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Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use
American Journal of Hematology
Abstract
The results of studies investigating the relationship of smoking with venous thrombosis are inconsistent. Therefore, in the MEGA study, a large population-based case-control study, we evaluated smoking as a risk factor for venous thrombosis and the joint effect with oral contraceptive use and the factor V Leiden mutation. Consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. Partners of patients were asked to participate and additional controls were recruited using a random digit dialing method. Participants completed a standardized questionnaire. Individuals with known malignancies were excluded from the analyses, leaving a total of 3,989 patients and 4,900 controls. Current and former smoking resulted in a moderately increased risk of venous thrombosis (odds ratio (OR)(current) 1.43, 95% confidence interval (CI95) 1.28-1.60, OR(former) 1.23, CI95 1.09-1.38) compared with nonsmoking. Adjustment for fibrinogen levels did not substantially change these risk estimates. A high number of pack-years resulted in the highest risk among young current smokers (OR(>or=20 pack-years) 4.30, CI95 2.59-7.14) compared with young nonsmokers. Women who were current smokers and used oral contraceptives had an 8.8-fold higher risk (OR 8.79, CI95 5.73-13.49) than nonsmoking women who did not use oral contraceptives. Relative to nonsmoking noncarriers, the joint effect of factor V Leiden and current smoking led to a 5.0-fold increased risk; for the prothrombin 20210A mutation this was a 6.0-fold increased risk. In conclusion, smoking appears to be a risk factor for venous thrombosis with the greatest relative effect among young women using oral contraceptives.
... [4][5][6][7] Furthermore, several cardiovascular risk factors have been associated with the risk of VTE in young and middle-aged populations, albeit results were often inconsistent. Some studies reported a positive association between obesity, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] smoking, 8,9,12,15,[24][25][26][27][28] hypertension, 15 and diabetes, 29,30 and the risk of VTE. However, the conclusions of other studies varied from no association for smoking, 19,21,31,32 alcohol intake, 9,19,21 hypertension, 26 systolic or diastolic blood pressure, 21,33 and diabetes 26,34 to an inverse association for alcohol intake, 35 systolic and diastolic blood pressure, 12,26 and the risk of VTE. ...
... In our study, we considered the influence of statin use on the risk estimates of cardiovascular risk factors and we further adjusted for statin use in our model, but the results only marginally changed.With regard to the combined effect of a genetic predisposition and the presence of a cardiovascular risk factor, we observed that, in the presence of a genetic predisposition, being in the top 50% of the distribution of height and weight could further increase the risk of VTE albeit confidence intervals overlapped. Several studies investigated the combined effect of genetic markers and cardiovascular risk factors in young and middle-aged population6,16,28,36,40,41,43,56 and they showed that smoking and obesity could further increase the risk of VTE caused by FVL or prothrombin mutations16,28,36,40,41,56 and that obesity further increased the risk of VTE in individuals with non-O blood type.6,36 Horvei et al. found that prothrombotic genotypes did not yield excess risk of VTE in taller people,43 in contrast with our results. ...
... In our study, we considered the influence of statin use on the risk estimates of cardiovascular risk factors and we further adjusted for statin use in our model, but the results only marginally changed.With regard to the combined effect of a genetic predisposition and the presence of a cardiovascular risk factor, we observed that, in the presence of a genetic predisposition, being in the top 50% of the distribution of height and weight could further increase the risk of VTE albeit confidence intervals overlapped. Several studies investigated the combined effect of genetic markers and cardiovascular risk factors in young and middle-aged population6,16,28,36,40,41,43,56 and they showed that smoking and obesity could further increase the risk of VTE caused by FVL or prothrombin mutations16,28,36,40,41,56 and that obesity further increased the risk of VTE in individuals with non-O blood type.6,36 Horvei et al. found that prothrombotic genotypes did not yield excess risk of VTE in taller people,43 in contrast with our results. ...
Background:
The preponderance of the evidence supports no association between traditional cardiovascular risk factors and venous thromboembolism (VTE), other than obesity. There are limited data in older people.
Objectives:
To investigate whether cardiovascular risk factors (body mass index, smoking, alcohol intake, hypertension, and diabetes) are associated with the risk of VTE in elderly and to assess the combined effect between cardiovascular risk factors and genetic risk factors for VTE (factor V Leiden/prothrombin 20210A, positive family history of VTE, and non-O blood group).
Methods:
The Age and Thrombosis, Acquired and Genetic risk factors in the Elderly study is a multicenter case-control study performed in Vermont, USA and Leiden, the Netherlands, comprising 401 cases with first VTE and 431 control subjects, all aged ≥70 years. To assess the risk of VTE, odds ratios (OR) with 95% confidence intervals (CIs) were calculated, adjusting for potential confounders.
Results:
Both height and weight were positively associated with VTE risk: the ORs were 2.2 (95% CI, 1.2-3.9) and 1.5 (95% CI, 1.0-2.4) in the top quartile for height and weight separately. This risk was more pronounced for unprovoked VTE. Smoking, alcohol intake, and diabetes were not associated with VTE. Higher systolic and diastolic blood pressure and hypertension were associated with a decreased risk of VTE. In the presence of a genetic predisposition, height and weight further increased the risk of VTE.
Conclusions:
In the elderly, height and weight are positively associated with the risk of VTE. With genetic predisposition, higher levels of height and weight further increase the risk of VTE.
... Individual risk factors (RF, risk ratio, RR) for TED development used for calculations were taken from studies from the Czech Republic or Central Europe. Where several studies reported various values, mean values were used for calculation [21][22][23][24][25]. ...
... The risk of a TED event is up to 35× higher (mean value among studies 27.5×) than in the general population in women using OCs and up to 100× (mean 90×) higher in FV Leiden heterozygotes and homozygotes using OC, respectively [22,23]. As the FV Leiden heterozygote:homozygote ratio in the Czech population is approximately 30:1 [24], we can calculate with a weighted mean of the risk factor being 29.5. ...
... As the FV Leiden heterozygote:homozygote ratio in the Czech population is approximately 30:1 [24], we can calculate with a weighted mean of the risk factor being 29.5. The risk in women using OC with FII mutation is 16x increased compared to the general population [22]. ...
Background:
Thrombophilic mutations in genes for factor V Leiden and factor II prothrombin are among the most important risk factors for developing the thromboembolic disease (TED), along with the use of oral contraceptives (OCs) or smoking.
Aim:
This study aimed to investigate the occurrence of risk factors in young women using droplet digital PCR (ddPCR) and, based on the results of this investigation, to perform a cost-benefit analysis of ddPCR-based screening in young women starting to take OCs compared to the treatment costs of patients who develop preventable TED in the Czech Republic.
Methods:
In this cross-sectional study, female university students filled in a questionnaire and provided a blood sample for DNA isolation and ddPCR analysis of both aforementioned genetic risk factors. The results, along with data from literature and web search, were used for cost-benefit analysis valid for the Czech Republic.
Results:
Out of 148 participants, 30 (20%) were smokers and 49 (33%) took OCs. A mutation was confirmed in 6 women (4.1%) in the factor V gene and in 3 women (2%) in the factor II gene, respectively. A model calculation on a cohort of 50,000 women starting to use contraceptives in the Czech Republic every year showed that at maximum compliance, (i.e., non-use of OC and smoking cessation), screening could prevent 68 cases of TED over the course of the mean period of OC use (5.7 years). Economically, the costs of testing in this cohort (2.25 mil. USD) would be significantly lower than prevented treatment costs (16 mil. USD at maximum compliance); the cost-benefit break-even point would be at 14.1% compliance.
Conclusion:
The cost-benefit analysis based on our results indicates that screening for factor V Leiden and factor II prothrombin in young women before starting to use OCs would, in the conditions of the Czech Republic, likely be highly economically effective.
... Transdermal estrogen formulations used for HRT in postmenopausal women do not seem to be associated with a significant increase in the VTE risk (12,(14)(15)(16) and had showed a low thrombogenic profile in AMAB trans people, although there are no head-to-head studies with other estrogen formulations (17,18). However, thrombophilia, smoking, obesity, age, major surgery and fractures are well-recognized risk factors in the general population and could contribute, alone or in combination, to promote VTE in COC and HRT users (19)(20)(21)(22). ...
... A number of factors could contribute to the variable VTE risk in transgender people undergoing gender affirming treatment, including the type of estrogen and the route of administration, age at the estrogen therapy onset, length of therapy, concomitant conditions such as smoking, obesity, thrombophilia and comorbidities (16,(20)(21)(22)(54)(55)(56). In the present study, metaregression analyses showed no significant relationship of VTE with BMI, smoking, diagnosis of T2DM, dyslipidemia and hypertension, albeit with the due caution this subject deserves due to the lack of information about these variables in many studies ( Table 1 and Supplementary Table 3). ...
... In the present study, metaregression analyses showed no significant relationship of VTE with BMI, smoking, diagnosis of T2DM, dyslipidemia and hypertension, albeit with the due caution this subject deserves due to the lack of information about these variables in many studies ( Table 1 and Supplementary Table 3). Indeed, it is known that obesity increases the risk of VTE in cisgender women using COCs (21) and the combination of COCs and smoking could exert a synergistic effect (22). Interestingly, consistent with our findings, in the recent systematic review by Kotamarty et al. (24), although AMAB trans people exhibited a lower BMI and an almost 2-fold higher prevalence of smoking compared to cisgender women, these variables were not correlated with the risk of VTE. ...
Background
Although venous thromboembolism (VTE) is a recognized side effect of some formulations of estrogen therapy, its impact in transgender people remains uncertain. The aim of this study was to define pooled prevalence estimate and correlates of VTE in Assigned Males at Birth (AMAB) trans people undergoing gender affirming hormone therapy.
Methods
A thorough search of MEDLINE, COCHRANE LIBRARY, SCOPUS and WEB OF SCIENCE databases was carried out to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effects models and the between-study heterogeneity was assessed by the Cochrane’s Q and I².
Results
The eighteen studies included gave information about 11,542 AMAB undergoing gender affirming hormone therapy. The pooled prevalence of VTE was 2% (95%CI:1-3%), with a large heterogeneity (I2 = 89.18%, P<0.0001). Trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimate. At the meta-regression analysis, a higher prevalence of VTE was significantly associated with an older age (S=0.0063; 95%CI:0.0022,0.0104, P=0.0027) and a longer length of estrogen therapy (S=0.0011; 95%CI:0.0006,0.0016, P<0.0001). When, according to the meta-regression results, the analysis was restricted to series with a mean age ≥37.5 years, the prevalence estimate for VTE increased up to 3% (95%CI:0-5%), but with persistence of a large heterogeneity (I2 = 88,2%, P<0.0001); studies on younger participants (<37.5 years) collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-2%) with no heterogeneity (I² = 0%, P=0.97). Prevalence estimate for VTE in series with a mean length of estrogen therapy ≥53 months was 1% (95%CI:0-3%), with persistent significant heterogeneity (I2 = 84,8%, P=0.0006); studies on participants subjected to a shorter length of estrogen therapy (<53 months), collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-3%) with no heterogeneity (I2 = 0%, P=0.76).
Conclusions
The overall rate of VTE in AMAB trans people undergoing gender affirming hormone therapy was 2%. In AMAB population with <37.5 years undergoing estrogen therapy for less than 53 months, the risk of VTE appears to be negligible. Further studies are warranted to assess whether different types and administration routes of estrogen therapy could decrease the VTE risk in AMAB trans people over 37.5 years subjected to long-term therapy.
Systematic Review Registration
[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021229916].
... Several studies have shown an inverse correlation between smoking and laboratory hemostasis tests as well as bleeding time [15][16][17]. These results translate clinically to an increased incidence of thrombotic events in smokers such as myocardial infarction [18], stroke [19], venous thrombosis and its feared subsequent complication of pulmonary embolism [20,21]. However, we found no data in the literature concerning the use of ACT after UFH administration to assess the procoagulant state of smokers. ...
... Procoagulant status in smokers is well known as shown by an increased incidence of thrombotic events in smokers such as myocardial infarction [18], stroke [19], venous thrombosis/pulmonary embolism [20,21]. Multiple mechanisms have been proposed to explain a smoking-induced prothrombotic status such as endothelial dysfunction [29], increased oxidative stress [17], increased inflammatory parameters [30], and hemostatic dysfunction. ...
Background:
During percutaneous transluminal coronary angioplasty (PTCA), activated clotting time (ACT) measurements are recommended to attest a correct anticoagulation level and, if needed, to administer further unfractionated heparin (UFH) to obtain a therapeutic ACT value. Our clinical routine led us to observe that smokers had lower ACT values after standardized UFH administration during PTCA. Procoagulant status in smokers is well documented.
Objectives:
To determine whether tobacco negatively affects UFH anticoagulation during PTCA when evaluated by ACT.
Methods:
The ACT-TOBACCO trial is a single-center, noninterventional, prospective study. The primary end point is the comparison of ACT values after standardized UFH administration between active smokers and nonsmokers (active smoker group vs nonsmoker group) requiring coronary angiography followed by PTCA. The main secondary end points include ACT comparison after the first and second standardized UFH administration according to the patient's smoking status (active, ex-, or nonsmoker) and the clinical presentation of ischemic cardiomyopathy: stable (silent ischemia or stable angina) or unstable (unstable angina or acute coronary syndrome without or with ST-segment elevation).
Conclusions:
To the best of our knowledge, ACT values during PTCA between smokers and nonsmokers have not previously been compared. As current PTCA procedures increase in complexity and duration, the understanding of procoagulant risk factors such as smoking and the need for reliable anticoagulation monitoring becomes essential to balance hemorrhagic risk against thrombotic risk.
... Although smoking alone may not prevent you from getting pregnant, it can significantly harm your chances. Sadly, women who smoke are twice as likely to be infertile as non-smokers [38][39][40]. It is against this backdrop that this study attempts to investigate the influences of smoking and contraception on women's ability to become pregnant in Ghana by specifically assessing if smoking influences women's ability to become pregnant in Ghana and analysing whether contraception predicts women's ability to become pregnant in Ghana. ...
Background: Women currently using hormonal contraceptive are more likely to smoke. It appeared the link between smoking and the lungs is well-known,
but the link between smoking, contraception and women’s ability to become pregnant is less.
Objective: The study aimed at investigating the influences of smoking and contraception on women’s ability to become pregnant in Ghana.
Methods: Data were extracted from the 2022 DHS. Frequency distribution and binary logistic regression were used to analyse the data. The sample was
34663. The ethical clearance to conduct the 2022GDHS was taken from both Ghana Health Service Ethical Review Committee and ICF Institutional
Review Board. The frequency distribution was used to summarise socio-demographic characteristics of the participants. The Pearson’s chi-squared test
of independence was used to test the hypotheses postulated in the study to either confirm or reject the null hypothesis. The binary logistic regression was
used to identify from the various explanatory variables thus, smoking and contraception those that are related to women’s ability to become pregnant.
Results: The study revealed that more than ninety-nine per cent (99.2%) of the participants do not smoke cigarettes. It was revealed that more than sixty
per cent (66.2%) of the participants were currently not using any contraceptive method. Frequently smoking cigarettes every day was statistically significant
related to women’s ability to become pregnant at p<0.001, (OR=5.176, 95%CI ([2.744-9.764]). Frequently uses other type of tobacco every day as statistically
significant at P=0.006, (OR=0.057, 95%CI [0.007-0.445]).
Conclusions: The study recommends that laws and policies should be enacted to support and ensure comprehensive contraceptive information and services
dissemination to all segments of the population especially disadvantaged and marginalised populations in their access to these services.
... Both were considered very important and frequently taken into account, in line with previous studies reporting an 11.63-fold increased risk of VTE in overweight users and a 23.78-fold increase in obese users versus those with a normal BMI. 31 Several studies regarding smokers' status report an 8.8-fold increased risk for smokers using OC compared with neversmokers not using OC. 32 Surprisingly, blood pressure was rarely evaluated, although considered very important. The participants highlighted that blood pressure should always be evaluated before choosing an OC, as COC are contraindicated for users with high blood pressure. ...
Objectives: This study aimed to develop an anamnesis checklist for oral contraceptive (OC) choice focused on their safety profile and associated risk factors.
Study Design: This study involved eight health care professionals in Spain, including six gynecologists and two internists, selected for their expertise in contraception counseling. We employed the design-thinking process, structured in five phases: empathizing with patients’ needs, defining key areas of impact, devising innovative solutions, prototyping ideas into testable proposals, and validating prototypes. This process involved an analysis of the available literature, online discussions, and an online survey to evaluate importance and frequency of variables in anamnesis. Medians were computed for each variable, and the study group collaboratively determined the variables to include in the anamnesis checklist.
Results: Women must be informed about contraceptive options, according to health care professionals. Body mass index, smoking status, blood pressure, and personal history were identified and prioritized as variables to consider during OC counseling. Participants emphasized the need to individualize the treatment, highlightling the safety profile of progestin-only pills over OCs due to the lack of increased venous thromboembolism risk.
Conclusions: The study emphasizes the importance of an anamnesis prior to prescribing an oral hormonal contraceptive, as well as the most relevant risk factors that should be analyzed. A checklist was developed to facilitate safe OC prescribing.
... Similarly, Arul et al. [15] reported a case of splenic infarction secondary to celiac thrombosis in a young female on OCP. Additionally, smoking increases the thrombotic risk in the female population in comparison to the male population, and there exists a synergistic effect between smoking and oral contraceptive use in increasing the risk of thrombosis [16]. Tzankova et al. reported that in women who are smokers and on OCPs the risk of venous thromboembolisms and their complications, such as pulmonary embolisms, are substantially increased [17]. ...
Introduction
Accessory spleens are a common anatomical variant, consisting of ectopic splenic tissue present in different locations in the peritoneal cavity. Typically asymptomatic, the presence of these tissue grows to be of clinical importance when complicated by infarction, rupture, or torsion.
Presentation of case
We report the case of a 36-year-old female that presented to the Emergency Department for diffuse abdominal pain and was found to have a partially ruptured splenule secondary to a venous infarct on abdominal computed tomography scan. The patient was admitted to the hospital for pain management and further workup. Her hospital stay was uncomplicated with complete resolution of symptoms after 5 days.
Discussion
The usually asymptomatic accessory spleen can present in case of infarction with vague symptoms like abdominal pain, nausea, or vomiting. It is triggered by conditions such hematologic disorders, embolic disorders, vascular disorders, and trauma. Oral contraceptive pills increase thrombosis risk by affecting coagulation factors, making them a potential cause of infarction. Diagnosis typically involves CT imaging, and treatment ranges from supportive care to surgical intervention.
Conclusion
Accessory spleen infarction, although rare, is a diagnosis that should be considered in the assessment of a patient presenting to the emergency with acute abdominal pain.
... That is, the combined risk of smoking and using those contraceptives for acute myocardial infarction and venous thrombosis is larger than simply adding the effects of each of the behaviors on their own. 14 In the Netherlands, 56% of women who use contraceptives use those that contain ethinylestradiol. This makes women who smoke and use contraception a relevant target group for health interventions. ...
Background
Smoking while using contraception containing ethinylestradiol increases the risk of cardiovascular diseases. Therefore, it is especially important to stimulate women who use these contraceptives to quit smoking.
Objectives
This study aimed to examine the role of risk perception and coping in relation to the intention of these women to quit smoking, using the Protection Motivation Theory as the theoretical foundation.
Design
This was an explanatory sequential mixed-methods design.
Methods
An online survey (n = 68) was used to examine the relationship among risk perception, coping assessment, and intention to quit smoking. After that 15 in-depth semi-structured interviews were conducted to understand how women appraised risk and coping strategies during their quit attempt(s).
Results
Results from the survey showed that risk perception induces the intention to quit smoking. More specifically, perceived vulnerability appeared to be a significant predictor. The interviews showed that women were largely unfamiliar with the combined risks surrounding smoking and contraception use but acknowledged the risks of smoking. In the survey, women seemed to perceive themselves as self-efficacious. However, interview participants mentioned that they encountered many difficulties.
Conclusion
Based on these findings, we conclude women are largely unaware of the synergetic risk of contraception use and smoking. Stimulating risk perception and knowledge might help women to create the intention to quit smoking. However, to turn this intention into behavior, providing women with concrete tools to assist them might successfully sustain their quit attempt.
... for hypertension [20]. In a large, population-based case-control study [Multiple Environmental and Genetic Assessment (MEGA) study], the relative risk of venous thromboembolism was determined to be 1.42 (95% CI 1.28-1.58) in smokers and 1.23 (95% CI 1.10-1.37) in former smokers, compared to the risk in individuals who had never smoked [21]. In our study, we did not evaluate patient BMI. ...
Background
Thromboembolic events are a well-recognized cause of in-hospital deaths of patients with infectious diseases. However, thromboembolic events in patients with scrub typhus, caused by Orientia tsutsugamushi have rarely been reported. This study aimed to assess risk factors associated with thromboembolic events in patients with scrub typhus.
Methods
All 93 scrub typhus patients’ diagnoses were confirmed serologically or by positive nested polymerase chain reaction (PCR). The clinical and laboratory findings from 12 scrub typhus patients with thromboembolic events and 81 scrub typhus patients with nonthromboembolic events were retrospectively studied. To determine the factors implicated in thromboembolic events, we performed multivariate logistic regression analysis using the six independent factors identified by the univariate analysis.
Findings
The mean age of the patients in the thromboembolic group was 76.4 years (median, 76 years), and in nonthromboembolic group it was 64.6 years (median, 65 years) (P<0·001). Thromboembolic events were observed in 12 patients. These events included acute coronary syndrome (n = 5), acute limb ischemia (n = 4), ischemic stroke (n = 1), deep vein thrombosis combined with pulmonary thromboembolism (n = 1), and left common iliac artery aneurysm with a thrombus (n = 1). According to multivariate analysis, the following four factors were significantly associated with the thromboembolic events: 1) treatment with rifampin (OR = 57.63; P = 0.039; CI 1.230–2700.27)., 2) Taguchi genotype (OR = 41.5; P = 0.028; CI 1.5–1154.6), 3) atrial fibrillation (OR = 9.4; P = 0.034; CI 1.2–74.0), and 4) age (OR = 1.1; P = 0.046; CI 1.0–1.3).
Conclusions
Our study suggests that clinicians should be cautious when managing patients with scrub typhus to avoid the development of thromboembolic events, especially in patients with risk factors such as treatment with rifampin, Taguchi genotype, atrial fibrillation, and advanced age.
... Smoking was observed in 7.3% of adults, mostly males in the same age group. These findings are compared with national and regional data, showing variations in prevalence due to sampling methods and sociodemographic factors [33][34][35][36][37][38]. ...
Cerebrocardiovascular diseases are a major global public health concern, significantly impacting morbidity, mortality, and posing substantial socio-economic challenges. In Cabo Verde, non-communicable diseases have become the leading causes of morbidity and mortality. This study aimed to estimate the prevalence of risk factors for cerebrocardiovascular diseases and their association with cardiac electrical alterations in adults on Santiago Island, Cabo Verde. A cross-sectional population-based study using simple random sampling was conducted on individuals over 18 years of age. The sample size of 599 was based on Santiago Island’s 2021 population projection. Data collection occurred in October and November 2021, involving questionnaires on risk factors and cerebrocardiovascular diseases; blood pressure assessments; and capillary blood glucose measurements. The sample was predominantly female, with the 18–27 age group being the largest. Key risk factors included physical inactivity (65.1%), BMI ≥ 25 kg/m² (42.6%), hypertension (32.6%), and family history of cerebrocardiovascular diseases (19.9%). Other factors were alcoholism (14.4%), hypercholesterolemia (8.3%), smoking (7.3%), diabetes (4.5%), and hypertriglyceridemia (1.3%). Notably, 9.3% had no risk factors, 27.5% had one, 36.2% had two, and 26.9% had three or more. There is a high prevalence of risk factors for cerebrocardiovascular diseases on Santiago Island, particularly among females.
... Sí es cierto que, al igual que lo reportado por otros autores, observan un mayor riesgo en pacientes de edad avanzada, con antecedentes de trombosis o que reciben TPO-RA durante mucho tiempo. Este riesgo en el contexto de la PTI es lógico si se consideran los aspectos epidemiológicos referidos al inicio y que el riesgo de ETEV aumenta con la edad, en especial por la mayor comorbilidad y otros factores de riesgo trombótico en este grupo de población 28,29 . Recientemente el RIETE (Registro Informatizado de Pacientes con Enfermedad TromboEmbólica) 30 reportaba que, de los 100.000 pacientes con enfermedad tromboembólica confirmada incluidos en el registro entre 2001 y 2021, el 47,9% eran de edad avanzada (> 70 años), y de ellos, el 58,2% eran mujeres. ...
... There are several studies that have demonstrated no significant relationship between smoking and VTE [73,76]. However, others have demonstrated a link between smoking and VTE, with several demonstrating a dose-dependent link between smoking and non-smoking, with those having a higher pack year and currently smoking being at the highest risk [77,78]. ...
Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant cause of morbidity and mortality worldwide. There are many factors, both acquired and inherited, known to increase the risk of VTE. Most of these result in increased risk via several common mechanisms including circulatory stasis, endothelial damage, or increased hypercoagulability. Overall, a risk factor can be identified in the majority of patients with VTE; however, not all risk factors carry the same predictive value. It is important for clinicians to understand the potency of each individual risk factor when managing patients who have a VTE or are at risk of developing VTE. With this, many providers consider performing a thrombophilia evaluation to further define a patient’s risk. However, guidance on who to test and when to test is controversial and not always clear. This comprehensive review attempts to address these aspects/concerns by providing an overview of the multifaceted risk factors associated with VTE as well as examining the role of performing a thrombophilia evaluation, including the indications and timing of performing such an evaluation.
... 25 Others have estimated that smoking doubles the risk of DVT independent of contraceptive use, and smoking while using COCs may confer up to an eight-fold increase in DVT risk. 52 These factors should all be taken into consideration during surgical planning for women using hormonal contraception. It is imperative that we continue to expand our understanding of the differential safety profiles to improve perioperative management of hormonal contraception and appropriate VTE risk assessment. ...
BACKGROUND: Exogenous estrogen is a double-edged sword in the realm of orthopaedic surgery, providing many musculoskeletal health benefits to menopausal women yet adding an additional risk of venous thromboembolism (VTE) in the perioperative setting for patients using certain forms of hormonal contraception and menopausal hormone therapy (MHT). The primary objective of this review is to summarize the known literature regarding the VTE risks of perioperative medications containing exogenous estrogen among orthopaedic patients. A secondary objective is to provide guidance to orthopaedic surgeons regarding perioperative management of commonly encountered forms of hormonal contraception and MHT. METHODS: A summative review of existing literature regarding VTE risk of various forms of hormonal contraception and MHT is provided, with emphasis on perioperative VTE risk surrounding major and minor orthopaedic surgery. RESULTS: Increased risk of VTE has been identified after arthroscopic knee procedures in patients utilizing oral contraceptive pills and after major lower extremity surgery in patients using MHT, yet there is not a clear standard of care as to how to manage these medications after surgery or how and when to adjust VTE prophylaxis. Regardless of the mode of delivery (pills, patches, vaginal rings), hormonal contraception with exogenous estrogen carries some associated VTE risk that can be compounded by surgery. Depo-Provera has also demonstrated increased risk. Forms of hormonal contraception without elevated VTE risk are progestin only pills and intrauterine devices (IUDs) as well as Nexplanon. MHT with systemic level doses of exogenous estrogen delivered orally has associated VTE risk. While systemic transdermal and transvaginal formulations of estrogen have not been shown to increase VTE risk in the non-surgical state, the risk when combined with the perioperative state after major operations is not yet known. Local estrogen therapies for vaginal symptoms of menopause do not increase risk of VTE. CONCLUSION: Given the frequent utilization of hormonal contraception and MHT, orthopaedic surgeons should consider the use of medications containing exogenous estrogen in the perioperative VTE risk assessment of patients. Further discussion toward the perioperative management of these medications and standardization of care for patients with increased VTE risks should be encouraged.
... Por otro lado, entre las consumidoras parece existir un inadecuado conocimiento acerca de efectos secundarios de los anticonceptivos hormonales: el más llamativo, al evaluar el conocimiento sobre el riesgo de trombosis mientras se consumen ACH, la quinta parte de las encuestadas afirmó no conocer este aumento del riesgo, con otro tanto que afirmó desconocer el mayor incremento del riesgo debido al consumo concomitante con tabaco, la segunda sustancia psicoactiva más consumida en España 17,18 . Llaman la atención los datos obtenidos, dado que las participantes en el estudio pertenecen al sector sanitario y se les presupone un nivel de conocimientos mayor en este sector. ...
... Surgery necessitates an environment of stasis and endothelial insult that increases the likelihood of VTE [3,4]. Surgical factors are compounded by patient factors known to increase the likelihood of a venous thromboembolic event [5,6]. Given the major role such factors play, to what extent does the literature show that restoring physiological estrogen and progesterone levels in postmenopausal women plays an important role in increasing the risk of VTE? ...
Objectives:
Hormone replacement therapy (HRT), Menopausal Hormone Therapy (MHT), and estrogen-containing medications are frequently withheld before elective lower limb arthroplasty, based on a perceived risk of venous thromboembolism (VTE). However, evidence for the link between HRT, MHT, and increased VTE risk is equivocal. This systematic review evaluated the concordance of international Clinical Practice Guidelines (CPGs) on the withholding of HRT or MHT.
Methods:
The PubMed, Google Scholar, Cochrane, and Ovid databases were searched for CPGs for the pre-, peri- and post-operative management of patients on HRT and MHT undergoing elective lower limb arthroplasty. This was then supplemented by a search of the internet. There were seven international CPGs in English, from Europe and North America, published between January 2000 and February 2023 reviewed against the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE-II) criteria, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.
Results:
The guidelines reviewed revealed a mixed picture on HRT or MHT withdrawal and use in arthroplasty, with some featuring detailed advice on the pre- and post-operative management of HRT or MHT (Scottish Intercollegiate Guidelines Network), while others featured no guidance (American College of Chest Physicians). Reviewing the evidence referenced in these guidelines highlighted studies showing HRT or MHT to play a limited role in increasing VTE risk, with most studies from the 1990s and 2000s.
Conclusions:
Based on current evidence, non-estrogen-containing transdermal HRT or MHT should not be withheld in patients undergoing elective joint arthroplasty, though further evidence is required to justify withholding estrogen-containing forms.
... Estrogen is also known to negatively impact the metabolic, coagulation, and nervous systems, as well as the mammary glands, to varying degrees, contributing to a higher risk of outcomes such as psychosis, thrombosis, depression, and abnormal glucose or lipid metabolism [10][11][12][13][14]. Is estrogen necessary for pregnancy maintenance? ...
Background
Hormone-replacement therapy (HRT) is usually used before frozen-thawed embryo transfer (FET) in women undergoing assisted reproduction. Estrogen is used first in the HRT cycle to stimulate endometrial proliferation, followed by combined estrogen and progesterone therapy to imitate the secretory phase of the endometrium. The progesterone is continued until 8–10 weeks of gestation when the placenta begins the function of luteal support. However, to date, there has been no comprehensive evaluation of the recommended duration of estrogen treatment in the HRT cycle. Prolonged estrogen use can contribute to increased risk of metabolic, coagulation, and neurological outcomes as well as mammary gland diseases.
Methods
The present protocol outlines a proposed single-center, prospective, randomized, controlled, non-inferiority trial. The trial will include clinically pregnant women between 20 and 40 years of age with singleton pregnancies resulting from FET during a hormone replacement cycle. The goal of the trial is to determine whether the live birth rates are impacted by the duration of oral estradiol valerate supplementation (6 vs 10 weeks). The live birth rate will be the primary study outcome, while secondary outcomes include maternal morbidity and neonatal outcomes at birth. Adverse events will be monitored and recorded during the trial.
Discussion
We do not expect to observe any differences in live birth rates, obstetric, or pediatric outcomes when oral estrogen supplementation is discontinued at 6 versus 10 weeks of pregnancy. The clinical data obtained from this trial may provide evidence for improving luteal support guidelines for women undergoing HRT cycles.
Trial registration
The study has been approved by the Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University, and will be performed according to the Good Clinical Practices guidelines. The protocol has been registered on ClinicalTrials.gov (No: ChiCTR2100041917).
... 33,34 Women smokers have a greater risk of developing CAD and dying from IHD. 35,36 It is also important to note that the concomitant use of oral contraceptives while smoking results in an increased risk of MI, stroke, and venous thromboembolism. 37,38 Women present a 25% higher risk for CAD by smoking (Figure 2). 27 ...
... 19, 20 Pomp et al. found that smoking appears to be a risk factor for venous thrombosis with the greatest relative effect among young female patients using oral contraceptives. 20 Our study has strengths, including a multicentre, prospective design with long-term follow-up. Our study also has some limitations. ...
Background
Female hormone therapy (oral contraception in female patients of reproductive age and menopausal hormone therapy in postmenopausal patients) are not withheld from patients with cerebral cavernous malformations, although the effects of these drugs on the risk of intracranial hemorrhage are unknown. We investigated the association between female hormone therapy and intracranial hemorrhage in female patients with CCM in two large prospective, multicentre, observational cohort studies.
Methods
We included consecutive patients with a CCM. We compared the association between use of female hormone therapy and the occurrence of intracranial hemorrhage due to the CCM during up to 5 years of prospective follow-up in multivariable Cox proportional hazards regression. We performed an additionally systematic review through Ovid MEDLINE and EMBASE from inception to November 2, 2021 to identify comparative studies and assess their intracranial haemorrhage incidence rate ratio according to female hormone therapy use.
Results
Of 722 female patients, aged 10 years or older at time of cerebral cavernous malformation diagnosis, 137 used female hormone therapy at any point during follow-up. Female hormone therapy use (adjusted for age, mode of presentation, and CCM location) was associated with an increased risk of subsequent intracranial haemorrhage (46/137 [33·6%] versus 91/585 [15·6%], adjusted hazard ratio 1·56, 95% CI 1·09 to 2·24; p=0·015). Use of oral contraceptives in female patients aged 10-44 years adjusted for the same factors was associated with a higher risk of subsequent intracranial hemorrhage (adjusted hazard ratio 2·00, 95% CI 1·26-3·17; p=0·003). Our systematic literature search showed no studies reporting on the effect of female hormone therapy on the risk of intracranial hemorrhage during follow-up.
Discussion
Female hormone therapy use is associated with a higher risk of intracranial hemorrhage from cerebral cavernous malformations. These findings raise questions about the safety of female hormone therapy in clinical practice in patients with cerebral cavernous malformation. Further studies evaluating clinical factors raising risk of thrombosis may be useful to determine which patients may be most susceptible to intracranial hemorrhage.
Classification of evidence
This study provides Class III evidence that female hormone therapy increased the risk of intracranial hemorrhage in patients with CCM.
... Oral contraceptives increase the levels of fibrinogen and factors II (prothrombin), VII, VIII, and X; decrease the levels of antithrombin and protein S; and lead to acquired protein C resistance [24,25]. Risk factors such as thrombophilia, age, smoking, obesity, and transient provoking factors (eg, surgery) further increase the risk of VTE in oral contraceptive users [26]. In our cohort, patients always discontinued estrogen therapy before stopping anticoagulation, and these women of rather advanced age had a strikingly low recurrence risk. ...
Background:
Deep vein thrombosis (DVT) is a multifactorial disease with several outcomes, but current classifications solely stratify based on recurrence risk.
Objectives:
We aimed to identify DVT phenotypes and assess their relation to recurrent venous thromboembolism (VTE), post-thrombotic syndrome, arterial events, and cancer.
Patients/methods:
Hierarchical clustering was performed on a DVT cohort with up to five years follow-up using 23 baseline characteristics. Phenotypes were summarized by discriminative characteristics. Hazard ratios (HR) were calculated using Cox regression; recurrence risk was adjusted for anticoagulant therapy duration. The study was carried out in accordance with the Declaration of Helsinki and approved by the medical ethics committee.
Results:
In total 825 patients were clustered into four phenotypes: 1.women using estrogen therapy (n=112); 2.patients with a cardiovascular risk profile (n=268); 3.patients with previous VTE (n=128); 4.patients without discriminant characteristics (n=317). Overall, risks of recurrence, post-thrombotic syndrome, arterial events, and cancer were low in phenotype 1 (reference), intermediate in phenotype 4 (HR 4.6, 1.2, 2.2, 1.8) and high in phenotypes 2 (HR 6.1, 1.6, 4.5, 2.9) and 3 (HR 5.7, 2.5, 2.3, 3.7).
Conclusions:
This study identified four distinct phenotypes among DVT patients that are not only associated with increasing recurrence risk, but also with outcomes beyond recurrence. Our results thereby highlight the limitations of current risk stratifications that stratify based on predictors of recurrence risk only. Overall, risks were lowest in women using estrogen therapy and highest in patients with a cardiovascular risk profile. These findings might inform a more personalized approach to clinical management.
... than non-smoking women who did not use oral contraceptives. Relative to non-smoking non-carriers, the combined effect of factor V Leiden and current smoking led to a 5.0-fold increased risk; for the prothrombin 20210 A mutation, this was a 6.0-fold increased risk [28]. ...
Objectives:
Progestins used in contraception are either components of combined hormonal contraceptives or are used as a single active ingredient. Progestins are highly effective in long-term contraception and have a very good safety profile with very few contraindications.
Methods:
An oestrogen-free ovulation inhibitor POP has been authorised in the USA and the EU. It contains 4 mg of drospirenone (DRSP). The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular- phase levels, preventing oestrogen deficiency.
Results:
Clinical trials have demonstrated high contraceptive effectiveness, a very low risk of cardiovascular risk events and a favourable bleeding pattern. Due to the long half-life of DRSP (30-34 h), the effectiveness is maintained even in case of a forgotten pill on a single occasion. Studies involving deliberate 4 days in one cycle 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed.
Conclusions:
This review article will describe the clinical impact in the daily use of the 4 mg DRSP only pill and the resulting data on the effectiveness and safety of this hormonal contraceptive.
... High plasma fibrinogen levels are associated with smoking, whereas increased fibrinogen levels are related to a higher risk of pulmonary embolism. [10], [11] [12] The majority of the pulmonary embolism patients in this study were between the ages of 36-45 and 56-65, with an average age of around 50. These results are supported by a 2021 study that states that the average age of pulmonary embolism patients is 60 -65 years [13]. ...
... Two recent papers show that smoking reduced sex differences, especially in COC users stressing that COC use and smoking attitude select different cohorts of women (Campesi et al., 2021c;Franconi et al., 2020). Progesterone and estradiol can influence smoking-related outcomes and COC increase the risk of thrombosis in smoking women (Pomp et al., 2008;Allen et al., 2019a;Agabio et al., 2017). COC are contraindicated in women with renal disease, increasing blood pressure (Allen et al., 2019b), and favoring thrombotic and vascular events (Attini et al., 2020;Raggi and D'Marco, 2015). ...
The influence of sex combined with smoking and combined oral contraceptives (COC) use on atherogenic indexes is scarcely studied. Thus, traditional lipid parameters were measured, and non-traditional atherogenic indexes were calculated in a young and healthy population of men, COC-free women, and COC users.
Total cholesterol (TChol), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and HDL/LDL ratio were lower in men, while triglycerides (TG)/HDL ratio, atherogenic index of plasma (AIP), Castelli's Risk Index I (CRII) and CRI-II, atherogenic coefficient (AC), creatinine, creatinine clearance, and estimated glomerular filtration rate (eGFR) were higher in men. The use of COC modified TChol, HDL, TG, TG/HDL, and AIP which had significantly higher values in COC users. In addition, TG were also increased in COC users in comparison with men.
Smoking reduced sexually divergent parameters: BMI, TG, HDL/LDL, TG/HDL, AIP, CRII, CRI-II, and AC became similar among the three cohorts, losing the reported sex differences.
Smoking also reduced differences in TChol, HDL, TG, and AIP between COC-free women and COC users, but it does not affect CRII, CRI-II, creatinine, creatinine clearance, and eGFR, underlining that COC users and COC-free women have to be considered two different populations.
Our results represent a complex landscape suggesting that for both sexes smoking should be an independent variable in medical studies. Moreover, in women, the use of COC evidenced two different cohorts. Thus, more variables should be considered during a single study indicating that sex, smoking, and COC should be studied together to get a picture of the real-life context.
... Obesity and smoking are also associated with higher risk for DVTs (8) (9). Obesity increases the likelihood of developing DVT by 2-3 folds(3). ...
... Inna analiza dowiodła, iż roczna częstość incydentów zakrzepowo-zatorowych u osób stosujących antykoncepcję hormonalną z jednoczesnym występowaniem niedoborów białka C, białka S lub antytrombiny wynosiła 4,62% w porównaniu z 0,48% u osób bez niedoboru [8]. Palenie papierosów również doprowadza do 8,8-krotnego zwiększenia ryzyka zakrzepicy żylnej przy jednoczesnym stosowaniu COC [9]. Wśród innych czynników wymieniane są m. że kobiety, które stosowały preparaty zawierające wysokie dawki estrogenu/progesteronu miały nieistotnie zwiększone ryzyko raka jajnika w porównaniu z kobietami, które stosowały małe dawki estrogenu/progesteronu [24]. ...
Introduction and objective:: Combined oral contraceptives (COCs) are one of the most popular methods of contraception worldwide. The universality of this method leads to the constant analysis of its influence on the female body. The purpose of this study is to discuss selected side effects of COC use.
Review methods: In July 2022, articles found in the Medline (Pubmed) and Google Scholar databases were selected by using the following keywords: oral contraceptive use; risk of cancer; depression; side effects of hormonal contraception; venous thrombosis.
Brief description of the state of knowledge: COC use has been shown to be associated with a 2-6 fold increase in the risk of developing venous thromboembolism (VTE). The component responsible for this side effect was initially thought to be synthetic estrogen - ethinylestradiol. It is now recognized as having the greatest influence on mood disorders. An increased risk of cancer has been reported in women taking COCs in case of breast cancer and liver cancer. Inverse relationship was observed in colorectal cancer, ovarian cancer and endometrial cancer.
Summary: COC use can have side effects, but it also has many health benefits. Therefore, it is important to constantly learn about this topic and minimize the risk of adverse side effects.
... VT development is based on blood-flow stasis, hypercoagulability, and endothelial damage as the components of the Virchow Triad (2). Factors such as age, genetic factors, immobilization, sedentary life, obesity, malignancy, and smoking are blamed as risk factors, and age increases the risk of VT independently of other risk factors (3)(4)(5)(6)(7)(8)(9). ...
... A study published in 2011 concluded that the adjusted relative risk increased 6.8-fold from the youngest (15-19 years old) to the oldest (40-49 years old) age category of women [15]. Smoking also increases the risk of venous and arterial thrombosis and acts synergistically with oral contraceptive use [16,17]. ...
Background
Combined oral contraceptives (COCs) are frequently prescribed for contraception, to regulate ovulation and treat endometriosis, and to control menopausal symptoms. A major risk of hormonal contraceptives is vascular thrombosis.
Methods
A retrospective chart review of female patients with deep vein thrombosis (DVT), pulmonary embolism (PE), or other sites of thrombosis or emboli seen in the thrombosis clinic of the department of internal medicine at a tertiary care hospital in Saudi Arabia between March 2010 and February 2015 was performed to identify and characterize which women were taking COCs.
Results
Of 1,008 patients treated for DVT, PE, or other sites of thrombosis or emboli, 100 (9.9%) were taking COCs. Venous (98%) and arterial (2%) thromboses were seen. Overall, 62% of the patients experienced a DVT and 26% pulmonary emboli, and 20% of the patients experienced unusual sites of thrombosis. Furthermore, 53% were obese or morbidly obese. The incidence of venous thrombosis was the highest during the first year of COC use (73%). Of the patients, 8% had thrombophilia.
Conclusion
This study characterizes Saudi women with thrombotic events taking COCs and identifies risk factors, including unusual sites of thrombosis. Most patients experienced the vascular event during the first year of taking COCs. Age of 40-50 years, obesity, and thrombophilia were the commonly observed risk factors.
... In contrast, VTE risk is increased at least four times during pregnancy and as much as 20 times during the postpartum period [96]. VTE risk among CHC users is concentrated in higher risk individuals, such as those who are obese or who smoke [97,98]. Older age also increases the risk of VTE in the general population [99]. ...
The coronavirus disease 2019 (COVID-19) pandemic has posed a significant burden to healthcare systems around the world and has fundamentally changed the way people access health services, including contraception. This document sets forth guidance from the Society of Family Planning for providing contraceptive care in the context of the COVID-19 pandemic, including when access to healthcare is restricted due to pandemic response. It also outlines the role of technology for providing contraceptive care beyond the pandemic. Clinicians can use synchronous telemedicine visits and other forms of telehealth to provide many aspects of contraceptive care. Both audio-video and audio-only visits are acceptable forms of telemedicine. Access to permanent contraception should be maintained, especially in the postpartum period. Combined hormonal contraceptive (CHC) users who have asymptomatic or mild COVID-19 infection may continue their contraceptive method, while those admitted to the hospital with severe COVID-19 infection should suspend CHC use until they are clinically recovered. CHC users who take Paxlovid for mild-moderate COVID-19 infection can consider a back-up contraceptive method for the duration of therapy. Future research should examine contraceptive outcomes in people who receive care via telemedicine; and access to telemedicine among historically excluded populations such as adolescents, people of color, people of low socioeconomic status, disabled people, or people who do not speak English as a primary language.
... Prior studies also revealed that the combined effect of rs6025 (F5) and smoking increased the risk of VTE (69,70). A large population-based case-control study also supported our finding, where the joint effect of rs6025 (F5) and current smoking resulted in a 5-fold increased VTE risk (71). Another cohort study revealed that the simultaneous presence of smoking in addition to rs6025 (F5) increased the VTE risk by 51 and 10% at 10 years for homozygous and heterozygous risk variants, respectively (72). ...
Background: Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.
Objective: To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.
Methods: The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking].
Results: Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher ( p > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10 ⁻⁸ ). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0–1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; p > 0.05) than for the general Hungarian population (OR = 1.5; p > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (β = 0.819, p = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (β = 0.389, p = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (β = 0.370, p < 0.001) than for the general population (β = −0.042, p = 0.6). The VTE risk increased in the Roma population (β = 0.280, p = 0.001), but was higher in the general population (β = 0.423, p = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (β = 0.143, p = 0.046) but not for the general population (β = −0.329, p < 0.001).
Conclusions: rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.
Research regarding the hematologic sequelae of estrogen and testosterone therapy for transgender people is an emerging area. While estrogen therapy has been widely studied in cisgender women, studies in transgender individuals are limited, revealing variable adverse effects influenced by the dose and formulation of estrogen used. Thrombotic risk factors in transgender and gender-diverse individuals are multifactorial, involving both modifiable and nonmodifiable factors. Management of venous thromboembolism (VTE) in individuals receiving gender-affirming estrogen entails standard anticoagulation therapy alongside shared decision-making regarding hormone continuation and risk factor modification. While data and guidance from cisgender women can offer a reference for managing thrombotic risk in transgender individuals on hormone therapy, fully applying these insights can be challenging. The benefits of gender-affirming hormone therapy include significantly reducing the risk of suicide and depression, highlighting the importance of a contemplative approach to the management of hormonal therapy after a VTE event. Although limited, the available data in the literature indicate a low thrombotic risk for transgender individuals undergoing gender-affirming testosterone therapy. However, polycythemia is a common adverse effect necessitating monitoring and, occasionally, adjustments to hormonal therapy. Additionally, iron deficiency may arise due to the physiological effects of testosterone or health care providers' use of phlebotomy, an aspect that remains unstudied in this population. In conclusion, while the set of clinical data is expanding, further research remains vital to refine management strategies and improve hematologic outcomes for transgender individuals undergoing gender-affirming hormone therapy.
Uterine leiomyomas are the most common pelvic tumor in women and the most frequent indication for hysterectomy. Although benign lesions, leiomyomas can cause dysfunctional uterine bleeding, pelvic pain or discomfort, infertility, and spontaneous abortion. Despite the fact that uterine leiomyomas can result in a significant amount of morbidity, it is relatively rare for these common tumors to lead to death. Here we present a case of fatal pulmonary thromboembolism that occurred due to pelvic vein thrombosis in the setting of leiomyomas.
Despite the decrease in cardiovascular mortality over the past 3 decades, it still remains the leading cause of death in women. Young women have a lower risk of cardiovascular disease (CVD), but this trend is reversed after menopause. There are many reasons for this difference between men and women, including traditional risk factors such as diabetes, smoking, dyslipidemia, or aging for which women are clearly more impacted than men. Additionally, there are female-specific risk factors, called non-traditional risk factors, that are associated with increased risk of cardiovascular disease in women. These so-called non-traditional risk factors concern women with pre-eclampsia, recurrent pre-eclampsia, gestational diabetes and premature delivery. In addition, there is also an increased risk for women who use contraceptives, who have suffered recurrent miscarriages, premature ovarian failure and early menopause. There are also psychological, social and cultural aspects related to sex. Indeed, lower level of education is more frequently observed in women. Further, numerous pre-clinical animal studies have highlighted some of the cellular mechanisms involved in the differences in the cardiovascular risk in females. These studies have shown a link between high estradiol levels, calcium handling and cardioprotection in young females. In addition, it seems that the mitochondria, which are essential to cardiac function by providing ATP for contraction and play a central role in the management of oxygen and calcium, are also, differentially regulated between males and females. Therefore, it is important to better understand the origin of these differences between men and women in order to improve the diagnosis, prevention and management of CVD in the future.
Background:
Although vitamin D is antithrombotic, associations between serum vitamin D status and the risk of venous thromboembolism (VTE) remain inconsistent.
Methods:
We searched the EMBASE, MEDLINE, Cochrane Library, and Google Scholar databases from inception to June 2022 to identify observational studies examining associations between vitamin D status and VTE risk in adults. The primary outcome presented as odds ratio (OR) or hazard ratio (HR) was the association of vitamin D levels with the risk of VTE. Secondary outcomes included the impacts of vitamin D status (i.e., deficiency or insufficiency), study design, and the presence of neurological diseases on the associations.
Results:
Pooled evidence from a meta-analysis of sixteen observational studies, including 47648 individuals published from 2013 to 2021, revealed a negative relationship between vitamin D levels and the risk of VTE either based on OR (1.74, 95% confidence interval (CI): 1.37 to 2.20, p < 0.00001; I2 = 31%, 14 studies, 16074 individuals) or HR (1.25, 95% CI: 1.07 to 1.46, p = 0.006; I2 = 0%, 3 studies, 37,564 individuals). This association remained significant in subgroup analyses of the study design and in the presence of neurological diseases. Compared to individuals with normal vitamin D status, an increased risk of VTE was noted in those with vitamin D deficiency (OR = 2.03, 95% CI: 1.33 to 3.11) but not with vitamin D insufficiency.
Conclusions:
This meta-analysis demonstrated a negative association between serum vitamin D status and the risk of VTE. Further studies are required to investigate the potential beneficial effect of vitamin D supplementation on the long-term risk of VTE.
Background. Oral contraceptives (OCs) modify the hemostatic system in the direction of hypercoagulability, which leads to an increased risk of venous thromboembolism. The risk of venous thrombosis with oral contraceptives (OCs) use is estimated at 2-3x, or 4-7x normal with third-generation OCs. Aim. The effect of OCs, taken for >3 months, on hemostatic disorders in young women was examined. Objectives were to examine whether OCs, or OCs together with smoking, induced a hypercoagulable state. Material and methods: Healthy women (n=73), aged 19-25 years, formed two groups: OC group (n=37): OCs used for >3 previous months; Control group (n=36): never used OCs. Most important assessed parameters were: prothrombin time (PT), activated partial thromboplastin time (APTT), global activity of protein C (PiCi) and resistance to activated protein C (APCR). Results. OC group had lower PiCi/APTT mean values relative to controls (PiCi: 79.9 ± 6 vs 84.2±4%, p=0.0006; APTT: 29.7±2.7 vs 32.1±2.6 s, p=0.0003), suggesting hemostatic disturbance in anticoagulant protein C pathway (PiCi) and plasma coagulation (APTT). Smoking women taking OCs had lower APRC (2.70±0.46 vs 3.02±0.20, p= 0.037). Moreover, lower APCR had high correlation with shorter APTT (r=0.65, p=0.081) or PT (r=0.77, p=0.025), indicating changes in the protein C anticoagulant pathway under influence of smoking and OCs. Conclusions. OCs possibly induce hemostatic disorders with hypercoagulation condition. This on the one hand weakness manifested protein C anticoagulant activity, expressed most strongly among women smokers, on the other hand the activation of plasma coagulation. Hypercoagulability activates anticoagulant compensatory mechanisms including increases in fibrinolytic and antithrombotic activities. Absolute indication for nicotine abstinence and healthy body mass are recommended for women using OCs.
As rural-urban pulmonary hypertension (PH)-related mortality trends have not been reported past 2011, it is important to update the literature to provide guidance for necessary initiatives geared at minimizing barriers to social determinants of health. We extracted PH-related data between 2004 and 2019 from the Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research (CDC WONDER). Crude-mortality rate (CMR) and age-adjusted mortality rate (AAMR) were determined. Associated annual percent changes (APCs) and average annual percentage changes (AAPCs) were computed using Joinpoint Regression Program trend analysis software. A total of 353, 916 pulmonary hypertension-related deaths occurred in the study population within the US between 2004 and 2019 out of 3,326,222,482 total deaths. The overall rural PH-related AAMR was 10.75 per 100,000 individuals. The overall urban PH-related AAMR was 9.70 per 100,000 individuals. Both rural and urban county subgroups demonstrated increases in AAMR during the study period. Notably, 8.5% of specialty centers are in rural counties while 91.5% of centers are located in urban counties. Given the crucial role of early treatment at specialty centers in PH disease course, we highlight higher mortality rates among rural county individuals. Specialty center accessibility for these patients must improve.
Objective The aim of the study is to assess the causal effects of cardiovascular risk factors on venous thromboembolism (VTE) and its subtypes including deep vein thrombosis (DVT) and pulmonary embolism (PE).
Methods A summary-level Mendelian randomization (MR) analysis was performed by extracting data from public and large-scale genome-wide association studies for cardiovascular risk factors (hypertension, systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], type 2 diabetes, fasting glucose, body mass index [BMI], smoking, alcohol, and physical activity), VTE, DVT, and PE to identify genetic instruments.
Results BMI (per standard deviation [SD] increase; odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.25–1.54; p = 8.02 × 10−10) could increase the VTE risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–0.99; p = 0.0005) could decrease the VTE risk. For DVT, BMI (per SD increase; OR: 1.48; 95% CI: 1.28–1.72; p = 1.53 × 10−7) could increase the risk, whereas physical activity (per SD increase; OR: 0.05; 95% CI: 0.01–0.33; p = 0.0020) could decrease the risk. For PE, BMI (per SD increase; OR: 1.29; 95% CI: 1.12–1.49; p = 0.0005) could increase the risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–1.00; p = 0.0032) could decrease the risk. Suggestive evidence between smoking and higher risks of VTE and DVT was also observed.
Conclusion Our study supports that BMI is a causal risk factor for VTE, DVT, and PE. SBP is a protective factor for VTE and PE. Physical activity is a protective factor for DVT. However, the effects of other cardiovascular risk factors are not identified.
Os anticoncepcionais hormonais orais são fármacos utilizados com o principal objetivo de evitar uma gravidez e hoje apresentam uma eficácia de 99% se tomado corretamente. Sua composição é bem variada tanto em relação a dosagem quanto ao princípio ativo. Entretanto, apesar dos inúmeros benefícios é preciso tomar cuidado com os riscos que podem ser gerados à saúde das mulheres. Este estudo é uma revisão bibliográfica sobre a relação dos anticoncepcionais com a trombose. O estudo evidenciou que apesar de os anticoncepcionais serem substâncias valiosas na vida das mulheres, eles precisam de atenção ao serem utilizados já que também possuem efeitos adversos, dentre eles o mais severo, a trombose, e com isso é ressaltada a importância da atenção farmacêutica na orientação dos fármacos.
Two main clinical manifestations of venous thrombo-embolism (VTE) include deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT refers to a blood clot that starts in vein, usually in the deep veins of the legs or pelvis area. This blood clot (thrombus) may dislodge from its site of generation and travel through blood stream into lungs, causing PE, a potentially fatal condition. While incidence rate of VTE vary among different age groups and population, various reports are available on its differential occurrence in men and women, with contrasting data. Although any individual can succumb to VTE due to various inherited and acquired risk factors, the majority of the published data indicates that women are more prone to first incidence of venous thrombosis during different stages of life (from puberty till menopause), while men are more prone to recurrent VTE. The prevention and treatment of VTE thus poses distinct gender-specific challenges. It is extremely important for women to know the stages of life when they are more prone to develop DVT/VTE. Subsequently, women also need to have information about the risks associated with treatments using oral contraceptives, ovarian stimulation, pregnancy, etc. Thus the aim of this review is to (1) assess the incidence and risk factors of VTE in women and (2) to summarize the current guidelines and recommendation of VTE management. Early diagnosis of signs and symptoms of DVT/VTE and use of systematic anticoagulation therapy can prevent progression of thrombus and subsequent PE.
Risk for atherosclerotic cardiovascular disease (ASCVD) shows considerable heterogeneity both in generally healthy persons and in those with known ASCVD. The foundation of preventive cardiology begins with assessing baseline ASCVD risk using global risk scores based on standard office-based measures. Persons at low risk are generally recommended for lifestyle management only and those at highest risk are recommended for both lifestyle and pharmacologic therapy. Additional “risk enhancing” factors, including both traditional risk factors and novel biomarkers and inflammatory factors can be used to further assess ASCVD risk, especially in those at borderline or intermediate risk. There are also female-specific risk enhancers, social determinants of health, and considerations for high-risk ethnic groups. Screening for subclinical atherosclerosis, especially with the use of coronary calcium screening, can further inform the treatment decision if uncertain based on the above strategies. Persons with pre-existing ASCVD also have variable risk, affected by the number of major ASCVD events, whether recurrent events have occurred recently, and the presence of other major risk factors or high-risk conditions. Current guidelines define high to very high risk ASCVD accordingly. Accurate ASCVD risk assessment is crucial for the appropriate targeting of preventive therapies to reduce ASCVD risk. Finally, the clinician-patient risk discussion focusing on lifestyle management and the risks and benefits of evidence-based pharmacologic therapies to best lower ASCVD risk is central to this process. This clinical practice statement provides the preventive cardiology specialist with guidance and tools for assessment of ASCVD risk with the goal of appropriately targeting treatment approaches for prevention of ASCVD events.
Background: Venous thromboembolism (VTE) is a rare side effect of hormonal therapy in transgender persons. Prothrombotic genetic variants can increase this risk. For this reason, previous VTE and/or genetic thrombophilia may be considered by some as contraindications to hormonal treatment.
Aim: To formulate directions for clinical practice about the indications for thrombophilia screening and when to consider combination therapy of therapeutic anticoagulation and hormonal treatment as a safe alternative to withholding hormonal treatment.
Methods: We conducted a literature search and describe a case series. All adult patients with gender dysphoria and a known prothrombotic genetic variant or history of VTE were invited by letter to participate in this study.
Results: In our center, thrombophilia screening before start of hormonal treatment was restricted to those with a personal or family history of VTE. Sixteen individuals with a history of VTE and/or an underlying prothrombogenic condition were described. The time of follow up varied from 4 months to 20 years. Seven trans women had a positive thrombophilia screening (2 Factor V Leiden (FVL), 1 FVL + anticardiolipin antibodies, 1 FVL + high Factor VIII coagulant activity, 1 protein C deficiency, 1 prothrombin mutation, 1 positive lupus anticoagulant). Three trans women experienced an unprovoked VTE after start of hormonal therapy of which one lead to a positive thrombophilia screening. One VTE event in a trans woman was assumed to be provoked by surgery. Five trans men were identified with a prothrombogenic mutation (3 FVL, 1 protein C deficiency, 1 prothrombin mutation). One trans man, with a negative thrombophilia screen, experienced multiple provoked VTE events before start of hormonal therapy.
Conclusion: Based on our literature review and case series we offer guidance when confronted with patients with previous VTE and/or genetic thrombophilia requesting hormonal interventions.
Background
Previous studies that assessed risk factors for venous thromboembolism (VTE) in COVID-19 patients have shown inconsistent results. Our aim was to investigate VTE predictors by both logistic regression (LR) and machine learning (ML) approaches, due to their potential complementarity.
Methods
This substudy of a large Brazilian COVID-19 Registry included COVID-19 adult patients from 16 hospitals. Symptomatic VTE was confirmed by objective imaging. LR analysis, tree-based boosting and bagging were used to investigate the association of variables upon hospital presentation with VTE.
Results
Among 4,120 patients (55·5% men, 39·3% critical patients), VTE was confirmed in 6·7%. In multivariate LR analysis, obesity (OR 1·50, 95%CI 1·11-2·02); being an ex-smoker (OR 1·44, 95%CI 1·03-2·01); surgery ≤ 90 days (OR 2·20, 95%CI 1·14-4·23); axillary temperature (OR 1·41, 95%CI 1·22-1·63); D-dimer ≥ 4 times above the upper limit of reference value (OR 2·16, 95%CI 1·26-3·67), lactate (OR 1·10, 95%CI 1·02-1·19), C-reactive protein levels (CRP, OR 1·09, 95% CI 1·01-1·18); and neutrophil count (OR 1·04, 95%CI 1·005-1·075) were independent predictors of VTE. Atrial fibrillation, peripheral oxygen saturation/inspired oxygen fraction (SF) ratio and prophylactic use of anticoagulants were protective. Temperature at admission, SF ratio, neutrophil count, D-dimer, CRP and lactate levels were also identified as predictors by ML methods.
Conclusion
By using ML and LR analyse, we showed that D-dimer, axillary temperature, neutrophil count, CRP and lactate levels are risk factors for VTE in COVID-19 patients.
Multiple control groups in case-control studies are used to control for different sources of confounding. For example, cases can be contrasted with matched controls to adjust for multiple genetic or unknown lifestyle factors and simultaneously contrasted with an unmatched population-based control group. Inclusion of different control groups for a single exposure analysis yields several estimates of the odds ratio, all using only part of the data. Here the authors introduce an easy way to combine odds ratios from several case-control analyses with the same cases. The approach is based upon methods used for meta-analysis but takes into account the fact that the same cases are used and that the estimated odds ratios are therefore correlated. Two ways of estimating this correlation are discussed: sandwich methodology and the bootstrap. Confidence intervals for the pooled estimates and a test for checking whether the odds ratios in the separate case-control studies differ significantly are derived. The performance of the method is studied by simulation and by applying the methods to a large study on risk factors for thrombosis, the MEGA Study (1999-2004), wherein cases with first venous thrombosis were included with a matched control group of partners and an unmatched population-based control group.
A community-wide study was conducted in 16 short-stay hospitals in metropolitan Worcester, Mass, to examine the incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism in patients hospitalized between July 1, 1985, and December 31, 1986. The average annual incidence of deep vein thrombosis alone was 48 per 100000, while the incidence of pulmonary embolism with or without deep vein thrombosis was 23 per 100 000. The incidence rates of deep vein thrombosis and pulmonary embolism increased exponentially with age. The inhospital case-fatality rate of venous thromboembolism was 12%. Among patients discharged from the hospital, the long-term case-fatality rates were 19%, 25%, and 30% at 1, 2, and 3 years after hospital discharge. Extrapolation of the data from this population-based study suggests that there are approximately 170 000 new cases of clinically recognized venous thromboembolism in patients treated in short-stay hospitals in the United States each year, and 99 000 hospitalizations for recurrent disease. Because of the silent nature of this disease and the low rate of autopsy in the United States, the total incidence, prevalence, and mortality rates of venous thromboembolism remain elusive.
(Arch Intern Med. 1991;151:933-938)
Protein S enhances the rate of Factor Va inactivation by activated Protein C (Walker, F. J. (1980) J. Biol. Chem. 255, 5521-5524). The activity of protein S is saturable, appearing to interact stoichiometrically with activated Protein C. Diisopropylphosphate-modified activated Protein C reversed the effect of Protein S, further indicating that a Protein S-activated Protein C interaction is required for expression of the activity of Protein S. In the absence of phospholipid, Protein S had no effect on the rate of activated Protein C-catalyzed inactivation of Factor Va. The activity of Protein S was only expressed in the presence of phospholipid vesicles, where it appeared to increase the affinity of the inactivation system for phospholipid. Protein S had no effect upon the rate of Factor Va inactivation in the presence of saturating levels of phospholipid vesicles. The effects of Protein S on the kinetics of Factor Va inactivation corresponded with its effect on the interaction between activated Protein C and phospholipid vesicles, measured by light scattering. In the presence of Protein S, the binding of activated Protein C to phospholipid vesicles was enhanced. Protein S had no effect upon the binding on the zymogen (Protein C to phospholipid vesicles). In conclusion, the stimulatory effect of Protein S on the inactivation of Factor Va by activated Protein C can be attributed, in part, to the enhancement of the binding of activated Protein C to phospholipid vesicles.
A family with a history of recurring thrombosis was studied to determine if a plasma protein deficiency could account for the observed disease. Protein C levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his father, and his paternal uncle, who are severely affected, had 38-49% of normal levels of protein C antigen, whereas unaffected family members had normal levels. There was no familial deficiency of antithrombin III and plasminogen. Because activated protein C is a potent in vitro anticoagulant enzyme and an in vivo profibrinolytic agent, it is suggested that the recurrent thrombotic disease in this family is due to an inherited deficiency in protein C.
A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.
Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.
Thrombosis occurs most often as myocardial infarction, cerebral infarction or venous thromboembolism, ie, deep-vein thrombosis and pulmonary embolism. The incidence of all types of thrombosis is strongly dependent on age. Among young individuals, up to age 40, venous thrombosis is the most common form of thrombosis. The risk factors for arterial and venous thrombosis differ, and among the latter disorders of hemostasis appear to be more prominent. In children venous thrombosis appears almost exclusively in association with venous catheters, with an exception of the renal vein thrombosis of the newborn, which has an unknown etiology. In young adults, the risk factors for venous thrombosis are essentially the same as in older individuals, excepting oral contraceptives, pregnancy and puerperium which are limited to young women. In young women, most venous thrombotic events can be attributed to oral contraceptives. Venous thrombosis is a multicausal disease: more than one risk factor needs to be present before thrombosis occurs. The younger an individual, the more risk factors are required to precipitate thrombosis: in children often three or four, and in young adults often two or more.
To examine the relationship of obesity, body fat distribution, and fasting plasma insulin concentrations with the plasma levels of both pro-thrombotic and anti-thrombotic factors in premenopausal women.
32 obese women with BMI > 28 and 33 age-matched non-obese = women with BMI < 25.
(i) plasma concentrations of plasminogen activator inhibitor-1 antigen (PAI-1 Ag), plasminogen activator inhibitor-1 activity (PAI-1 activity), fibrinogen, von Willebrand factor antigen (vWF Ag), von Willebrand factor activity (vWF activity), and factor VII activity as pro-thrombotic factors; (ii) plasma concentrations of tissue plasminogen activator antigen (t-PA Ag), protein C, and antithrombin III as anti-thrombotic factors; (iii) fasting plasma insulin and glucose concentrations, and the lipid pattern (triglycerides, total and HDL-cholesterol) as metabolic parameters. The body fat distribution was evaluated by measuring the waist circumference and the waist-to-hip ratio (WHR).
Obese subjects had higher plasma concentrations of all pro-thrombotic factors as compared to non-obese controls (PAI-1 Ag, P < 0.001; PAI-1 activity, P < 0.05; fibrinogen, P < 0.001; vWF Ag, P < 0.001; vWF activity, P < 0.05; factor VII, P < 0.05). The plasma concentrations of PAI-1 Ag and vWF Ag were directly correlated with the waist circumference independently of other metabolic and non-metabolic variables (P < 0.05). Obese women were also characterized by higher plasma concentrations of anti-thrombotic factors such as t-PA Ag and protein C as compared to non-obese controls (P < 0.001 and P < 0.001, respectively), although these factors were not independently correlated with the waist circumference or the WHR.
Plasma concentrations of the pro-thrombotic factors are increased in obese women as compared to non-obese controls, and plasma levels of PAI-1 Ag and vWF Ag correlate with central fat accumulation specifically. Plasma concentrations of anti-thrombotic factors (namely protein C and t-PA Ag) are also raised in obese women, but they are not correlated with parameters of body fat distribution. The increase in protein C levels may represent a protective response partly counteracting the increase in pro-thrombotic factors in these individuals.
To determine whether serum concentrations of the cytokines tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which regulate C reactive protein, are associated with cardiovascular risk factors and prevalent coronary heart disease.
A population based cross sectional study.
198 men aged 50 to 69 years were part of a random population sample drawn from south London. Serum cytokine and C reactive protein concentrations were determined by enzyme linked immunosorbent assay. The presence of coronary heart disease was determined by Rose angina questionnaire and Minnesota coded electrocardiogram.
Serum TNF alpha concentrations were positively related to body mass index and Helicobacter pylori infection, but inversely related to alcohol consumption. IL-6 concentrations were positively associated with smoking, symptoms of chronic bronchitis, age, and father having a manual occupation. TNF alpha was associated with increased IL-6 and triglycerides, and reduced high density lipoprotein cholesterol. IL-6 was associated with raised fibrinogen, sialic acid, and triglycerides. ECG abnormalities were independently associated with increases in IL-6 and TNF alpha, each by approximately 50% (P < 0.05 for TNF alpha, P < 0.1 for IL-6). The corresponding increases in men with an abnormal ECG or symptomatic coronary heart disease were 28% for TNF alpha and 36% for IL-6 (P = 0.14 for TNF alpha and P < 0.05 for IL-6).
This study confirms that many of the phenomena with which C reactive protein is associated, are also associated with serum levels of cytokine, which may be the mechanism.
The products of tobacco combustion are absorbed into the systemic circulation. Absorbed nicotine stimulates the release of catecholamines, whilst other products (perhaps including nicotine) injure the arterial endothelium and promote atherogenesis. Free radicals and aromatic compounds diminish the endothelial synthesis of nitric oxide, causing impaired endothelium-dependent relaxation of arteries, the earliest clinical sign of endothelial dysfunction. Smoking alters the shear forces and rheology at the endothelial surface and these changes enhance the effects of products of tobacco combustion to upregulate leucocyte adhesion molecules on the endothelial surface. The increased oxidation of low density lipoprotein (LDL) in smokers has synergistic effects to promote monocyte adhesion and monocyte migration into the subintimal space. Continued stimulation of intimal cells by oxidized LDL leads to the development of atherosclerosis. Many of these effects are ameliorated by high concentrations of vitamin C. Smoking also potentiates thrombosis at the dysfunctional endothelium by increasing the concentration of plasma fibrinogen and altering the activity of platelets. All these proatherogenic effects of smoking to injure the endothelium also are observed, albeit to lesser extent, in passive smokers.
Background: Few studies have examined the relationship between cigarette smoking and novel risk factors for cardiovascular disease in a general population or have included a biochemical marker of current smoking. Objective: To examine the relationship between cigarette smoking and serum C-reactive protein, fibrinogen, and homocysteine levels. Design: Cross-sectional study. Setting: The U.S. general population. Patients: 4187 current smokers, 4791 former smokers, and 8375 never-smokers 18 years of age or older who participated in the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994. Measurements: Serum C-reactive protein levels were categorized as detectable (2.2 to 9.9 mg/L) or clinically elevated (≥10 mg/L), and fibrinogen and homocysteine levels were defined as elevated if in the 85th percentile or greater (11.1 μmol/L and 12.7 mmol/L, respectively). Results: After adjustment for traditional cardiovascular disease risk factors, cigarette smoking was related to elevated levels of C-reactive protein, fibrinogen, and homocysteine. Compared with never smoking cigarettes, self-reported current cigarette smoking was associated with a C-reactive protein level in the detectable (odds ratio, 1.66 [95% Cl, 1.40 to 1.97]; P < 0.001) or clinically elevated (odds ratio, 1.98 [Cl, 1.57 to 2.51]; P< 0.001) ranges, with elevated levels of fibrinogen (odds ratio, 2.15 [Cl, 1.65 to 2.80]; P < 0.001) and homocysteine (odds ratio, 2.10 [Cl, 1.62 to 2.74]; P<0.001). There were positive and significant dose-response relationships between measures of cigarette smoking (cigarettes per day, pack-years, and serum cotinine levels) and elevated levels of novel risk factors. Conclusions: These findings suggest that inflammation and hyperhomocysteinemia may be important mechanisms by which smoking promotes atherosclerotic disease.
A community-wide study was conducted in 16 short-stay hospitals in metropolitan Worcester, Mass, to examine the incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism in patients hospitalized between July 1, 1985, and December 31, 1986. The average annual incidence of deep vein thrombosis alone was 48 per 100,000, while the incidence of pulmonary embolism with or without deep vein thrombosis was 23 per 100,000. The incidence rates of deep vein thrombosis and pulmonary embolism increased exponentially with age. The in-hospital case-fatality rate of venous thromboembolism was 12%. Among patients discharged from the hospital, the long-term case-fatality rates were 19%, 25%, and 30% at 1, 2, and 3 years after hospital discharge. Extrapolation of the data from this population-based study suggests that there are approximately 170,000 new cases of clinically recognized venous thromboembolism in patients treated in short-stay hospitals in the United States each year, and 99,000 hospitalizations for recurrent disease. Because of the silent nature of this disease and the low rate of autopsy in the United States, the total incidence, prevalence, and mortality rates of venous thromboembolism remain elusive.
Background
Risk factors for deep vein thrombosis and pulmonary embolism are mostly derived from case-control studies of hospitalized patients, and there are few long-term population-based studies.
Objective
To study the long-term risk factors for deep vein thrombosis and pulmonary embolism among middle-aged men.
Design
A prospective cohort study.
Setting
General community, "The Study of Men Born in 1913."
Subjects
A random population sample of 855 men, all aged 50 years at baseline.
Main Outcome Measures
Eight-hundred fifty-five men participated in a screening examination in 1963 at the age of 50 years, and 792 of these men were reexamined in 1967 at the age of 54. All the men were followed up with periodic examinations until the age of 80. Objective methods were used to ascertain a diagnosis of deep vein thrombosis or pulmonary embolism.
Results
Waist circumference (P=.004) and smoking (P=.02) predicted a venous thromboembolic event in multivariate survival analysis. Men in the highest decile of waist circumference (≥100 cm) had an adjusted relative risk of 3.92 (95% confidence interval, 2.10-7.29; P<.001) compared with men with a waist circumference of less than 100 cm. For men who smoked 15 g of tobacco (15 cigarettes) a day or more, the adjusted relative risk was 2.82 (95% confidence interval, 1.30-6.13; P=.009) compared with nonsmokers.
Conclusions
Smoking and abdominal obesity were independent risk factors for venous thromboembolic events during follow-up. In addition to the prevention of smoking and obesity, a more aggressive strategy regarding the use of prophylactic agents among smokers and obese patients, in various risk situations, may be justified.
Objective.
—To investigate risk factors for pulmonary embolism in women.Design.
—Prospective study based on biennial, mailed questionnaires.Setting.
—Nurses' Health Study with 16 years of follow-up from 1976 to 1992.Patients.
—A group of 112 822 women aged 30 to 55 years in 1976, free from diagnosed cardiovascular disease or cancer at baseline. Overall, there were 1 619770 person-years of follow-up.Measurements.
—Based on self-report and medical records, we documented 280 cases of pulmonary embolism, of which 125 were primary (no identified antecedent cancer, trauma, surgery, or immobilization). Information on height, weight, cigarette smoking, hypertension, diabetes, and hypercholesterolemia was collected by questionnaire.Results.
—In multivariate analysis, obesity, cigarette smoking, and hypertension were independent predictors of pulmonary embolism. Specifically, obese women (body mass index ≥ 29.0 kg/m2) had an increased risk of primary pulmonary embolism (multivariate relative risk=2.9; 95% confidence interval [CI], 1.5-5.4). Heavy cigarette smokers also had an increased risk of primary pulmonary embolism. The relative risk (RR) of primary pulmonary embolism was 1.9 (95% CI, 0.9-3.7) for women currently smoking 25 to 34 cigarettes per day and 3.3 (95% CI, 1.7-6.5) for those smoking 35 cigarettes or more daily as compared with never smokers. Hypertension, even after adjustment for body mass index, was also associated with an increased risk of primary pulmonary embolism (RR=1.9; 95% CI, 1.2-2.8). High serum cholesterol levels (RR=1.1; 95% CI, 0.62-1.8) and diabetes (RR=0.7; 95% CI, 0.3-1.9) did not appear to be related to primary pulmonary embolism.Conclusion.
—These prospective data indicate that obesity, cigarette smoking, and hypertension are associated with increased risk of pulmonary embolism in women. Control of these risk factors will decrease risks of pulmonary embolism as well as coronary heart disease.
Spurious correlation refers to the correlation between indices that have a common component. A 'per ratio' standard is based on a biological measurement adjusted for some physical measurement by division. Renowned statisticians and biologists (Pearson, Neyman and Tanner) have warned about the problems in interpretation that ratios cause. This warning has been largely ignored. The consequences of using a single ratio as either the dependent or one of the independent variables in a multiple-regression analysis are described. It is shown that the use of ratios in regression analyses can lead to incorrect or misleading inferences. A recommendation is made that the use of ratios in regression analyses be avoided.
A method of sample selection for household telephone interviewing via random digit dialing is developed which significantly reduces the cost of such surveys as compared to dialing numbers completely at random. The sampling is carried out through a two-stage design and has the unusual feature that although all units have the same probability of selection, it is not necessary to know the probabilities of selection of the first-stage or the second-stage units. Simple random sampling of possible telephone numbers, within existing telephone exchanges, is inefficient because only about 20 percent of these numbers are actually telephone numbers assigned to households. The method of selection proposed reduces the proportion of unused numbers sharply.
This death certificate-based case-control study linked Connecticut Tumor Registry and Connecticut Division of Vital Statistics death data to determine whether machining fluid exposure is associated with laryngeal cancer risk. Laryngeal cancer cases were compared with oral cancer controls and general population controls. Level of exposure to machining fluids was imputed from the usual occupation and industry on the death certificate. Because exposure was infrequent among females, analysis was limited to males. When cases were compared to oral cancer controls, high exposure to machining fluids was associated with laryngeal cancer (odds ratio = 1.48; 95% confidence interval = 1.01–2.16), with a p–value for trend of 0.08. When cases were compared to population controls, no association between machining fluid exposure and laryngeal cancer was observed. A possible reason for the contrasting results, other than chance, is that exposure data quality for the cases and oral cancer controls may have differed from that of the population controls. Am. J. Ind. Med. 31:166–171, 1997. © 1997 Wiley-Liss, Inc.
Numerous case-control studies have reported higher prevalence of non-O blood type among venous thromboembolism (VTE) patients than controls, but potential mechanisms or effect modifiers for the association are not fully established.
Using a nested case-control design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, ABO blood type and other VTE risk factors were measured on pre-event blood samples of 492 participants who subsequently developed VTE and 1008 participants who remained free of VTE.
A total of 64.4% of cases and 52.5% of controls had non-O blood type. Among controls, mean values of factor VIIIc (FVIIIc) and von Willebrand factor among the non-O blood type group were higher than among the O group. Compared with O blood type, the age-adjusted odds ratio (OR) of VTE for non-O blood type was 1.64 (95% CI, 1.32-2.05) and was similar for the two parent studies and race groups. Further adjustment for sex, race, body mass index, diabetes mellitus and FVIIIc reduced the OR: 1.31 (95% CI, 1.02-1.68). Factor V Leiden (FV Leiden) appeared to modify the non-O blood type association with VTE in a supra-additive fashion, with an age-, sex- and race-adjusted OR of 6.77 (95% CI, 3.65-12.6) for having both risk factors.
Non-O blood type was independently associated with risk of VTE, and added to the risk associated with FV Leiden.
The effects of chronic cigarette smoking on the coagulation system were examined in 2964 men aged 50 to 61 years and clinically free of cardiovascular disease. Factor VII activity (VIIc), factor VII antigen (VIIag), prothrombin fragment 1+2 (F1.2), fibrinopeptide A (FPA) and fibrinogen were measured in all participants, and activated factor VII (VIIa), factor IX activation peptide (IX pep) and factor X activation peptide (X pep) in a large sub-sample. The levels of all indices except FPA differed significantly between non-smokers, ex-smokers and current smokers. After adjustment for other conventional cardiovascular risk factors, mean VIIc was raised slightly by 3% in ex-smokers and current smokers as compared with non-smokers, owing to increases in VIIa and VIIag. Plasma IX pep, X pep, F1.2 and fibrinogen concentration were highest in current smokers, intermediate in ex-smokers and lowest in non-smokers. These findings accord with the increased risk of arterial thrombosis in smokers.
In order to determine the relative frequencies of left and right leg venous thrombosis during pregnancy and the frequencies of venous thrombosis during the three trimesters, a cohort study of 60 consecutive patients with a first episode of venous thrombosis during pregnancy was performed. Fifty-eight women had isolated left leg thrombosis, two patients had bilateral venous thrombosis and no patient had isolated right leg venous thrombosis. Thirteen patients had venous thrombosis during the first trimester (21.7%), 28 during the second trimester (46.7%) and 19 during the third trimester (31.7%). These findings indicate that patients with symptoms in the right leg rarely have venous thrombosis. Because leg pain and swelling occur most frequently during the third trimester but venous thrombosis is relatively equally distributed during all three trimesters, patients presenting earlier during pregnancy are more likely to have venous thrombosis than patients presenting later during pregnancy.
Types of control groups are evaluated using the principles described in paper 1 of the series, “Selection of Controls in Case-Control Studies* (S. Wacholder et al. Am J Epidemiol 1992; 135: 1019–28). Advantages and disadvantages of population controls, neighborhood controls, hospital or registry controls, medical practice controls, friend controls, and relative controls are considered. Problems with the use of deceased controls and proxy respondents are discussed. Am J Epidemiol 1992; 135: 1029–41
This report summarizes the documented cases of homozygous protein C deficiency in the United States and Europe. Procedures for diagnosing and treating this disorder (both initially and over the long term) have been compiled by a working party on homozygous protein C deficiency of the Subcommittee on Protein C of the International Committee on Thrombosis and Haemostasis. Homozygous protein C deficiency is an autosomal recessive disorder that usually manifests itself by purpura fulminans and, less commonly, by massive large vein thrombosis; severe diffuse intravascular coagulation also develops in these infants, and there is evidence of intrauterine thrombosis. For confirmation of homozygous protein C deficiency in a neonate with purpura fulminans or massive venous thrombosis, the infant should have undetectable protein C activity and both parents should be heterozygous for protein C deficiency. At the onset of symptoms, the initial treatment should be plasma (8 to 12 ml/kg every 12 hours) until all lesions have healed. Two modalities for long-term treatment are accepted as useful in these children: oral anticoagulant therapy or protein C replacement (fresh frozen plasma or prothrombin complex concentrate). Liver transplantation has been performed in only one child, with success. Oral anticoagulation (vitamin K antagonists, maintaining the prothrombin time from one and one-half to two times control values or at the International Normalized Ratio of 2.5 to 4.4) is our recommendation of choice for long-term treatment. With appropriate care, these children are able to be free of coagulopathy and live relatively normal lives.
During the tenth biennial examination, 1315 Framingham study participants free of cardiovascular disease had fibrinogen measured along with other major cardiovascular risk factors including cigarette smoking. The fibrinogen values were significantly higher in smokers than in nonsmokers, increased with the amount smoked in each sex, and exsmokers had values as low as those of nonsmokers. Over 10 years of follow-up, 165 men and 147 women developed cardiovascular disease, the risk in both sexes increasing progressively in relation to antecedent fibrinogen values over the 180 to 450 mg/dl range. Risk gradients for cardiovascular disease in men diminished with advancing age. In men, risk of cardiovascular disease was related to cigarette smoking. This was true in the multivariate case taking all standard risk factors into account. As for fibrinogen, the impact diminished with advancing age. Regression coefficients were actually larger in the multivariate than in the univariate case because of a negative correlation between smoking and blood pressure. Fibrinogen contributed to cardiovascular disease, risk taking into account both cigarette smoking and other risk factors. When fibrinogen is added to the multivariate model for prediction of cardiovascular disease the coefficient for smoking becomes much reduced and is no longer statistically significant. However, each independently contributed to risk in cross-sectional analysis. These data provide another mechanism whereby cigarette smoking influences the occurrence of atherocardiovascular disease and also another reason for prohibiting cigarette use.
For valid selection of subjects in "case-control" (case-referent) studies it is critical to understand that these studies do not represent an alternative to cohort studies but, rather, to census-ascertainment of the facts about the study base. Specifically, in these studies, the fact-finding scheme is to obtain a census of the study base with respect to outcome, and then a census of the cases together with a sample of the base to gather information on the determinant(s) as well as modifiers and confounders. If the base is defined a priori (primary base), then the challenge is to devise a scheme to obtain a census of the cases in it and a sample of the base itself ("control" or reference series) that is representative of it, conditional on the covariates that will be controlled in the analysis of the data. On the other hand, if the definition of the base is secondary, a corollary of the way the cases are selected, then the case series is best viewed as the totality of the cases in the base as a matter of definition. The corresponding secondary base is the population experience in which each potential case, had it occurred, would have been included in the case series. Representative sampling of a secondary base tends to call for the use of subjects coming to the source of cases because of other conditions--conditions whose occurrence is known to be unrelated to the determinant under study and whose diagnosis and referral to the source are known to have the same relation to the determinant as those of the illness under study. With both types of base, primary and secondary, the accuracy of the information on the determinant should be comparable between the case and reference series, and this requirement of comparability, just as that of representativeness, can have important implications for the selection of the study subjects.
Results are described from four epidemiologic studies in the United States which used random digit dialing in over 30,000
households to identify controls from the general population for use in case-control studies. Methods and problems in telephone
sampling are discussed. It Is concluded that if complete population rosters are unavailable and if the population to be sampled
has the high rates of telephone ownership typical of much of the United States, telephone-based sampling can yield a nearly
random sample of the individuals in a population, often at much less expense than can dwelling-based sampling.
Investigation of 118 patients for protein C deficiency using an immunological and a functional assay, and subsequent investigation of those (nine) found to be deficient, identified 22 patients (14 women, eight men) with protein C deficiency, of whom six were asymptomatic, 15 had histories of venous thromboembolism, and one had a history of arterial thromboembolism. Protein C deficiency was associated in the nine probands with young age at first episode of thromboembolic disease (mean 24.1 (SD 11.9) years), absence of a precipitating condition (five (56%], and a family history of thromboembolic disease (six (66%]. Investigation of the nine families suggested autosomal dominant transmission of the defect. Thromboembolic episodes were seen in patients with protein C antigen concentrations below 0.6 U/ml. Mean (SD) protein C antigen concentrations were 0.48 (0.12) U/ml in 18 patients not receiving oral anticoagulant treatment and 0.28 (0.05) U/ml in four receiving such treatment. One patient with severe protein C deficiency (0.16 U/ml) developed skin necrosis soon after starting oral anticoagulant treatment.
Protein C is the zymogen of a vitamin K-dependent serine protease involved in blood coagulation. In the absence of protein C the inactivation of activated factors V and VIIIC is impaired, and the fibrinolytic capacity of the circulating blood is reduced. These conditions promote excessive fibrin formation and thus constitute a risk factor for thrombosis. Using an immunologic assay for protein C, we identified 18 patients (11 male and 7 female) in three unrelated Dutch families as fulfilling the criteria for an isolated protein C deficiency. In 12 patients who were not receiving oral anticoagulant treatment the mean protein C antigen concentration was 0.48 +/- 0.09 U per milliliter (+/- S.D.), and in 6 patients who were receiving adjusted doses of oral anticoagulants and had stable anticoagulation, the mean value was 0.17 +/- 0.05 U per milliliter. (The value in healthy subjects is 0.98 +/- 0.19 U per milliliter.) Fourteen of the 18 patients had a history of venous thromboembolism, with superficial thrombophlebitis as the hallmark of this condition (in 13 patients). These data are consistent with an autosomal dominant trait with variable expressivity.
This comparison of hospital and neighbourhood controls would be more useful if the source of the control group were not confounded with the city in which the controls were identified. However, in spite of these reasons for expecting differences between the two groups, they are remarkably similar for a wide variety of characteristics. Therefore, where two types of controls for the same cases cannot be used for practical reasons, the experience described here may provide some help to investigators. Firstly, if hospital controls must be used for any reason, the investigator can have some confidence that the estimated frequencies of characteristics are likely to be similar to estimates that would be obtained with population controls, for those characteristics not related to illness and hospitalization. Berkson in any early paper [13] warned investigators about the spurious correlations between a disease and a characteristic which arise when both disease and characteristic are related to hospitalization, and epidemiologists continue to be plagued by the problem as a recent discussion shows [14]. Secondly, where population controls are used, perhaps to avoid Berkson's bias, this comparison provides some evidence that the poorer response obtained with population controls may introduce less bias than has been feared.Our experience cannot resolve the controversy about whether a medical care facility or the general population is the best source for a control group. More empirical evidence is required, and we have presented this comparison in the hope that it will encourage investigators to use both types of controls, so that we may begin to determine how frequently different results are obtained, and what control group differences contribute to these results. Only in this way can we add to our understanding of the bias, if any, arising from either type of control.
To assess potential long-term risk factors for major pulmonary embolism, 46 subjects from the Framingham Heart Study with autopsy-confirmed and clinically significant pulmonary embolism were identified in whom age, systolic blood pressure, cholesterol level, cigarette use, glucose level, Metropolitan relative weight, and varicose veins were ascertained at entry into the Study. These variables were compared among these 46 subjects, all 3,470 subjects in whom these variables were measured at the inception of the Study, and the 998 of these subjects who died within 26 years of follow-up. In multivariate analysis of subjects with autopsy-confirmed major pulmonary embolism and all subjects who died, only Metropolitan relative weight was significantly and independently associated with pulmonary embolism and only among women (p less than 0.001). These findings indicate that, in this cohort, increased adiposity in women is an important long-term factor for significant pulmonary embolism at autopsy. This raises the possibility that weight reduction in obese women may decrease the chances of pulmonary embolism.
Several studies have shown that obesity is associated with atherosclerosis. The reason may be that there is often a gathering together of risk factors for cardiovascular disease in obesity. Recently plasma fibrinogen level has been identified as an important cardiovascular risk factor. The aim of the study was to investigate fibrinogen levels in obesity before and after weight reduction.
Obese but otherwise healthy patients with overweight problems were studied. 448 female patients (39.1 ± 13.2 years, body mass index 38.7 kg/m2) and 136 male patients (39.4 ± 12.8 years, body mass index 40.7 kg/m2) were examined after overnight fasting.
Sixty patients (44 female, 16 male) were studied after 9.5 ± 6.2 month of dieting (1200 kcal/day: 20% protein, 30% fat and 50% carbohydrates). The weight loss was 16.7 ± 11.0 kg in the female and 16.2 ± 6.7 kg in the male patients, and blood pressure, triglycerides, blood glucose and uric acid had declined.
The fibrinogen level correlated with the body mass index, the waist circumference, the hip circumference and the waist to hip ratio. The fibrinogen level also correlated with insulin. A partial correlation of fibrinogen and insulin continued to exist after removing the linear effects of the other variables measured. After weight reduction, the level of fibrinogen was lower. In patients with extreme overweight and high fibrinogen levels, who reduced their BMI by 7.4 ± 1.24 kg/m2, the weight loss correlated with the decrease in fibrinogen.
The results suggest that fibrinogen is associated with the degree of obesity and with the fasting insulin level. Fibrinogen concentration is lowered by weight reduction. However decrease of fibrinogen was observed only in patients with considerable weight loss.
Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals with protein C deficiency are at risk for thrombophlebitis, deep-vein thrombosis, and pulmonary embolism. Genetic analysis of a number of randomly chosen healthy individuals revealed three polymorphisms, C/T at -654, A/G at -641, and A/T at -476, in the protein C promoter region. To investigate whether these genetic variations associate with the plasma protein C level, we determined the genotype for the three polymorphisms and measured plasma protein C levels in 240 individuals not deficient in protein C. The mean protein C level of these individuals was 103%. Interestingly, individuals with the homozygous CGT genotype (n = 40) had a mean protein C level of 94%, whereas individuals with a homozygous TAA genotype (n = 28) had a mean protein C level of 116%. This difference in mean protein C levels between the CGT and TAA groups (P < .001) could not be explained by environmental factors known to influence protein C levels in the normal population. Plasma factor II and factor X levels did not differ between the two groups, which makes a difference in liver function an unlikely cause. Finally, we tested whether the genotype associated with lower protein C levels is associated with higher thrombotic risks. This analysis showed that compared with the genetic variant associated with higher protein C levels (TT/AA/AA), the genetic variant associated with lower protein C levels (CC/GG/TT genotype) is indeed a risk factor for thrombosis (OR, 1.6; 95% confidence interval, 1.0 to 2.5).
We investigated whether the occurrence of venous thrombosis in young women who use oral contraceptives might be explained by the factor V Leiden mutation, which leads to resistance to activated protein C and enhances susceptibility to thrombosis. We compared 155 consecutive premenopausal women, aged 15 to 49, who had developed deep venous thrombosis in the absence of other underlying diseases, with 169 population controls. The risk of thrombosis among users of oral contraceptives was increased 4-fold (relative risk 3.8 [95% CI 2.4-6.0]). The risk of thrombosis among carriers of the mutation compared with non-carriers was increased 8-fold (7.9 [3.2-19.4]). Compared with women who did not use oral contraceptives and were not carriers of the mutation, the risk of thrombosis among those with both risk factors was increased more than 30-fold (34.7 [7.8-154]). Recalculation of population incidences from these relative risks shows that the absolute risk of venous thrombosis in young women who use oral contraceptives is much larger when they carry the factor V Leiden mutation. When a young woman develops thrombosis, her factor V Leiden status should be considered in counselling about her future method of contraception.
Heterozygous protein C deficiency is associated with an increased risk for thrombosis. This association is restricted to a minority of protein C-deficient families, which have been defined as clinically dominant protein C-deficient. In contrast, in the clinically recessive protein C-deficient families, only the homozygous family members are (severely) affected. One possible explanation for this difference in thrombotic risk between families may be the presence of a second hereditary risk factor. A good candidate for this second risk factor is the recently identified resistance to activated protein C (APC). APC resistance, which is associated with a mutation in the FV gene (FV Leiden), is a common and strong risk factor for thrombosis. We show here that the prevalence of the FV Leiden mutation is high among symptomatic protein C-deficient probands (19%). In 6 clinically dominant protein C-deficient families, the segregation of the FV Leiden mutation and the protein C gene mutation was studied. A thrombotic episode had been experienced by 73% of the family members having both the protein C gene mutation and the FV Leiden mutation. In contrast, respectively, 31% and 13% of the family members having either the protein C gene mutation or the FV Leiden mutation had experienced a thrombotic episode. Moreover, the result of a two locus linkage analysis support the assumption that the FV gene and the protein C gene are the two trait loci responsible for the thrombophilia. These results indicate that carriers of both gene defects have an increased risk for thrombosis compared with related carriers of the single defect.
The effects of oral contraceptives on coagulation in 258 nonsmoking and in 190 smoking women were determined. In smokers and in nonsmokers taking oral contraceptives, fibrinogen and fibrinopeptide A concentrations were higher than in oral contraceptive nonusers. In nonsmokers, oral contraceptives increased antithrombin III activity. The effects on coagulation of oral contraceptives with a different ethinylestradiol content (from 35 mcg to 20 mcg) were then evaluated in 333 of these women. The biggest changes in coagulation were observed in smokers taking the preparation with the highest estrogen content. Reduction of the ethinylestradiol dose caused a decrease of the changes in coagulation induced by oral contraceptives both in smokers and nonsmokers. These results might suggest that during oral contraception the coagulation system is affected mainly in smokers and that the decrease of the estrogen dose might lower the effects of the association of smoking and oral contraception on coagulation.
To evaluate the association of plasma protein C levels with constitutional, socioeconomic, life-style and biochemical factors important in cardiovascular diseases, we measured protein C levels in 12,290 middle aged (45-64 years) subjects participating in the ARIC study. Protein C levels had a normal distribution with a mean value of 3.17 micrograms/ml. They were higher in women than men and in whites than blacks; higher in postmenopausal women and further increased by hormonal supplements. The age influence was inconsistent and was considered to be inconsequential. Protein C levels were positively correlated with body mass index, LDL-cholesterol, HDL-cholesterol, and triglycerides and negatively associated with cigarette smoking. These factors should be taken into consideration when establishing normal protein C levels and when analyzing the relation between protein C and arterial and venous thrombotic disorders.
Interpretation of protein C (PC) levels in a given individual has several limitations. A normal PC activity does not necessarily exclude a genetic deficiency nor can a reduced level confirm it. Measuring PC amidolytic activity in 9,648 healthy blood donors has allowed identification of demographic factors which cause variation in PC activity and further hinder interpretation. PC activity displays a log normal distribution and significant variation with age. This is most marked in young adult males when mean PC activity rises from 0.86 iu/ml (15–19 years) to 1.04 iu/ml (45–49 years; P <0.0001). Pre-menopausal females, who for most age ranges, have mean PC activity below their male contemporaries, show a less marked rise with age until the menopause when PC activity rises further. The use of hormonal contraceptive preparations is associated with an increase in mean PC activity of 0.05–0.08 iu/ml while smoking habit has no influence on PC activity.
In view of these findings we strongly recommend the use of age and sex restricted reference ranges when interpreting PC activity.
To investigate a possible interrelationship between obesity and the coagulation and fibrinolytic systems of ethnic Chinese.
The Cardiovascular Disease Risk Factor Two-Township Study, a longitudinal, prospective study in Taiwan, which focuses on the evolution of cardiovascular disease risk factors.
Haemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, factor VIIc, factor VIIIc, antithrombin III and plasminogen.
Present data demonstrated that all haemostatic parameters show a dose-dependent change with body weight. PT and APTT shortened with increased body mass index (BMI). Fibrinogen, factor VIIc, factor VIIIc, plasminogen and antithrombin III increased with higher BMI.
The present result shows that haemorrheological abnormalities do exist in obese subjects and this thrombophilic phenomenon sheds further light on the study of higher cardiovascular and cerebrovascular mortality and morbidity in the obese.
To investigate risk factors for pulmonary embolism in women.
Prospective study based on biennial, mailed questionnaires.
Nurses' Health Study with 16 years of follow-up from 1976 to 1992.
A group of 112822 women aged 30 to 55 years in 1976, free from diagnosed cardiovascular disease or cancer at baseline. Overall, there were 1619770 person-years of follow-up.
Based on self-report and medical records, we documented 280 cases of pulmonary embolism, of which 125 were primary (no identified antecedent cancer, trauma, surgery, or immobilization). Information on height, weight, cigarette smoking, hypertension, diabetes, and hypercholesterolemia was collected by questionnaire.
In multivariate analysis, obesity, cigarette smoking, and hypertension were independent predictors of pulmonary embolism. Specifically, obese women (body mass index > or = 29.0 kg/m2) had an increased risk of primary pulmonary embolism (multivariate relative risk=2.9; 95% confidence interval [CI], 1.5-5.4). Heavy cigarette smokers also had an increased risk of primary pulmonary embolism. The relative risk (RR) of primary pulmonary embolism was 1.9 (95% CI, 0.9-3.7) for women currently smoking 25 to 34 cigarettes per day and 3.3 (95% CI, 1.7-6.5) for those smoking 35 cigarettes or more daily as compared with never smokers. Hypertension, even after adjustment for body mass index, was also associated with an increased risk of primary pulmonary embolism (RR=1.9; 95% CI, 1.2-2.8). High serum cholesterol levels (RR=1.1; 95% CI, 0.62-1.8) and diabetes (RR=0.7; 95% CI, 0.3-1.9) did not appear to be related to primary pulmonary embolism.
These prospective data indicate that obesity, cigarette smoking, and hypertension are associated with increased risk of pulmonary embolism in women. Control of these risk factors will decrease risks of pulmonary embolism as well as coronary heart disease.
In an attempt to reduce the incidence of pregnancy associated venous thromboembolism (PA-VTE), some researchers have advocated screening of all women for the factor V(Leiden) mutation during early pregnancy. We have conducted a large retrospective study (over 72,000 deliveries) to determine if this would be useful. Sixty-two objectively confirmed venous thrombotic events (51 DVT, 11 PE) were recorded at two maternity units in the UK. The incidence of DVT was 0.71 per 1000 deliveries (95% CI 0.5-0.9) with 0.50 occurring in the antenatal period (95% CI 0.34-0.66) and 0.21 in the puerperium (95% CI 0.11-0.31). The incidence of PE was 0.15 per 1000 deliveries (95% CI 0.06-0.24), 0.07 antenatal (95% CI 0.01-0.13) and 0.08 in the puerperium (95% CI 0.02-0.14). Of these 62, 50 attended for follow-up and thrombophilia screening. 28% of all episodes of PA-VTE had no clinical risk factor for thrombosis or an identifiable thrombophilic abnormality. Deficiency of antithrombin was identified in 12% of individuals (95% CI 3-21) and the factor V(Leiden) mutation in 8% (95% CI 0.5-15.5). Based on estimates of the prevalence of the factor V(Leiden) mutation in the population, we estimate that the thrombotic risk for a woman during pregnancy or the puerperium with the defect is approximately 1 in 400-500. This figure would not lend support to the idea of random screening for the mutation in early pregnancy.
This study's objective was to evaluate the association between venous thromboembolism during pregnancy and the postpartum period and the factor V Arg 506 Gln (factor V Leiden), the prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphisms.
In this case-control study 42 case patients and 213 control subjects (parous age-matched women without history of thrombosis) were genotyped for all the polymorphisms. Moreover, antiphospholipid antibodies and protein C, protein S, and antithrombin III deficiencies were investigated in each case.
Ten case patients (23.8%) and 4 control subjects (1.9%; odds ratio 16.3, 95% confidence interval 4.8-54.9) carried the factor V Leiden mutation; 13 case patients (31.0%) and 9 control subjects (4.2%; odds ratio 10.2, 95% confidence interval 4.0-25.9) were carriers of the prothrombin G20210A allele. Finally, 12 case patients (28.6%) and 34 control subjects (16.0%; odds ratio 2.1, 95% confidence interval 1.0-4.5) were homozygotes for methylenetetrahydrofolate reductase C677T. Overall, mutations were found in 25 case patients (59.5%) and 47 control patients (22.2%; odds ratio 5.2, 95% confidence interval 4.9-19.6). One patient carried the antithrombin III deficiency and 1 the protein S deficiency, whereas 2 women had a primary antiphospholipid syndrome.
The significant risk estimates of having a pregnancy-related venous thromboembolism in the presence of the prothrombotic genetic risk factors analyzed suggest to screen for these mutations women with a personal history of thromboembolic events during pregnancy or the postpartum period.