Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20

Gender related issues in thrombosis and hemostasis Anne-Mette Hvas & Emmanuel J Favaloro To cite this article: Anne-Mette Hvas & Emmanuel J Favaloro (2017): Gender related issues in thrombosis and hemostasis, Expert Review of Hematology, DOI: 10.1080/17474086.2017.1371010 To link to this article: http://dx.doi.org/10.1080/17474086.2017.1371010

Accepted author version posted online: 22 Aug 2017.

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Date: 23 August 2017, At: 04:31

Publisher: Taylor & Francis Journal: Expert Review of Hematology DOI: 10.1080/17474086.2017.1371010

Gender related issues in thrombosis and hemostasis

Aarhus University Hospital, Aarhus, Denmark

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1. Centre for Hemophilia and Thrombosis, Department of Clinical Biochemistry,

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2. Department of Hematology, Sydney Centres for Thrombosis and Hemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital,

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NSW Health Pathology, NSW, Australia

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Corresponding author: Anne-Mette Hvas

Department of Clinical Biochemistry

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Aarhus University Hospital

Palle Juul-Jensens Boulevard 99

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DK- 8200 Aarhus N Denmark

E-mail: [email protected]

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Anne-Mette Hvas1 and Emmanuel J Favaloro2

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Abstract Introduction: Many aspects of hemostasis, both primary and secondary, as well as

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fibrinolysis display sex differences. From a clinical viewpoint, certain differential

phenotypic presentations clearly arise within various disorders of thrombosis and

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Areas Covered: The present mini-review summarizes selected clinical entities where

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sex differences are reflected in both frequency and clinical presentation of

hemostasis disorders. Sex differences are discussed within the settings of

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cardiovascular disease, including coronary artery disease and ischemic stroke, venous thromboembolism and inherited bleeding disorders. Moreover, pregnancy and labor present particular challenges in terms of increased thromboembolic and

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bleeding risk, and this is also summarized.

Expert Commentary: Available knowledge on sex differences in risk factors and

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clinical presentation of disorders within thrombosis and hemostasis is increasing. However, more evidence is needed to further clarify different risk factors and treatment effect in men and women, both as regards to cardiovascular disease and

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venous thromboembolism. This should facilitate improved gender guided risk stratification, and prevention and treatment of these diseases. Finally, risk assessment during pregnancy remains a challenge; this applies both to thromboembolic risk assessment during normal pregnancy and special care of women with inherited bleeding disorders during labor.

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hemostasis.

Key words: Bleeding disorders; gender; hemostasis; pregnancy; sex; thrombosis

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1. Introduction In medicine, the terms ‘gender’ and ‘sex’ and are often used synonymously. However, in literature related to women’s studies, as derived from the social sciences, each term is used in distinction. The term ‘sex’ refers to biological and physiological characteristics in males and females, whereas ‘gender’ refers to how differences between men and women are constructed in different cultures [1,2].

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Accordingly, we will use the term sex throughout this manuscript, except where this term seems less appropriate.

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relatively recently [3]. According to Verdonk et al., gender health issues can be

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defined as diseases or conditions unique to, or more prevalent or serious in, men or women [3]. Notably, such differences are more influenced by biology than by ethnic or socioeconomic considerations [4].

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Biological differences between male and female, based on distinct expression of sex chromosomes, on varied gene-expression and on hormonal expression, lead

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to substantial differences in physiology and pathophysiology. For example, an increasing body of evidence suggests that human platelet activity may be influenced

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by sex hormones [5], and estrogens likely play a crucial role in transcriptional regulation of coagulation protein genes [6]; however, the real impact of sex-related differences remains unclear. The sex differences in primary [7-13] and secondary

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hemostasis [14-17] as well as fibrinolysis [15,18] are summarized in Table 1, with most evidence available for primary hemostasis. From a clinical viewpoint, sex differences more clearly arise in thrombosis and

hemostasis disorders. Several inherited disorders of hemostasis are recognized, with classical hemophilia and von Willebrand disease (VWD) representing major

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The idea that men and women differ in terms of pathophysiology has emerged

presentations. Sex plays a part in most inherited bleeding disorders – either because they may arise differentially based on sex (e.g., hemophilia A and B), or ‘predominantly’ affect one sex because of sex related challenges (e.g., menstruation, pregnancy and child birth). Similarly, thromboembolic diseases are present in both men and women, but may exhibit differences in presentation and frequency. The present mini-review summarizes some essential issues on sex differences within the field of thrombosis and hemostasis. Selected clinical entities are presented

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including coronary artery disease, ischemic stroke, first and recurrent venous thromboembolism (VTE) and inherited bleeding disorders, with the focus on differences in risk factors and clinical presentation in men and women. 2. Where sex makes a difference - selected clinical entities Here, the most frequent arterial and venous thromboembolic manifestations are

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reviewed. A summary of the present evidence on sex difference in clinical

presentation of thromboembolic disease and inherited bleeding disorders are

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2.1 Cardiovascular disease

Cardiovascular disease (CVD) remains the number one killer in both men and women [19,20]. Globally, the majority of CVD deaths takes place in low- and

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middle-income countries and occurs almost equally in males and females [20]. However, in Europe, more men (0.9 million) than women (0.5 million) die per year

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from CVD before the age of 75, and the observed sex differences in number of deaths are greater at younger ages, with more than twice as many men than women

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dying from CVD under the age of 65 [19]. The mechanisms underlying this disparity remain to be clarified, but the hypothesis that estrogen in particular could play a key role predominates (Figure 1). However, the evidence is not clear as regards to the

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association between endogenous estrogens and CVD risk[21]. An additional important issue is the association reported between increased risk of CVD and presence of systemic autoimmune diseases as systemic lupus erythematosus [2224] or rheumatoid arthritis [25,26], which are far more common in females. Thus, recognition of the occurrence of this group of diseases was implemented in the 2014

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summarized in Table 2.

guideline for CVD risk assessment published by The National Institute of Care Excellence (NICE) [27]. Coronary heart disease and cerebrovascular disease are the most common

causes of death due to CVD and are further discussed below. 2.1.1 Coronary artery disease

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Coronary heart disease accounts for up to half of the total cases of CVD with a lifetime risk at age 70 years at 34.9% for men and 24.2% for women [28]. Notably, many studies on CVD included mainly men; thus, the relative knowledge regarding women has largely been extrapolated [29]. Morbidity and mortality from coronary artery disease are higher in men than women, but differences narrow after menopause [30], suggesting a protective role of estrogen.

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Classical risk factors for CVD (e.g., hypertension, diabetes mellitus) and lifestyle risk factors (e.g., smoking, obesity) are similar in women and men [31], but there are

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risk factor the risk is higher in women during the first 10 years follow-up compared to

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men and the same was found as regards to smoking [31]. This supports early and intensive prevention strategies directed towards risk factor modification in women with diabetes mellitus and in women who smoke [31,33]. However, Jousilahti et al

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showed in a large prospective study including 14,786 individuals that most risk factors were more favorable in women, and gender differences in risk factors,

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particularly HDL/total cholesterol ratio and smoking, explained almost half the differences in coronary artery disease [34]. In addition, cholesterol synthesis markers

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have been found to be associated with lower risk of coronary death in women, whereas in men, it was associated with higher risk of coronary death [35]. An inverse relationship between HDL and coronary heart disease has previously been

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established [36,37]. Notably, coronary heart disease risk persists also among people with very high HDL, in both men and women [38]. Aspirin is the cornerstone of primary and secondary prophylaxis of coronary

artery disease [39,40]. Several studies have reported reduced response to aspirin in women compared to men [41-45]. The Hypertension Optimal Treatment trial

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gender differences in their prevalence [32]. As regards to diabetes mellitus as a CVD

investigated the effect of aspirin in primary prevention in women, and found no significant reduction in myocardial infarction in women, while a 42% reduction was observed in men [46], and the large Women’s Health Study demonstrated that aspirin did not reduce the risk of myocardial infarction or cardiovascular death [47]. However, in women above age 65 years, aspirin showed beneficial effects including myocardial infarction risk reduction, whereas women younger that 65 years had no reduction in CVD events [47]. In addition, a meta-analysis by Berger et al

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demonstrated that clopidogrel was associated with a significant reduction in risk of cardiovascular events in individuals with known risk factor of coronary heart disease, but in women only the risk of myocardial infarction was significantly reduced, whereas men showed significant reductions in all endpoints including all-cause mortality[48]. Such findings suggest that women may benefit less from antiplatelet therapy than men, both biochemically in terms of platelet inhibition and clinically in

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terms of primary protection from myocardial infarction or mortality.

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Ischemic stroke accounts for almost 90% of all strokes and is therefore an important

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target for novel preventive and therapeutic strategies [49]. Recent evidence identifies that women show disproportionately lower incidence of ischemic stroke than men across most age groups; however, compared to men, women above 85 years of age

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have higher stroke incidence [50] and above 65 years of age have higher agespecific mortality rates from ischemic stroke than men [51]. Thus, stroke is the 3rd

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leading cause of death for women and 5th leading cause of death for men[52] with female stroke survivors suffering more disability following stroke than men [53,54].

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To date, most research on stroke risk has focused on the contribution of estrogens on ischemic sensitivity, while androgens such as testosterone are believed to play a key role in the cerebral vasculature, as recently reviewed by Gonzales et al.

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[55].

The neuroprotective effects of estrogen have been demonstrated in animal

stroke models[56] with young female mice showing protection against ischemic damage compared to male mice, whereas older female mice demonstrated greater infarct volumes compared to age-matched male mice and younger female mice [57].

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2.1.2. Ischemic stroke

Although preclinical studies have focused on estrogen as the most likely cause of the lower stroke incidence seen in pre-menopausal women [58], clinical studies suggest that hormone replacement therapy increases the risk of ischemic stroke [59]. Furthermore, a strong association has been found between impaired cerebrovascular reactivity and stroke risk [60-62]. Sex hormones, especially estrogen, have been found to significantly influence cerebrovascular reactivity,

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probably by stimulation of nitrous oxide production and release [63,64]. This effect of estrogens might also contribute to sex differences in vascular function. To summarize, men are at a higher risk of stoke than women, except in the elderly above 85 years. However, as women have longer life expectancy, they are usually older at stroke onset and suffer more severe strokes. Furthermore, pregnancy [65,66] and menopause[67] are two conditions unique to women that

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increase stroke risk.

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In 1856, Virchow explained VTE as the result of stasis, changes in blood

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composition, and damage of the vessel wall [68]. Thus, sex was not included in this triangle as a risk factor for VTE. The debate on the significance of sex differences in VTE began recently, following a 2004 publication by Kyrle et al., which identified men

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as having an unexplained 3.6-fold higher risk of recurrent VTE compared to women [69], a finding that has since been consistently confirmed [70-74].

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Interestingly, a risk difference between men and women for first VTE event is less apparent [75-77]; however, sex differences become apparent when considering

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age. It appears that the incidence of first VTE is higher in women during childbearing age compared to men at similar age [75]. This difference is probably caused by changes in female endogenous hormone levels, female exposure to exogenous

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estrogens, and/or pregnancy, because when these female reproductive risk factors were taken into account, the risk of first VTE was 2.1-fold (95% confidence interval 1.9-2.4-fold) higher in men than in women [78]. It is essentially impossible to investigate the “true” difference in coagulation

status among women and men, as women of childbearing age are variously affected

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2.2 Venous thromboembolism

by exposure to exogenous estrogens and reproductive risk factors. Thus, other differences in risk factors for the first VTE have to be considered. For example, body height and VTE risk seem to be associated, given taller individuals have a higher risk of VTE compared to shorter individuals [79,80]. Thus, part of the risk difference between men and women might be explained by overall differences in height. None of the genetic characteristics increasing thromboembolic risk (e.g. factor V Leiden, prothrombin G20210A, deficiency of natural anticoagulants) are sex-linked. In

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accordance, data from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study demonstrated no sex difference in relative risk of VTE associated with genetic risk factors [81]. Furthermore, there is no evidence to support that body weight, smoking profile or different levels of testosterone explain the sex related risk difference for first VTE [78]. Thus, men have a higher risk of both first and recurrent VTE than women, but a

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far more pronounced risk of recurrent VTE. The mechanistic pathophysiology behind

this is unclear, and requires further research to develop and establish effective future

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As regards to the VTE risk in women, pregnancy represents a particular entity,

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as normal pregnancy is associated with major changes in all aspects of

hemostasis[82-85] (Table 1). The increase in fibrin d-dimer during pregnancy challenges the diagnostic work-up in suspicion of VTE [82,83,86]. Notably, only

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subtle changes occur in soluble fibrin and fibrin monomer complex during normal pregnancy [87,88]. However, these latter tests are not implemented in daily clinical

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practice. The hypercoagulability of normal pregnancy predisposes to an approximately five-fold higher risk of VTE in pregnancy compared to non-pregnant

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women [89]. The risk is further increased throughout pregnancy with the highest risk in the third trimester (odds ratio, 8.8; 95% confidence interval, 4.5-17.3) and during the first 6 weeks after delivery [89].

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Pregnancy related VTE risk factors include, among others, multipara,

hyperemesis, preeclampsia and cesarean section[90]. General risk factors include increasing age[91], high body mass index (>30 kg/m2) and smoking [90]. Previous VTE increases the risk for recurrence during pregnancy, especially when the VTE was unprovoked[92] or previously related to estrogen influence [93]. Moreover, some

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sex-specific VTE prevention and treatment.

medical diseases (e.g. systemic lupus erythematosus, sickle cell anemia and inflammatory bowel disease) contribute to an increased VTE risk during pregnancy [90]. Finally, presence of thrombophilia may further increase the VTE risk[94]. Antithrombin deficiency poses the highest risk for VTE among the hereditary thrombophilias [95], and the risk is particularly high in pregnancy [96]. As regards to acquired thrombophilia, antiphospholipid syndrome is particularly associated with an increased thromboembolic risk [97], as any vascular bed can be affected in these

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women. The assessment of the need for thromboprophylaxis is complicated and involves evaluation of several risk factors [98,99]. When thromboprophylaxis is indicated during pregnancy, low-molecular weight heparin is the drug of choice[100], which in antiphospholipid syndrome is typically supplemented with aspirin[97]. An particularly high thromboembolic risk in these women [101].

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von Willebrand disease (VWD), believed to be the commonest inherited bleeding

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disorder in both men and women, was first described in a female child by Eric von Willebrand in 1926 [102], and remains identified and treated in more women than men. Nevertheless, the particular issue of bleeding disorders in women remained

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under-recognized until the late 1990s [103]. Conversely, classical hemophilia affects more males than females, and generally has a stronger phenotype in men, being an

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X-linked disorder, so that the diagnosis is sometimes ‘missed’ in women for this reason. The main issues in regards to VWD or hemophilia for women are heavy

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menstrual bleeding, more complex pregnancy care (including prenatal diagnosis), and postpartum hemorrhage (PPH).

Heavy menstrual bleeding is often the first symptom of VWD in women, and

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sometimes can present as the only bleeding symptom [104]. Among 150 women presenting with heavy menstrual bleeding, VWD was found in 13% [104]. This wellestablished association is also reflected in international guidelines that recommend consideration of testing for inherited bleeding disorders in women with heavy menstrual bleeding [105]. However, there is no consensus on how and when to

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2.3 Bleeding disorders; von Willebrand disease and hemophilia

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exception to this choice of drug is women with mechanical heart valves due to a

screen women who are likely to have an underlying bleeding disorder, although the use of quantitative bleeding assessment tools (BAT) has been recommended for screening patients with bleeding symptoms [106] in order to determine the need for detailed hemostatic assessment. The management of labor in women with inherited bleeding disorders requires a specialized and individualized multidisciplinary approach, as proposed by Huq and Kadir [107]. PPH is significantly greater among women with inherited bleeding

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disorders than in women without [108,109]. A large population-based study demonstrated a three-fold increased risk of PPH among women with VWD, and VWD was the most frequent cause of severe PPH (>1500 mL) after emergency cesarean section [110]. Thus, early recognition and diagnosis of inherited bleeding disorders is essential as it enhances the care and safety of affected women, and an individual management plan for blood product replacement should be made before delivery.

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The clinical phenotype of hemophilia is primarily dependent on the severity of factor VIII or factor IX deficiency [111]. As the disease is X-linked, males are more

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severe hemophilia was characterized by spontaneous bleeds into joints and muscles

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in an early age with subsequent intermittent and chronic pain and later a recurring need for orthopedic surgery [111], but regular infusions of factor concentrates has revolutionized the lives of hemophilia patients [112].

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In industrialized parts of the world, the most serious complication in hemophilia is the development of inactivating antibodies, termed inhibitors, to therapeutic factor

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concentrates. The overall incidence of inhibitor development is 20-30% in severe hemophilia, and is most often found in hemophilia A [113]. Risk factors for early

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inhibitor development include a family history of inhibitors, nonwhite ethnicity, factor VIII mutation, and intense factor VIII replacement therapy [113], but as the risk of inhibitor development is also strongly associated with the severity of the disease, this

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risk is relatively higher in men than in women. However, recent studies point to fact that inhibitor development in non-severe hemophilia seems to be an overlooked entity [114,115]. At present, evidence is scarce for optimal treatment of bleeding episodes due to inhibitor development in patients with non-severe hemophilia. Thus, this issue remains a clinical challenge.

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prone to a severe phenotype than women. Previously, the life of a male patient with

Besides the inherited bleeding disorders, many acquired bleeding

disorders exist. Among these, immune thrombocytopenia is more frequent among women [116,117] (Table 2), however, this is beyond the scope of the present review. 4. Conclusion Evident sex differences exist in frequency, presentation and treatment effect of CVD. The relative number of CVD deaths is higher in women than in men, but in younger

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ages, more men die from CVD than women. Remarkably, studies indicate that both aspirin and clopidogrel is less efficient in women than in men. As regards to VTE, men have a higher risk of both first and recurrent VTE than women, with the increased risk being most pronounced for recurrent VTE [69]. The inherited bleeding disorder VWD clinically affects more females than males, with the opposite picture

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being evident for hemophilia. 5. Expert Commentary

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studies that mainly included men, future studies are needed to clarify CVD risk

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factors, pathogenesis and treatment effect in women. The mechanisms behind the reported sex differences in CVD remain largely unclarified, although the risk profile in women indicates a protective role of endogenous estrogens in pre-menopausal

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women. This is also supported by a higher ischemic stroke incidence in elderly women compared to men [50]. Thus, the association between endogenous estrogens

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and CVD risk also requires further investigation. Additionally, previous studies indicate a reduced effect of both aspirin and clopidogrel in women compared to men,

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both in terms of less platelet inhibition and in terms of less protection cardiovascular events compared to men [43,46,48]. This phenomenon should also be further investigated, including the mechanisms behind this suggested reduced effect of

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antiplatelet therapy.

The mechanisms illuminating higher risk of unexplained VTE in men, especially

recurrent VTE, need to be further investigated in order to provide future more targeted and sex-specific VTE prevention. As normal pregnancy is associated with a five-fold increased VTE risk an individualized risk assessment is needed during

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As the present knowledge on CVD has to a large extent been extrapolated from

pregnancy and postpartum taking both general and pregnancy related risk factor into account in order to estimate the potential need for thromboprophylaxis during pregnancy and/or postpartum. A major present challenge in VWD is the diagnostic work-up and disease management [118,119]. Such processes need a substantial re-evaluation and improved clinical education in order to increase both sensitivity and specificity of the tools used in particular to diagnose and manage women with increased bleeding

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tendency. A major challenge remains in hemophilia treatment complicated with neutralizing antibodies against the factor concentrates, as this is the greatest threat for hemophilia patients in industrialized parts of the world. 6. Five-year View Sex differences in thrombosis and hemostasis will continue to be identified, and the

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mechanisms clarified. For example, there is additional scope for differential based on sex-specific or predominant cancer related events, such as prostate cancer in men

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mechanism in CVD will be further investigated, and a possible sex difference in the

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effect of antiplatelet therapy will be clarified. The mechanisms behind sex differences in recurrent VTE risk will be further investigated, and operational tools will be developed for individualized VTE risk assessment during pregnancy and post

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partum. The diagnostic work-up in patients with increased bleeding tendency will be improved in order to more specifically recognize bleeding disorders. Investigations of

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the mechanisms underlying development of inactivating antibodies to factor concentrates in hemophilia patients will be continuously undertaken with an

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intensified focus on patients with non-severe hemophilia. Such developments will have an element of sex focus, considering that congenital bleeding disorders such as

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VWD and mild hemophilia in women are under-recognized. 7. Key-issues •

Evident sex differences exist in normal hemostasis, primarily in primary

hemostasis.



More men than women die from CVD, especially at younger ages.



Classical risk factors for coronary artery disease are similar in men and

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[120]. For women, the role of endogenous estrogens as a potential protective

women but most risk factors are more favorable in women, except at older

age.



The clinical and mechanistic effectiveness of antiplatelet therapy seems to be reduced in women compared to men.



The risk of VTE, and especially for recurrent VTE, is higher in men than in women.

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An individualized VTE risk assessment is required during pregnancy and postpartum to estimate the need for thromboprophylaxis.



VWD, being the commonest inherited bleeding disorder, presents a stronger phenotype in women than in men, being dominated by heavy menstrual bleeding and risk for postpartum bleeding.



Hemophilia, being a sex-linked disorder, presents a stronger phenotype in

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men than in women, and is dominated by joint and muscle bleeds and

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Funding

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This paper was not funded.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject

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matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or

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patents received or pending, or royalties.

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bleeding risk during surgery.

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Table and figure legends Table 1 Examples of sex differences in hemostasis and fibrinolysis in healthy individuals Table 2 Examples of conditions expected to yield clinically significant sex differences in

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thrombosis and bleeding risk.

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Outline of gender-related factors associated with increased risk of cardiovascular

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disease in women. References

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Papers of special note have been highlighted as: ** of considerable interest

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patients with primary immune thrombocytopenia: a Danish population-based cohort

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Table 1. Examples of sex differences in hemostasis and fibrinolysis in healthy individuals Primary hemostasis

Main findings Platelet count and other platelet indices in women compared to men, regardless of age and menopausal status [7]

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No difference in platelet reactivity comparing pre- and post-menopausal women [13]

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During pregnancy: Occasional () platelet count [85] von Willebrand factor [82]

Postpartum (1 week) von Willebrand factor [82] Whole blood thromboelastography/metry (TEG®/ROTEM®) indicates more coagulability in women than in men [14,17]

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Secondary hemostasis

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Thrombin generation in women compared to men [16]

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Coagulation factors (fibrinogen and coagulation factor VII) and natural anticoagulants (antithrombin and protein C) did not differ substantially between men and women [15] During pregnancy: Coagulation factor VIII, coagulation factor VII, coagulation factor X, and fibrinogen [82,84] Protein S [83,84]

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Platelets from women are characterized by [9-12]: Fibrinogen binding upon ADP exposure Spontaneous aggregation Plasma thromboxane B2 levels

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Number of activated glycoprotein II/IIIa receptors per platelet in women [8]

Fibrinolysis

Postpartum (1 week) Coagulation factor VIII [82] No difference in fibrinolytic measures (plasminogen activator inhibitor-1 and tissue plasminogen activator) among men and women [18] During pregnancy and postpartum: Fibrin-D-dimer [82,83,86] Only very subtle changes occur in soluble fibrin and fibrin monomer complex during normal pregnancy [87,88] Fibrinolytic activity, which returns to normal about 1 hour after

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delivery [82] ADP: adenosine diphosphate

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Table 2. Examples of conditions expected to yield clinically significant sex differences in thrombosis and bleeding risk.

How it differentially affects males and females

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Thromboembolic risk Coronary artery disease

The lifetime risk is higher for men than for women (34.9% versus 24.2%) [28]

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Morbidity and mortality are higher for men than for women [30]

Classical cardiovascular risk factors are more favorable in women than in men [34] Ischemic stroke

The incidence is higher in men than in women except at ages above 85 years [50] Women are usually older at stroke onset and suffer clinically more severe strokes than men [53,54]

The effect of endogenous estrogen might contribute to sex differences Venous thromboembolism

The risk for first, and especially of recurrent VTE, is higher in men than in women [69]

te

d

The VTE risk is increased five-fold during pregnancy and further increased postpartum [89] Bleeding risk

Although not a sex-linked disorder, more women than men are diagnosed and treated.

Deficiency or defect in VWF

As a primary hemostasis disorder, bleeding issues include heavy menstruation and post-partum

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VWD:

hemorrhage.

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Condition

Levels of VWF rise during pregnancy, potentially masking a diagnosis of VWD.

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factor VIII deficiency or

bleeding severity.

abnormality) and

Bleeding issues include mainly joint and muscle bleeds, in severe hemophilia as spontaneous

Hemophilia B (coagulation

bleedings and in mild hemophilia mostly following trauma.

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X-linked disorders, thus males are more affected, both in terms of numbers affected as well as

factor IX deficiency or Immune thrombocytopenia

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abnormality)

Acquired disorder, which is more frequent in women than in men [116], especially in younger women [117].

Higher mortality rates have been demonstrated in ITP compared to the general population, predominantly due to increased cardiovascular disease, infection, bleeding, and hematological cancer [116].

ep

te

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ITP: Immune thrombocytopenia. VWD: von Willebrand disease; VWF: von Willebrand factor. VTE: venous thromboembolism.

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Hemophilia A (coagulation

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Figure 1:Outline of gender-rrelated factors associated with increased risk of cardiovascullar disease in women.

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Gender related issues in thrombosis and hemostasis.

Many aspects of hemostasis, both primary and secondary, as well as fibrinolysis display sex differences. From a clinical viewpoint, certain differenti...
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