Tamoxifen induces resistance to activated protein C

Introduction

The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.

Materials and Methods

Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.

Results

APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.

Conclusions

This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.     

The lowest VE/VCO2 ratio best identifies chronic thromboembolic pulmonary hypertension

Introduction

The natural history of acute pulmonary embolism (PE) under treatment is about a gradual resolution of the thrombi, and uncommonly, the development of chronic thromboembolic pulmonary hypertension (CTEPH). We hypothesized that ventilatory efficiency parameters during cardiopulmonary exercise testing (CPET) may be able to monitor the process and predict CTEPH.

Methods

15 patients rehabilitated from acute PE (total resolution of thrombi), 44 patients with chronic PE (with residual thrombi), 66 patients with CTEPH, and 36 sedentary healthy controls performed incremental CPET.

Results

The lowest VE/VCO₂ was higher in CTEPH patients than that in chronic PE and rehabilitated patients (43.4 L/min vs 29.9 L/min vs 27.1 L/min, p < 0.005). The VE/VCO₂ slope (48.4 L/min/L/min vs 29.9 L/min/L/min vs 28.0 L/min/L/min, p < 0.005) and oxygen uptake efficiency plateau (OUEP) (37.1 L/min vs 27.0 L/min vs 25.2 L/min, p < 0.005) had the similar changes. In logistic regression analysis, the lowest VE/VCO₂ ≥ 34.35 L/min was the best predictor of CTEPH (OR 159.0, 95% CI 36.0-702.3, p < 0.001). The lowest VE/VCO₂ was higher in chronic PE patients compared with the controls (29.9 L/min vs 26.5 L/min, p < 0.05), but there was no difference between the rehabilitated patients and the controls. In multiple linear regression analysis, the percentage of vascular obstruction by ventilation-perfusion lung scanning (PVO) was the most significant independent predictor for indices of ventilatory efficiency in chronic PE and rehabilitated patients.

Conclusions

CTEPH is associated with weakened ventilatory efficiency. The lowest VE/VCO2 ratio has the best capability to predict CTEPH. Ventilatory inefficiency improves along with recovery of acute PE.     

Echocardiographic evolution of pulmonary artery pressure after acute pulmonary embolism. Results from IPER registry

Aims

The aim of the study is to describe the course of the echocardiographically measured pulmonary artery systolic pressure (PAsP) in a series of patients included in the Italian Pulmonary Embolism Registry (IPER).

Methods

Patients with confirmed PE received an echo-Doppler evaluation within 24 hours from hospital admission and after one year. Pulmonary hypertension (PH) was considered “likely” , “possible” or “unlikely” with a right ventricular-right atrial (RV-RA) pressure gradient > 45 mm Hg, between 32 and 45 mm Hg and ≤ 31 mm Hg and no additional echocardiographic variables suggestive of PH, respectively.

Results

We studied 286 patients (169 females and 117 males, mean age 67 ± 15; mean follow-up 387 ± 45 days): 240 had a baseline tricuspid regurgitation (TR) and a RV-RA gradient of variable degree. PH was considered likely, unlikely and possible in 97, 93 and 50 patients respectively. At FU echocardiography, 6 patients (2.1%) had a likely PH and all of them were part of the group of 97 patients with a baseline likely PH; 24 patients (8.4%) had a possible PH, and 67% of them had an initial likely PH. No patients with a baseline unlikely PH or without TR developed a follow-up PH (both likely or possible). The probability to show a likely PH at FU echocardiography for patients with a baseline RV-RA gradient > 45 mm Hg was 6.2%, while the probability not to have a likely PH for patients with a baseline RV-RA gradient ≤ 45 mm Hg was 100%.

Conclusion

In our study population of patients with acute PE, we observed that those presenting with a baseline echocardiographic RV-RA pressure gradient ≤ 45 mm Hg were completely free from a likely PH after 1-year.     

华蟾素对SD大鼠膀胱肿瘤的抑制作用

目的 研究华蟾素对SD大鼠膀胱肿瘤的治疗作用.方法 50只SD大鼠按随机分为对照组和实验组,实验组40只大鼠膀胱灌注N-甲基-N-亚硝基脲(N-methyl-N-nitrosourea,MUN),每3周1次,共4次;于第14周将实验组大鼠随机分为生理盐水组(膀胱灌注生理盐水)、丝裂霉素组(5 mkg)、低浓度华蟾素组(5 mg/kg)及高浓度华蟾素组(20 mg/kg),每周灌注1次,连续灌注5次,计算抑瘤率,TUNEL法检测肿瘤细胞的凋亡情况.结果 MNU膀胱灌注成功建立膀胱肿瘤动物模型,以膀胱肿瘤质量计算高浓度华蟾素组的抑瘤率为76.7％,高浓度华蟾素组抑瘤率较丝裂霉素组及低浓度华蟾素组高;TUNEL法检测高浓度华蟾素组AI值为(24.21±1.24)％,较其他各组AI值明显增高,提示高浓度华蟾素组凋亡指数高于丝裂霉素及低浓度华蟾素组.结论 华蟾素对膀胱肿瘤有抑制生长、促进凋亡的作用,且高浓度时抑瘤作用及促凋亡作用较强.     

Increased activation of blood coagulation in pregnant women with the Factor V Leiden mutation

Background

The risk of venous thromboembolism is enhanced in pregnant carriers of the Factor V Leiden mutation. The primary aim of the study was to compare prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels in pregnant Factor V Leiden mutation carriers with those in non-carriers. Secondary aims were to evaluate whether these biomarkers could predict placenta-mediated complications or venous thromboembolism, and to study blood coagulation after caesarean section with thromboprophylaxis and after vaginal delivery without thromboprophylaxis.

Material/Methods

Prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels were studied longitudinally in 476 carriers with singleton pregnancies from gestational weeks 23–25 until 8–10 weeks postpartum.

Results

Prothrombin fragments 1 + 2 and D-dimer levels gradually increased during pregnancy. D-dimer levels were higher in carriers, both during pregnancy and puerperium, compared to non-carriers. D-dimer levels above 0.5 mg/l were found in about 30% and 20% of the heterozygous carriers at 4–5 and 8–10 weeks postpartum, respectively. Soluble fibrin levels were mainly unchanged during pregnancy, with no difference between carriers and non-carriers. Biomarker levels were similar in carriers with uncomplicated and complicated pregnancies.

Conclusion

Higher D-dimer levels indicate increased blood coagulation and fibrinolysis activity in carriers. The high proportion of carriers with D-dimer levels exceeding 0.5 mg/l postpartum must be considered when assessing the probability of venous thromboembolism. Large overlaps in biomarker levels in normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors. Thromboprophylaxis following caesarean section may prevent increased activation of blood coagulation.     

Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.