Menopausal Hormone Therapy & Haemostasis

Menopausal Hormone Therapy & Haemostasis The Haematologist Perspective Dr. Batia Roth-Yelinek Coagulation unit Hadassah MC

Menopausal Hormone Therapy & Hemostasis Hemostatic mechanism Mechanism of estrogen related thrombosis Thrombophilia and HRT Acquired risk factors: Age Other host factors Transient risk factors CV risk factors Effect of type of HRT & route of administration Risk stratification

Platelet Activation Adhesion Secretion Aggregation Pro-coagulant activity:

The Coagulation Cascade

Natural Anticoagulants & Fibrinolysis

The Haemostatic Balance Procoagulats Thrombosis Anticoagulants fibrinolysis bleeding 7

The effect of Postmenopausal HT on Hemostasis Procoagulants activity Increased amounts of coagulation factors (FVIII, FVII, TF, fibrinogen, prothrombin) Not consistent effect (different compounds, +/- progestones, dose, routes, older/new studies etc.) Anticoagulants activity Significantly reduced levels of antithrombin, protein C, protein S, and TFPI (by 5% 30%) Acquired APC-R (PS decreased, EPCR upregulated) Fibrinolytic activity Plasminogen activator inhibitor 1 (PAI-1) decreased with oral estrogens Increased d dimer & TAT complexes Sex hormone binding globulin (SHBG) increased: marker of estrogen stimulation ( total estrogenicity ) Endothelial function (???) Per Morten Sandset Thrombosis Research 131, Suppl. 1 (2013) S4 S7 Canonico M. Menopause 2014;21(7);753-762

HRT & Risk of VTE in Postmenopausal Women: observational studies 2015 update: 8 case-control studies 6 prospective cohort studies 6 randomized controlled trials (RCT) the risk of first VTE among women taking oral estrogens: OR close to 2 and very significant Finish cohort: estradiol-based (not CEE) HT reduced cardiovascular and all cause mortality Odds ratio of VTE associated with oral estrogen: 2.5 (95% CI 1.9 3.4) Canonico M. et al, BMJ. 2008;336(7655):1227-31; Canonico M. Maturitas 82 (2015) 303 306 Mikkola TS et al, Menopause 2015;22(9);976-983

HRT & Risk of VTE in Postmenopausal Women: Randomized controlled trials Canonico M. et al, BMJ. 2008;336(7655):1227-31;

Risk Factors for Thrombosis (VTE) Osinbowale O. et al Postgraduate Medicine May 2010;122(2) Coppola A. et al Semin Thromb Hemost 2009;35(7);683-94

Relative Risk Estimates for Common Clinical Manifestations of Thrombophilia AT deficiency PC Deficiency PS Deficiency Factor V Leiden PT 20210 Elevated FVIII APLs Ab s Prevalence in the general population 0.02% 0.2% 0.03%-0.13% 3%-7% 0.7%-4% Cut-off level 1%-8% RR for 1 st VTE 5-10 4-6.5 1-10 3-5 2-3 5 2.4-10 RR for recurrent VTE 1.9-2.6 1.4-1.8 1.0-1.4 1.4 1.4 1.3-6.7 1-6 RR for arterial thrombosis No association No consistent association No consistent association 1.3 0.9 3.1 1.5-10 Middledorp S. ASH Education Program December 2011 Lijfering WM. et al Blood 2009;114;2031-2036

Relative Risk Estimates for Common Clinical Manifestations of Thrombophilia Prevalence in the general population AT deficiency 0.02% PC Deficiency 0.2% PS Deficiency 0.03%-0.13% 32% 5% Factor V Leiden 5% 3%-7% 5% PT 20210 0.7%-4% Elevated FVIII Cut-off level APLs Ab s 1%-8% RR for 1 st VTE 5-10 4-6.5 1-10 18% 3-5 33% 2-3 5 2.4-10 RR for recurrent VTE 1.9-2.6 1.4-1.8 1.0-1.4 1.4 1.4 1.3-6.7 1-6 RR for arterial thrombosis No association No consistent association No consistent association 1.3 0.9 Prevalence of thrombophilia among first VTE patients 3.1 1.5-10 Middledorp S. ASH Education Program December 2011 Lijfering WM. et al Blood 2009;114;2031-2036

Selected Thrombophilias & HRT Use Absolute Risk of VTE by Factor V Leiden Genotype and treatment assignment Odds ratios for the risk of venous thromboembolism in studies of selected thrombophilias and hormone replacement therapy use Herrington: HERS and ERA trials Postmenopausal women, <80y, with CHD Cases (n =48): thrombotic event during trial Controls(n=112): no thrombosis Rosendaal: Cases (n =77): 1 st VTE 51% received HRT, 23% FVL or PT mutation No PT mutation and HRT Controls(n=163) diagnoses unrelated to thrombosis and HRT Wu O. et al. TREATS Study Thromb Haemost 2005; 94: 17-25 Herrington DM et al, Arterioscler Thromb Vasc Biol. 2002;22:1012-1017

Selected Thrombophilias & HRT Use Herrington: HERS and ERA trials Postmenopausal women, <80y, with CHD Cases (n =48): thrombotic event during trial Controls(n=112): no thrombosis Odds ratios for the risk of venous thromboembolism in studies of selected thrombophilias and hormone replacement therapy use Rosendaal: Cases (n =77): 1 st VTE 51% received HRT, 23% FVL or PT mutation No PT mutation and HRT Controls(n=163) diagnoses unrelated to thrombosis and HRT. Wu O. et al. TREATS Study Thromb Haemost 2005; 94: 17-25 Herrington DM et al, Arterioscler Thromb Vasc Biol. 2002;22:1012-1017

Thrombophilia, HRT, Venous Thrombosis the role of family history Data from the MEGA study: 2550 women, age >50y, 1082patients with 1 st VT and 1468 controls Roach REJ et al, J Thromb Haemost 2013; 11: 124 31

The Role of Family History: data from the TEHS The ThromboEmbolism Hormone Study (TEHS) Swedish nationwide case-control study 1433 cases and 1402 controls 1328 & 1288 analyzed, aged between 18 and 65 Cases: 1 st VTE Female controls: selected randomly from a population register HT: 187 (14%) of cases & 113(9%) of controls FVL: 298 (23%) & 106 (8%) PT mutation: 76 (6%) & 37 (3%) Family history, genetic carrier ship and the risk of VTE Family history of 1 st degree relatives and the risk of VTE Sonnevi K. et al. Thrombosis Research 2013;132;164 169

strong weak Acquired Risk Factors for Thrombosis obesity elderly Varicosity Immobility Medical conditions Previous VTE Hormone replacement therapy COC/pregnancy Malignancy & chemotherapy Major trauma Major orthopedic surgery

Incidence of Venous Thromboembolism According to Age First time VTE: 1:1,000 persons/year Age factor 15y: <5 :100,000/year 25-35y: 30/100,000/year 80y: 5/1,000/year (0.5%) 22% Age distribution of VTE events Heit JA Nat Rev Cardiol. 2015 August ; 12(8): 464 474 20

The Age Factor Rate of VTE (per 10,000 women/year) Average increase in risk with oral estrogen: X 2.5 In 1 st time users: X 4 Absolute risk of VTE in peri/post menopausal women with & without HRT Annualized rate/1,000 person-years Rate of stroke (per 10,000 women/year) Oral HRT vs. transdermal X 1.3increased risk Basal risk in 50-54 vs. 65-74: X11 Rott H. Intern J Gen Med2014:7;433 440 L Hermite M. Climacteric 2013;16(Suppl 1):44 53

Canonico M. et al, BMJ. 2008;336(7655):1227-31

Oral vs Transdermal Estrogen Therapy and Vascular Events 1 st episode Meta-analysis of risk of vascular events in postmenopausal women using oral estrogen vs transdermal ET 10 case control studies, 5 cohorts, no RCTs Transdermal better, except for MI Mohammed K. Et al, J Clin Endocrinol Metab 2015;100;4012 4020

Changes in Hemostatic Parameters after HRT Effect of oral and transdermal hormone therapy transdermal estrogens have little or no effect on hemostasis. Bagot CN et al, J Thromb Haemost 2010; 8: 1736 44

The Duration of HT and the Risk of Thrombosis data from the MEGA study Study population: women >50y 1082 patients, 1468 controls Roach REJ et al, J Thromb Haemost 2013; 11: 124 31 Canonico M. et al, BMJ. 2008 May 31;336(7655):1227-31

strong weak Canonico M. et al, BMJ. 2008 May 31;336(7655):1227-31 Acquired Risk Factors for Thrombosis obesity elderly Varicosity Immobility Medical conditions Previous VTE Hormone replacement therapy COC/pregnancy Malignancy & chemotherapy Major trauma Major orthopedic surgery

The Association between Venous & Arterial Thrombosis Arterial and venous thrombosis share common risk factors e.g. age, obesity, smoking, cancer etc. Data from nationwide Danish medical databases: Adjusted RR for MI/stroke 1y after PE: 2.73 (95% CI 2.36-3.13) Increased long-term (20yFU) risk of subsequent arterial event Sorensen HT. et al, Lancet 2007;370;1773-79 Common abnormalities of various blood constituents e.g. CRP, fibrinogen Luxembourg B. et al, thromb haemost, 2009; 102;668 675 Markers of endothelial dysfunction significantly higher in patients with unprovoked DVT than in matched controls Migliacci R. et al, haematologica, 2007;2;812 818 Microalbuminuria, usually associated with arterial cardiovascular events, independently associated with an increased risk for VTE as well Mahmoodi BK et al, JAMA, 2009;301;1790 1797 Cumulative incidence of arterial events in patients with idiopathic VTE and controls adjusted HR: 2.86; 95% CI:1.07 7.62

Thrombosis Research 134 (2014) 1028 1031 Previous study: higher prevalence of asymptomatic atherosclerosis in patients with unprovoked deep vein thrombosis (DVT) than in those with provoked DVT and in control subjects Prandoni P. et al. N Engl J Med 2003;348:1435 41 Prevalence of atherosclerosis in patients with VTE: Comparison between patients with unprovoked VTE (A), Provoked VTE (B), Controls (C) Clinical presentation symptomatic or subclinical atherosclerosis Symptomatic AS subclinical AS presence of plaques A to B 5.1 95% CI, 2.0 to 13.1 1.4 95% CI, 0.7 to 2.8 2.0 95% CI, 1.1 to 3.8 5.4 95% CI, 2.0 to 12.3 A to C 14.5 95% CI, 5.8 to 36.3 2.6 95% CI, 1.3 to 5.3 8.4 95% CI, 2.8 to 13.5 10.1 95% CI, 4.5 to 22.5 OR adjusted for thrombophilia and for other potential risk factors of atherosclerosis B to C NA 2.3 95%CI, 1.1 to 4.6 2.4 95% CI, 1.2 to 8.5 2.2 95% CI, 1.0 to 4.8

Is postmenopausal HT suitable after Arterial event?? HRT impact on cardiovascular events in randomized trials: non-fatal cardiovascular (CV) events, cardiovascular and total mortality not significantly affected Estrogen more risky for women > 60y and in later stages of atherosclerosis Anderson GL et al, for WHI JAMA 2004;291(14):1701 1712 Salpeter SR. et al, J Gen Intern Med 2006;21(4):363 366 Risk of CV events temporarily increased (X2.5) in the first year after starting HRT. Recommendation: not to start HRT within the first year after a CV event (WHI, HERS, NHS) Management of CV risk factors lowers risk (???) Choice of HRT: Low dose estradiol preferentially as transdermal patches, +/- metabolically neutral progestins appears to convey lower risk Should HRT be discontinued after the onset of a cardiovascular event? Observational studies not conclusive. Labeled as contraindicated in women after MI Cumulative incidence of arterial events Meta-analysis of relative risks of HRT in cardiovascular secondary prevention Windler E. et al, Arch Gynecol Obstet (2015) 291:213 217 Main C. et al, Cochrane Database Syst Rev 2013

Summary HT is the most effective treatment for climacteric symptoms The beneficial effect should be weighted against the risks, especially the thrombotic risk Choose wisely: Whom to treat: Thrombophilia or previous thrombosis Family history Age Other acquired risk factors and co-morbidities Management of transient risk factors Which treatment to administer chemical structure of estrogens, Pharmacologic class of progestogens Route dose duration