Rachel E. J. Roach

Sex Difference in Risk of Second but not of First Venous Thrombosis: Paradox Explained

Background— The risk of recurrent venous thrombosis is 2-fold higher in men than in women. In contrast, no such sex difference in the risk of first venous thrombosis has been reported. We hypothesized that, for a first event, a risk difference between the sexes is masked by female exposure to reproductive factors (oral contraception, pregnancy/puerperium, and postmenopausal hormone therapy). Methods and Results— From the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study, a population-based case-control study on risk factors for venous thrombosis, 2915 patients with a first venous thrombosis and their partners as control subjects were included. Odds ratios and 95% confidence intervals for first venous thrombosis were assessed in men compared with women without reproductive risk factors by use of conditional logistic regression. Analyses were stratified in 10-year age categories to account for the variation in exposure to reproductive risk factors over different age groups and adjusted for body mass index and smoking. Overall, men had a 2.1-fold (95% confidence interval, 1.9–2.4) increased risk of first venous thrombosis compared with women without reproductive risk factors. Similar results were found when 10-year age categories were viewed separately. Adjustment for body mass index and smoking and exclusion of cancer patients did not materially affect the results. Conclusions— When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women. These findings are in line with previous studies on recurrent venous thrombosis and may have implications for future treatment and prevention strategies.

The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy

Roach REJ, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013; 11: 124–31.

Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides

IMPORTANCE Large case series suggest that patients with folliculotropic mycosis fungoides (FMF) have a worse prognosis than patients with classic mycosis fungoides (MF). However, recent studies described a subgroup of patients with FMF with a more favorable prognosis. Distinction between indolent and aggressive FMF may have important therapeutic consequences but is hampered by the inability of the current tumor-node-metastasis-blood (TNMB) staging system to classify patients with FMF in a clinically meaningful way. OBJECTIVE To differentiate between indolent and aggressive FMF using clinicopathological criteria and to define prognostic factors in patients with FMF. DESIGN, SETTING, AND PARTICIPANTS In this prospective cohort study, we followed 203 patients with FMF, included in the Dutch Cutaneous Lymphoma Registry between October 1985 and May 2014 at a tertiary referral center hosting the Dutch Cutaneous Lymphoma Registry. Overall, 220 patients with FMF had been registered, but 17 patients with incomplete follow-up data or a history of classic MF were excluded. MAIN OUTCOMES AND MEASURES Main outcomes included clinical and histological characteristics, disease progression, and survival. Prognostic factors were investigated using Cox proportional hazard regression analysis. Distinction between early plaque-stage FMF and advanced plaque-stage FMF was made by a blinded review of skin biopsy specimens from patients presenting with plaques. RESULTS In a cohort of 147 men and 56 women (median [range] age, 59 [15-93] years), patients with histologically early plaque-stage FMF had a very similar overall survival (OS) rate to patients with only patches and/or follicular papules (10-year OS, 71% vs 80%), while the survival rate of patients with histologically advanced plaque-stage FMF was almost identical to that of patients presenting with tumors (10-year OS, 25% vs 27%). Subsequently, 3 clinical subgroups with significantly different survival data were distinguished: early skin-limited FMF (group A; n = 84; 5-year and 10-year OS, 92% and 72%); advanced skin-limited FMF (group B; n = 102; 5-year and 10-year OS, 55% and 28%); and FMF presenting with extracutaneous disease (group C; n = 17; 5-year and 10-year OS, 23% and 2%). Age at diagnosis, large cell transformation and secondary bacterial infection were independent risk factors for disease progression and/or poor survival. CONCLUSIONS AND RELEVANCE The results of this study provide useful criteria to differentiate between indolent and aggressive FMF and confirm the existence of a subgroup of FMF with a favorable prognosis.

The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors

Superficial vein thrombosis (SVT) increases the risk of venous thrombosis fourfold to sixfold. As most individuals with SVT do not develop venous thrombosis, additional risk factors may explain the risk of developing a venous thrombosis. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study, we assessed the risk of venous thrombosis in individuals with previous SVT and a mild thrombotic risk factor (smoking or overweight/obesity), a strong risk factor (surgery, hospitalization, plaster cast immobilization, or malignancy), or a reproductive factor in women (oral contraception, postmenopausal hormone therapy, or pregnancy/puerperium). Individuals with previous SVT alone had a 5.5-fold (95% confidence interval [CI], 4.4-6.8) increased risk of venous thrombosis. This was 9.3 (95% CI, 7.2-12.1) combined with a mild thrombotic risk factor, 31.4 (95% CI, 14.6-67.5) with a strong risk factor, and 34.9 (95% CI, 19.1-63.8) in women with a reproductive risk factor. The highest separate risk estimates were found for SVT with surgery (42.5; 95% CI, 10.2-177.6), hospitalization (49.8; 95% CI, 11.9-209.2), or oral contraception (43.0; 95% CI, 15.5-119.3 in women). In conclusion, the risk of venous thrombosis is markedly increased in individuals with previous SVT who have an acquired thrombotic risk factor.

Differential risks in men and women for first and recurrent venous thrombosis: the role of genes and environment: reply

Men have a higher risk of first and recurrent venous thrombosis than do women. However, the pathophysiology underlying this phenomenon is as yet unknown. In this review article, we assessed the prevalence and strength of genetic and acquired risk factors for venous thrombosis for men and women separately, because it is likely that either a difference in effect or distribution of a risk factor explains the risk difference between the sexes. We also summarized the sex‐specific results of previous studies on the risk of first and recurrent venous thrombosis. Few explanations for the sex difference were found. The major factor, explaining about 20% difference in population‐attributable fraction, was body height. No difference in prevalence or strength for other venous thrombosis risk factors was observed, such as plaster cast immobilization, hospitalization, surgery, trauma, malignancy, hyperhomocysteinemia, factor V Leiden, prothrombin G20210A, or blood group non‐O. Alternative explanations for the sex difference are hypothesized in this review, including X‐ or Y‐linked mutations or a mutation on a gene with a sex‐specific effect. Future studies should focus on the sex‐specific risk of venous thrombosis to unravel the pathophysiology and thereby improve sex‐specific treatment and prevention strategies. Even so, male sex can be used as a tool through which individuals at increased risk of first or recurrent venous thrombosis may be identified.

Increased risk of CVD after VT is determined by common etiologic factors

Patients with venous thrombosis (VT) have an increased risk of subsequent CVD (CVD), but the underlying pathophysiology is unclear. Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis follow-up study, 4480 patients with VT, 2926 partner control participants, and 2638 random digit dialing (RDD) control participants were followed-up between 1999 and 2008. Incidence rates and hazard ratios with 95% confidence intervals (95% CIs) of CVD (defined as myocardial infarction or ischemic stroke) were calculated for patients vs controls. Measurable confounders (age, sex, body mass index, smoking, chronic disease, malignancy, genetic thrombophilia, and procoagulant markers) were adjusted for when comparing patients with RDD controls. Unmeasured lifestyle-related factors were also considered by comparing patients with their partners. During a median follow-up time of 5 years, 124 CVD events occurred. Incidence of CVD per 1000 person-years was 3.2 (95% CI, 2.5-4.0) in patients, 2.2 (95% CI, 1.5-3.0) in partners, and 1.6 (95% CI, 0.9-2.6) in RDD controls. Crude hazard ratio was 2.2 (95% CI, 1.2-3.8) in patients compared with RDD controls and 1.5 (95% CI, 1.0-2.3) in patients compared with partners. After adjustment for all confounders, these risks attenuated to 1.8 (95% CI, 0.8-4.2) and 1.3 (95% CI, 0.7-2.5) for patients compared with RDD control participants and partners, respectively. In conclusion, individuals with VT had an increased risk of CVD. This could be explained by common etiologic factors.

Sex difference in the risk of recurrent venous thrombosis: a detailed analysis in four European cohorts

Previous analyses reported a higher risk of recurrent venous thrombosis in men than women.

Risk of cardiovascular disease in double heterozygous carriers and homozygous carriers of F5 R506Q (factor V Leiden) and F2 (prothrombin) G20210A: a retrospective family cohort study.

F5 R506Q (factor V Leiden) and F2 G20210A (prothrombin G20210A) are risk factors for venous thrombosis (Lijfering et al, 2010). The results of studies as to whether these mutations also increase the risk of cardiovascular disease (CVD) are inconsistent. A meta-analysis of 191 studies (N > 150 000) calculated a 30% increased risk of CVD among single heterozygous F5 R506Q or F2 G20210A carriers compared to non-carriers (Ye et al, 2006). Despite its large size, this study included too few double heterozygous and homozygous carriers to estimate the risk of CVD in individuals with these genetic traits. Therefore, we performed a post hoc analysis in a retrospective family cohort that contained a fairly large number of relatives who were double heterozygous or homozygous for F5 R506Q and F2 G20210A (n = 52). Details of our study have been published previously (Bank et al, 2004, 2005; Lijfering et al, 2007). Briefly, 1641 firstdegree relatives, aged 15 years or older, of consecutive patients (probands) with documented venous thrombosis or CVD before the age of 50 years and F2 G20210A, high FVIII or hyperhomocysteinaemia, were enrolled after informed consent was obtained. Information on CVD and exposure to classical cardiovascular risk factors was collected by using a standardized questionnaire and reviewing medical records. All patients were screened for F5 R506Q and F2 G20210A. Information was obtained without knowledge of the genetic status. Observation years were defined as the years from the age of 15 until the date of inclusion or until the date of the first thrombotic event. Incidences and 95% confidence intervals (95% CIs) were calculated under the Poisson distribution assumption. Relative risks and 95% CIs of CVD were calculated in the double heterozygous/homozygous group, using single heterozygous carriers as a reference group. As we studied a thrombophilic cohort, we only compared single heterozygous F5 R506Q or F2 G20210A carriers to double heterozygous and homozygous carriers. The a-priori CVD risk for other relatives was deemed too high for inclusion as a reference group. To avoid bias, we excluded probands from the analysis. To prevent the risk of CVD being based on relatives with cardiovascular risk factors, we intended to repeat the analysis after excluding all relatives with obesity or overweight, smoking, hypertension, dyslipidemia or diabetes mellitus. Unfortunately, as all relatives had at least one of these risk factors at the time of CVD, we were unable to do this. For similar reasons, another analysis was performed after excluding all relatives with concomitant thrombophilias. The pedigrees of 500 probands (373 patients with objectively documented venous thrombosis, 107 patients with CVD and 20 patients with both venous thrombosis and CVD) disclosed 1641 first-degree relatives aged 15 years or older. Of these relatives, 45 were not evaluable because of missing laboratory data and 1149 were non-carriers of F5 R506Q or F2 G20210A (8% of whom had a cardiovascular event). The remaining 447 relatives were analysed: 175 were single heterozygous for F5 R506Q, 220 were single heterozygous for F2 G20210A, 37 were double heterozygous for F5 R506Q and F2 G20210A, eight were homozygous for F5 R506Q and seven were homozygous for F2 G20210A. The clinical characteristics are summarized in Table I. Males and females were distributed equally. The median age at inclusion was 47 years (range, 15–91). Concomitant thrombophilias were found in approximately 60% of all relatives. During the observation period a total of 33 arterial thrombotic events occurred: 7% in single heterozygous F5 R506Q or F2 G20210A carriers and 12% in double heterozygous and homozygous carriers. The median age at onset was similar in both groups (53 years; range, 26–78). The annual incidence of CVD was 0Æ23% (95% CI, 0Æ13–0Æ79) in single heterozygous F5 R506Q or F2 G20210A carriers and 0Æ36% (95% CI, 0Æ13–0Æ79) in double heterozygous and homozygous carriers; relative risk 1Æ6 (95% CI 0Æ7–3Æ9) (Table II). After exclusion of relatives with concomitant thrombophilias, the relative risk of CVD increased to 5Æ1 (95% CI, 1Æ3–22Æ9) in double heterozygous or homozygous F5 R506Q and F2 G20210A carriers compared to single F5 R506Q or F2 G20210A carriers. In our study, double heterozygous and homozygous F5 R506Q and F2 G20210A carriers had a 1Æ6-fold (95% CI, 0Æ7–3Æ9) increased risk of CVD compared to single F5 R506Q or F2 G20210A carriers. Although these results did not reach statistical significance, they further the findings of two previous studies that found a modest association between single heterozygous F5 R506Q or F2 G20210A and CVD (Ye et al, 2006; Mannucci et al, 2010), but included too few subjects to calculate, as we did, a risk in homozygous and double heterzogygous carriers. It is unknown why, in F5 R506Q and F2 G20210A carriers, the risk of CVD appears to be more than 10 times weaker than the risk of venous thrombosis. A plausible explanation is that atherosclerosis plays a major role in CVD and a smaller role in venous thrombosis (Prandoni et al, 2003). Atherosclerosis is Correspondence

Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia

Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular-weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

Coffee consumption is associated with a reduced risk of venous thrombosis that is mediated through hemostatic factor levels

Summary.  Background: Coffee consumption is associated with a lower risk of venous thrombosis, but the role of confounding and the pathophysiology behind these findings are unclear. Objective: To assess the role of hemostatic factors in the relationship between coffee consumption and venous thrombosis. Methods: From a large case–control study, 1803 patients with a first venous thrombosis and 1803 partner controls were included. With conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for venous thrombosis were calculated for coffee consumption vs. no coffee consumption. In addition, mean differences in hemostatic factor levels between these groups were calculated in the controls. Results: Coffee consumption yielded a 30% lower risk of venous thrombosis than no coffee consumption (OR 0.7, 95% CI 0.5–0.9). Adjustment for several putative confounders (age, sex, body mass index, smoking, hormonal factors, statin, aspirin, alcohol, malignancy, and chronic disease) yielded an OR of 0.8 (95% CI 0.6–1.1). Results were similar for provoked and unprovoked events, and for deep vein thrombosis and pulmonary embolism. In controls, von Willebrand factor levels were 11 (3–19) IU dL−1 lower and factor (F) VIII levels were 11 (1–21) IU dL−1 lower in coffee consumers than in non‐consumers. After adjustment of the risk estimates for these hemostatic factors, the inverse association between coffee consumption and venous thrombosis diminished (OR 1.0, 95% CI 0.7–1.4). There was no association between coffee consumption and anticoagulant proteins, fibrinogen levels, or fibrinolytic markers. Conclusions: Coffee consumption is associated with a lower risk of venous thrombosis, which seems to be mediated through von Willebrand factor and FVIII.