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Hormones and Thrombosis

Jean M Connors MD

Medical Director, Anticoagulation Management and Stewardship Services Hematology DivisionBrigham and Women’s Hospital/Dana Farber Cancer InstituteAssociate Professor of Medicine, Harvard Medical Schooltwitter @Connors_md

Jean M Connors, MD

Johns Hopkins University School of Medicine

Medical Residency: BIDMC-East

Hematology-Oncology Fellowship: BWH

Transfusion Medicine Fellowship: HMS Program

in Transfusion Medicine

Associate Professor: HMS

Introduction

Sex hormones can affect coagulation parameters

Both exogenous estrogens and androgens are used in a variety of clinical settings

• Most common use is contraception

• Menopause

• Low testosterone

• Hypogonadism

• Transgender patients

Will focus primarily on COC use in women

• the largest number of patients using hormone treatments

• 65.3% of US women aged 15–49 yrs used any contraception in 2017-2019

• prescribed by many types of practitioners

VTE risk factors

Women and VTE

The absolute rate of VTE in women of childbearing years is low• approximately 5 per 10,000 patient years 1

The risk is increased with pregnancy and the post-partum state 2

• OR 6 during pregnancy• OR 22 postpartum

Hormonal contraceptivesMimic pregnancy state to suppress ovulation, VTE risk not as high as during pregnancy but is higher than baseline

Women with estrogen associated VTE have a very low risk of recurrence if estrogens are stopped3

1. Heineman, Contraception 2007. 2. Sultan, BJH 2012 3. Baglin, Lancet 2003

Pills• “Combination” estrogen/progesterone

• Progesterone agent only

Devices• estrogen/progesterone vaginal ring: Nuva-ring

• estrogen/progesterone patch: Evra

• progesterone coated IUD: Mirena, Lilletta, Skyla

• progesterone implants: Norplant, Nexplanon

Types of Hormonal Contraceptives

Shift in contraceptive use patterns

Contraceptive use patterns by age

• Decreased menstrual blood loss*Iron deficiencyvon Willebrand’s diseaseCoagulopathy or platelet disorders

• Endometriosis

• Dysmenorrhea

• Ovarian cysts

• Polycystic ovary syndrome

• Decreased risk uterine cancer

• Decreased acne

Additional benefits of COC

* Also seen with levonorgestrel IUD

Increase in prothrombotic factors

• Fibrinogen

• vWF

• VIII

• VII

• X

• Prothrombin

Decrease in natural anticoagulant factors

• Protein S

• Acquired resistance to activated protein C

• 40-60% decrease protein S coupled with increased FVIII creates APC resistance

• Inhibitors of fibrinolysis increase

Estrogen effects on coagulation

Middeldorp TH 2000; Kemmerman, Blood 2004

1st generation progestins

norethindrone

norethindrone acetate Lowest potency → issues with bleeding and spotting

ethynodiol diacetate

2nd generation progestins

levonorgestrel More potent & androgenic than 1st generation → improved

libido, but associated with dyslipidemia (↑ LDL, ↓ HDL),

acne and hirsutismnorgestrel

3rd generation progestins

desogestrel Less androgenic (but not much less than norethindrone);

designed to mitigate problems with 2nd generation

progestins (i.e. effective at improving acne and hirsutism

and ↓ LDL, ↑ HDL)norgestimate

4th generation progestins

drospirenone (DRSP)Mildly anti-androgenic; antimineralocorticoid activity;

spironolactone analog (similar diuretic effect)

dienogest

nomogestrol acetate (patch)

Mildly anti-androgenic; derived from testosterone; minimal

effect on lipids

COC: ethinyl estradiol + progestin

Estrogen VTE risk

12

Relative Thrombotic Risk Estrogen Preparation

high to intermediate ethinyl estradiol

high 50 micrograms

intermediate 30/35 micrograms

lower intermediate 20 micrograms

moderately low Conjugated equine estrogen

low Oral estradiol

low Estradiol valerate--parenteral

very low Transdermal estradiol

Manson, JAMA 2013; Scarabin, Lancet 2003; Canonico, BMJ 2008; Canonico, Circ 2007; van Kesteren, Clin Endo 1997;Arnold, J Sex Med 2013; Kahn, Clin Chem 2019; Ott, Fertil Steril 2010

USE

OCP

HRT

VTE risk: estrogen dose and type of progestin

Stegman, BMJ 2013

Network meta-analysis by ethinyl estradiol dose and type of progestin

VTE risk: type of hormonal contraceptive

Adjusted Contraceptive type Adjusted relative

risk

P

value

Non-use 1 --

COC with levonorgestrel and

30-40 mcg estrogen

3.21 (2.70 to 3.81) <0.001

COC with norgestimate 3.57 (2.98 to 4.27) <0.001

contraceptive patch 7.90 (3.54 to 17.65) <0.001

vaginal ring 6.48 (4.69 to 8.94) <0.001

implant 1.40 (0.58 to 3.38) 0.450

levonorgestrel IUD 0.57 (0.41 to 0.81) 0.002

1.6 million non-pregnant Danish women age 15-49 followed 2001-2010 Lidegaard BMJ 2012

Combined thrombophilia and COC risk for 1st VTE

Factor Relative risk Incidence

per yr

Non-use, no risks 1 0.008

PTG-htz 2.8 0.02

Combination oral

contraceptives

4 0.03

FVL-htz 7 0.06

COC + FVL-htz 35 0.29

COC + FVL-hmz 80 0.5 to 1

Vandenbroucke Lancet 1994

Type of thrombophilia Prevalence 1st

VTE

Increased procoagulant activity

Factor V Leiden White 5%

Hispanic 2.2%

Black 1.2%

Native American 1.2%

Asian 0.4%

4-5 x

Prothrombin gene G20210A White 3% 3-4 x

Decreased anticoagulant activity

Protein C deficiency < 0.5% 7 x

Protein S deficiency <0.5% 5 x

Antithrombin deficiency <0.5% 16 x

Ridker JAMA 1997, Ridker Circ 1999

Prevalence of inherited thrombophilias in the US population

• Age > 35 and smoking

• Multiple arterial cardiovascular risk factors

• HTN systolic >160 mmHg or diastolic > 100 mmHg

• VTE

• Known thrombogenic mutations

• Known ischemic heart disease

• History of stroke

• Complicated cardiac valve disease

• Breast cancer

• Cirrhosis

• Migraine with aura

• Hepatocellular adenoma or malignant hepatoma

CDC: unacceptable risk for use of COC

2016

Endorsed by the

American College of

Obstetrics & Gynecology

CDC Example: Smoking and Contraceptive Use

Cu IUD: Copper IUD; LNG-IUD: Levonorgestrel IUD; DMPA: Depo-Medroxyprogesterone Acetate; POPs: Progestin-only pills; CHCs: Combined hormonal contraceptives including pills, patch, and ring

Category 4:

unacceptable health

risks for MI and strokewww.cdc.gov/reproductivehealth/contraception/contraception_guidance.htm

Patients for whom COC are acceptable

• No personal or family history of VTE and no known thrombophilia

• Recommend:

lowest risk: Low estrogen dose and levonorgestrel

Discussion with patient, gynecologist regarding individual patient benefits

and risk with various COC profiles.

Thrombophilia screening prior to COC use in women without personal history or

family history of VTE not endorsed. NNT is 666 to prevent one VTE.

Middledorp, JTT 2011

What to advise

Patients for whom COC are not acceptable

• Personal or appropriate family history of VTE

• Known thrombophilia

• High risk deficiencies of protein S, protein C, AT, homozygous FVL, compound mutations without personal history of VTE

• Lower risk heterozygous FVL or PTG with personal or family history of VTE

• Recommend:

• Levonorgestrel IUD

• “mini” pill, progestin only

• Other non-hormonal forms of contraception

What to advise

Patients for whom COC risk are uncertain

• Controversial: low risk thrombophilia heterozygous FVL or heterozygous PTG and no personal or family history of VTE

For all patients:

Shared decision making after individualized risk-based counseling.

What to advise

• Smoking

• Obesity• Weight: BMI > 30 kg/m2

OR 2.4 for VTE with increased BMI

OR 24 with COC and obesity Pomp BJH 2007

• Personal and family history of VTE

• Lipid profile

• Diabetes

• Hypertension

Individual risk assessment profile needs to be considered in all patients

Assess standard VTE and cardiovascular risks

For women with acute VTE on anticoagulation continuation of COC is accepted practice

• ENSTEIN VTE and PE studies: no difference in recurrent VTE in women who continued hormone treatments vs those that stopped (3.7% vs 4.7%) Martinelli Blood 2016

For some women with complex medical conditions, use of COC in conjunction with anticoagulation can be necessary

• Including those deemed unacceptable by CDC

• Inherited thrombophilias

• Cystic fibrosis

• Congenital heart disease

• Endometriosis, Polycystic ovarian syndrome

• Consider reduced dose DOAC

Individual risk assessment profile needs to be considered in all patients

Pragmatic Management Approach

Thank you