identified as independent prognostic factors. CONCLUSION: Our data indicates that high plasma vWF concentrations correlate with advanced diseases and significantly poor prognosis of patients with metastatic colorectal carcinoma. It may serve as a potential biological marker of disease progression in these patients.     

Plasma fibrinogen, haemostatic factors and prediction of peripheral arterial disease in the Edinburgh Artery Study.

The role of fibrinogen and other haemostatic factors in prediction of peripheral arterial disease (PAD) has not been established. We examined the associations of plasma fibrinogen, von Willebrand Factor (vWF), tissue plasminogen activator (t-PA) antigen, fibrin D-dimer, and factor VII with the development and clinical progression of PAD. In the Edinburgh Artery Study, 1592 men and women, aged between 55 and 74 years, were followed prospectively over 5 years to detect the onset of PAD, and the deterioration of established PAD. At baseline, 418 individuals had evidence of PAD and 60 (14.4%) subsequently deteriorated. 1080 subjects had no baseline disease, but 59 (5.5%) developed PAD during follow-up. Median levels of fibrinogen and vWF were higher in the group developing disease compared with the group which did not (2.78 g/l versus 2.57 g/l, P< or =0.01; 116 IU/dl versus 104 IU/dl, P< or =0.05; respectively). After adjusting for age and sex, fibrinogen (P< or =0.01) and vWF (P< or =0.05) were significantly associated with the risk of developing PAD. The association between fibrinogen and development of disease remained after adjusting for cardiovascular risk factors and baseline ischaemic heart disease (relative risk, 1.35, 95% confidence interval, 1.05, 1.73; P< or =0.05). None of the haemostatic factors were significantly associated with progression of PAD. In conclusion, plasma fibrinogen levels are related to the future onset of PAD, providing further evidence of a possible role of elevated fibrinogen in the development of atherosclerotic disease.     

Thromboembolic risk in children with nephrotic syndrome.

The in vivo activation of the hemostatic system was evaluated in 14 children (4-13 years old) with nephrotic syndrome at different stages of the disease. The blood platelet count, beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), fibrinogen, the coagulation inhibitors antithrombin III and protein C (ATIII:Ag and PC:Ag), and D-dimers were determined. Platelet number was significantly higher at the onset of the disease than in the next stages (p less than 0.05). beta-TG, PF4 and fibrinogen were significantly increased as compared with controls at the onset (p less than 0.001) and decreased progressively during the course of the disease without reaching the control values. Blood coagulation inhibitors behaved differently; PC was higher in patients than in controls at all stages (p less than 0.05) whereas ATIII values were significantly decreased at the onset (p less than 0.05), but increased during the course the disease (p less than 0.01). No changes were observed in the D-dimer plasma levels. These data suggest that the thrombotic risk in nephrotic syndrome is particularly evident at the onset of the disease, and appears to be due mainly to changes in platelet number and function, and to increased fibrinogen levels rather than to alterations of plasma anticoagulant factors.     

ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. METHODS: The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). RESULTS: Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. CONCLUSIONS: Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.     

Significant elevation of protein C and protein S levels in thrombotic disorders by low dose danazol.

Six patients (three males and three females), mean age 35.2 years (range 31-43 years), with extensive venous thrombosis were studied. Initial laboratory data indicated that all patients had normal antithrombin III (ATIII), four patients had low protein C (PC), three patients had low protein S (PS) and two patients had low plasminogen. Four patients had high fibrinogen and all patients had reduced tissue-type plasminogen activator activity, elevated tissue plasminogen activator inhibitor and low fibrinolytic activity. All patients were treated with danazol, 5-7 mg/kg orally once daily. In all patients there was significant elevation of ATIII, PC, PS, and plasminogen, reduction in plasma fibrinogen and PAI and enhancement of fibrinolysis. During the 12-36 months period of follow-up, there were no symptoms or signs that suggested recurrence of thrombosis. Apart from weight gain of 5-10 kg and disturbed menstrual cycle in two women, no major side effects were seen. These data suggest that danazol is potentially useful therapy that may increase levels of natural anticoagulants in patients with thrombotic illnesses in which ATIII, PC and PS are low or normal. Further studies are needed to confirm these observations.