Women Issues and Thrombosis -...

Women Issues and Thrombosis

Sabine Eichinger

Dept. of Medicine IMedical University of Vienna/Austria

Annual incidence of VTE

0,0

0,4

0,8

1,2

1,6

2,0

DVT PE + DVTall VTE

Naess, J Thromb Haemost 2007

1.43(95% CI 1.33–1.54)

0.93(95% CI 0.85–1.02)

0.5(95% CI 0.44–0.56)

per

1000

per

sons

Risk conditions / risk factors of VTEAdvancing age

Obesity

Previous venous thromboembolism

Surgery

Trauma

Active cancer

Acute medical illnesses—eg, acute myocardial infarction,

Heart failure, respiratory failure, infection

Inflammatory bowel disease

Antiphospholipid syndrome

Dyslipoproteinaemia

Nephrotic syndrome

Paroxysmal nocturnal haemoglobinuria

Myeloproliferative diseases

Behçet’s syndrome

Varicose veins

Superficial vein thrombosis

Congenital venous malformation

Long-distance travel

Prolonged bed rest

Immobilisation

Limb paresis

Chronic care facility stay

Pregnancy/puerperium

Hormone contraceptives

Hormone replacement therapy

Heparin-induced thrombocytopenia

Other drugs

Chemotherapy

Tamoxifen

Thalidomide

Antipsychotics

Central venous catheter

Vena cava filter

Intravenous drug abuse

Factor V Leiden

Factor II G20210A

Natural inhibitor deficiency

High factor VIII, factor IX, or factor XI

Lupus anticoagulant

High thrombin activatable fibrinolysis inhibitor

Hyperhomocysteinaemia

Dysfibrinogenaemia or hyperfibrinogenaemia

Plasminogen deficiency

from Kyrle & Eichinger, Lancet 2005

• Sex related differences in hemostasis

Women issues and thrombosis

Coagulation factors in women compared to men

Sex-related differences

FibrinogenF VII, VIII, IX

Lowe, Br J Haematol 1997

Anticoagulant system

Antithrombin

Protein S

Protein C (except older age)



F1+2

TAT

(D-Dimer)

Coagulation activation




• Specific hormone-related issues– Pregnancy


Pulmonary embolism is the most frequent cause of death during pregnancy or puerperium

1 of 500 women will have a venous thrombosis during pregnancy or puerperium

Altered Rheology

Pregnancy

Vascular Injury

Altered Hemostasis

Prothrombotic State

Coagulation factors

Hemostasis during pregnancy

FibrinogenF VII, VIII, IX, X, XIIvWF

F V, XIII

F XI



ThrombomodulinTFPI

Protein SAPC-ratio

Protein C Antithrombin

Fibrinolytic system


PlasminogentPA

PAI-1PAI-2

TAFI

F1+2

TAT

FPA

Soluble fibrin

D-Dimer

Plasmin-antiplasmin complexes

Coagulation activation

Increased fibrin generation Increased fibrinolysis


12 24 34

week of gestation

1000

3000

500

D-D

imer

(ng

/ml)

*

**

P<0.001

P<0.001

with LMWH (n = 66)

w/o LMWH (n = 113)

* p<0.001

Hoke & Eichinger, Thromb Haemost 2004

D-Dimer during pregnancy

36 year old woman

• 1st pregnancy, 7th week of gestation after ovarian stimulation • Hormone therapy progesteron

• Regular consultancies at endocrinology clinic because of hypothyroidism

• Palpitations since 3 days• Dyspnoe, acute

• ER suspicion of PE

36 year old woman

• Otherwise healthy • No previous VTE• Father PE, FV Leiden heterozygous

• Patient‘s thrombophilia screen normal• Heart rate 101/min• ECG: normal

Approach to a patient with suspicion of VTE

Clinic ImagingLab

Diagnostic issues of VTE in pregnancy

Not validated for pregnant women

• Some signs and symptoms may be pregnancy related

• Probability of VTE similarly high throughout pregnancy

• In ~ 90% left leg affected

• OR for VTE: ~ 4 during pregnancy, ~14 during puerperium, higher after cesarian section

• Iliac vein thrombosis relatively frequent

– groin pain, radiating to the back

Clinical assessment - pretest probability


• D-Dimer 0.74 µg/ml ( < 0.5 µg/ml)

36 year old woman

Week of gestation Patients, n 95% CI

<12 0 (0%) 0 - 60

13-28 12 (24%) 14 - 37

>28 41 (51%) 40 - 61

Chan W, Ann Intern Med 2007

Positive D-Dimer result in pregnant women

• Cross-sectional study

• 194 unselected pregnant women with suspected DVT

• Intervention:

– CUS, follow-up 3 months

– Independent clinical assessment

• 17 women (8.8%) had documented DVT

Chan, Ann Intern Med 2009

Predicting DVT in pregnancy


Potential predictive variables for DVT in pregnancy


Pretest probability and performance of LEFt variables

Approach to a woman with suspicion of VTE

Imaging


DVTcompression ultrasoundphlebography

PEventilation/perfusion scancomputed tomography

Compression ultrasound to exclude DVT

Chan, CMAJ 2013

• No evidence for safety of ruling out PE by V/Q scan or CT from prospective studies

• Radiation– Teratogenesis

– Carcinogenesis

• Contrast media

Diagnosis of PE – concerns during pregnancy


Radiation dose to the fetus

Radiation (mSv)

Unilateral phlebography without shielding 3.14

Unilateral phlebography with shielding < 0.5

Perfusion scintigraphy (99mTc MAA, 200 MBq) 0.2-0.6

Perfusion scintigraphy (99mTc MAA, 40 MBq) 0.11-0.2

Ventilation sintigraphy (99mTc MAA, aerosol) 0.1-0.3

Ventilation scintigraphy (81m Kr, 600 MBq) 0.0001

Single-detector row helical CT 0.026

Multi-detector row helical CT 0.013

Natural radiation exposure 3.8/a

Nijkeuter, J Thromb Haemost 2006

• Teratogenesis no major concern after CT

• Carcinogenesis: – V/Q scan: higher risk for fetus

– CT: higher risk for mother

• Contrast media:– Iodinated: seems safe, usual procedure

– Gadolinium: contraindicated

Diagnosis of PE - imaging techniques


Suggested algorithm for exclusion of PE during pregnancy

Clinical Suspicion

CUS

no DVT DVT

treat

Multi-slice CT (+shielding) / VQ scan(consider clinic, risks, D-Dimer)

D-Dimer


consider clinic, risks, D-Dimer

36 year old woman

• Week 7 proximal DVT left leg• LMWH at therapeutic dose (weight adjusted)

• Duration: throughout pregnancy until 6-8 wks after delivery

• LMWH dose reduction before delivery • Outpatient care possible

Treatment of VTE during pregnancy

Bates, Chest 2012

Assisted reproduction

• For women undergoing assisted reproduction, we

recommend against the use of routine thrombosis

prophylaxis (1B).

• For women undergoing assisted reproduction who develop

severe ovarian hyperstimulation syndrome, we suggest

thrombosis prophylaxis (prophylactic LMWH) for 3 months

postresolution of clinical ovarian hyperstimulation syndrome

rather than no prophylaxis (2C) .

Fetal loss

Prevalent• 0.5 – 1% of couples (>3)• 3% of couples (>2)

Recurrent miscarriage (revised nomenclature 2005)

• 3 early (before 12 weeks of gestation) consecutive losses, or• 2 late (after 12 weeks of gestation) pregnancy losses

Rai, Lancet 2006; Farquharson, Hum Reprod 2005

Recurrent miscarriage

~ 50% explained

• Chromosomal abnormalities in the fetus• Abnormal karyotype in the parents• Cervical incompetence• Endometrial infections• Endocrine disorders

• Thrombophilia?

Thrombophilia and pregnancy complications

Rey, Lancet 2003; Robertson, Br J Haematol 2006; Nelen, Fertil Steril 2000

Thrombophilia Sporadic miscarriage OR

Recurrent miscarriageOR

IU fetal deathOR

Lupus anticoagulant 3.0 7.8 2.4

Anticardiolipin antibodies 3.4 3.6 - 5.1 3.3

AT deficiency 1.5 0.97.6 (1.3 - 42.8)

20.1 (3.7 - 109.2)

PC deficiency 1.4 1.6 3.1

PS deficiency heterogeneous data 14.7 (1.0 - 218.0)7.4 (1.3 - 42.8)

20.1 (3.7 - 109.2)

Factor V Leiden 1.7 2.0 2.1 - 3.3

Prothrombin 20210A 2.1 2.3 - 2.7 2.3 - 2.7

Homozygous/ combined defects 2.7 - -

Hyperhomocysteinemia 6.3 2.7 - 4.2 1.0

Clinical criteria

• Thrombosis and/or• pregnancy complications:

– >1 intrauterine fetal death (> 10th week); or– >3 consecutive miscarriages (< 10th week); or– >1 preterm delivery < 34th week because of eclampsia, severe

preeclampsia, or placental insufficiency

Laboratory criteria (2 exams, 12 weeks apart)

• Lupusanticoagulants; or • Anticardiolipin-ab (IgG or IgM) medium or high titer (>40 GPL or MPL

or >99th percentile); or • Anti-ß2 glycoprotein-I ab (IgG or IgM; > 99th percentile)

Miyakis, J Thromb Haemost 2006

APLA-Syndrome

Scenario 1: PLA +, previous miscarriage

Phospholipidantibodies during pregnancy

Relevance

LAC ACA ß2GP-AK

Recurrent pregnancy loss ++ + ?

Late pregnancy loss ++ + ?

Preeclampsia +/- +/- ?

Placental abruption +/- +/- ?

IUGR +/- +/- ?

Opatrny, J Rheumatol 2006


Pregnancy complications and PLA: metaanalysis

Early loss Late loss Preeclampsia IUGR

LAC 2.97 (1.0-9.8) 2.4 (0.8-7.0) 1.5 (0.7-4.6) 6.9 (2.7-17.7)

ACA 3.4 (1.3-8.7) 3.3 (1.6-6.7) 2.7 (1.7-4.5) NA

Robertson, Br J Haematol 2005


Pregnancy complications and PLA

Pregnancy lossHR (95% CI)

UFH+ASS vs. ASS 0.46 (0.3-0.7)

LMWH+ASS vs. ASS 0.78 (0.4-1.6)

Ig vs. UFH/LMWH+ASS 2.51 (1.3-5.0)

Empson, Cochrane Database of Systematic Reviews 2005


Aspirin and pregnancy loss



Heparin and pregnancy loss


Mak, Rheumatology 2010

RR 1.3 (95% CI 1.04 - 1.6)

Live births: metaanalysis


Recommendations

• For women who fulfill the laboratory criteria for PLA syndrome and meet the clinical PLA criteria based on a history of > 3 pregnancy losses, we recommend antepartum administration of prophylactic LMWH combined with low-dose aspirin, 75 to 100 mg/d, over no treatment (1B).

Bates, ACCP Guidelines, Chest 2012Keeling, Br J Haematol 2012


ALIFE Study

Kaandorp, N Eng J Med 2010

SPIN Study

Clark, Blood 2010

Enoxaparin 40 mg + ASA 75 mg

Intensive surveillance

> 2 consecutive pregnancy losses 147 147

Pregnancy loss 32 (22%) 29 (20%)OR 0.91 (95% CI 0.5-1.6)

HAPPY Trial

Martinelli, Blood 2012

N=63

N=65

Recommendations

• For women with recurrent early pregnancy loss (>3 miscarriages <10 weeks of gestation), we recommend screening for PLAs (1B).

• For women with a history of pregnancy complications, we suggest not to screen for inherited thrombophilia (2C).

• For women with APS and a history of preeclampsia or IUGR, low dose aspirin is recommended.

• Given the absence of evidence that women with PLA syndrome and a single late pregnancy loss, preeclampsia, or fetal growth restriction benefit from the addition of UFH or LMWH to aspirin, we do not recommend for or against screening for PLAs in women with these pregnancy complications.

Bates, ACCP Guidelines, Chest 2012Keeling, Br J Haematol 2012

Tender loving care

195 couples with recurrent (3 or more) miscarriage 85 without explanation

Dedicated antenatal care, psychological support: live birth rate 86% No specific antenatal care: live birth rate 33 %

Stray-Pedersen, Am J Obstet Gynecol 1984

Scenario 2: PLA +, previous VTE


Vitamin K antagonists and pregnancy

Warfarin-embryopathy- 6th to 9th (12th) gestational week- Dose dependent- Prevalence 5 – 7%- Bone and cartilage malformation

- CNS-defects (opticus atrophy, microcephaly, mental retardation), Pathomechanism unclear

• Conception during warfarin stop when pregnancy is confirmed

• LMWH at therapeutic dose (weight adjusted)

• Last therapeutic dose 24 before planned delivery

• Post partum switch to oral anticoagulant

Scenario 2: PLA +, previous VTE



• Specific hormone-related issues– Pregnancy

– Hormone use• Oral contraceptives

• Hormone replacement therapy


Coagulation factors during oral contraceptives

FibrinogenF II, VII, VIII, X

Lowe, Br J Haematol 1997; Middeldorp, Thromb Haemost 2000


F V


APC-ratioProtein S


Lowe, Br J Haematol 1997; Rosing, Lancet 1999; Tans, Thromb Haemost 2000

AntithrombinProtein C

Estimated annual incidence of venous thrombosis

OC –

Vandenbroucke, Lancet 1994

all > 70 yrs OC +

1/100

1/10 000 3-4/10 000

Thrombosis Risk According to Duration of OC Use

Van Hylckama Vlieg, BMJ 2009

Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis Study(MEGA)

Risk of venous thrombosis



Thrombosis risk according to oestrogen dose



Risks with use of combined contraceptives

van Hylckama Vlieg, J Thromb Haemost 2011

MEGA case-control study

OR (95% CI)

Danish nationalcohort study

RR (95% CI)

Combined oral contraceptivesEstrogen 30 µg + noresthisteroneEstrogen 30 µg + levonorgestrelEstrogen 37.5 µg + lynestrenolEstrogen 30 µg + norgestimateEstrogen 30 µg + desogestrelEstrogen 30 µg + gestodeneEstrogen 30 µg + drospirenoneEstrogen 35 µg + cyproterone acetate

IUD (Mirena)

3.9 (1.4-10.6)

3.6 (2.9-4.6)

5.6 (3.0-10.2)

5.9 (1.7-21.0)

7.3 (5.3-10.0)

5.6 (3.7-8.4)

6.3 (2.9-13.7)

6.8 (4.7-10.0)

0.3 (0.1-1.1)

2.02 (1.75-2.34)

3.55 (3.30-3.83)

4.00 (3.26-4.91)

0.89 (0.64-1.26)

Risks with use of progestin-only contraceptives

Mantha, Br Med Journal 2012

Oral preparations

Risks with use of progestin-only contraceptives

Mantha, Br Med Journal 2012

Injectables

Hormone contraceptives and thrombotic risk

• Female hormone intake increases the thrombotic risk• Combined oral contraceptives:

– risk related to dose of estrogen and type of progestogen– safest option levonorgestrel combined with a low dose of

estrogen

• Progestogen-only contraception:– Limited data – Oral preparations considered as generally safe – No increased risk with IUD-Mirena

Estimated annual incidence of venous thrombosis

OC –FVL –

Vandenbroucke, Lancet 1994

all > 70 yrs OC + OC +FVL +

FVL +

1/100

0.8/10 000 3/10 0005.7/10 000

28.5/10 000

Family history and the risk of a first VTE

Family history Odds Ratio (95% CI)

negative 1.0 (ref.)

AllAny relative>1 relative

2.5 (1.9 - 3.2)

4.2 (2.4 - 7.4)

Genetic factors*Any relative>1 relative

2.7 (1.7 - 4.4)

4.9 (1.8 - 13.4)

Bezemer, Arch Intern Med 2009

* Low AT/PS/PC, FVL, FII 20210A

Hormone contraception

Recommendations to a woman without VTE

First degree relative + VTE

• Not tested consider alternative contraception• Tested and positive consider alternative contraception• Tested but negative consider alternative contraception


• Estrogen (to relief symptoms)– oral, transdermal, intravaginal– daily

± Progestogen (for endometrial protection)– oral, transdermal, IUD– cyclic or daily

• Tibolone– oral synthetic steroid; estrogenic, androgenic, and

progestogenic actions

= FVIII, AT, PC, PS, F1+2, TAT

Fibrinogen, FVII, FIX

Menopause

Effect on hemostatic parameters


Effect on hemostatic parameters


Teede, ATVB 2000

Risk of thrombotic events: meta-analysis

Sare, Eur Heart J 2008

Subjects / Events OR (95% CI) P-value

VTE 42 381 / 547 2.05 (1.44–2.92) <0.0001

Cerebrovascular Disease 43 549 / 1034 1.24 (1.09–1.41) 0.001

Coronary Heart Disease 43 159 / 1636 1.00 (0.90–1.11) 0.97


Risk of VTE according to dose

HRT exposure Rate ratio (95% CI)

Oral estrogenLow doseHigh doseVery high dose

1.52 (1.44–1.61)

1.19 (1.04–1.35)

1.55 (1.45–1.65)

1.84 (1.63–2.09)


Renoux, J Thromb Haemost 2010

Risk of VTE according to dose

HRT exposure Rate ratio (95% CI)

Oral estrogenLow doseHigh doseVery high dose

1.52 (1.44–1.61)

1.19 (1.04–1.35)

1.55 (1.45–1.65)

1.84 (1.63–2.09)

PatchLow doseHigh dose

1.00 (0.89–1.12)

0.99 (0.87–1.12)

1.05 (0.81–1.36)


Renoux, J Thromb Haemost 2010

Cases / Controls OR (95% CI)

Non-users 93 / 261 1.0 (ref.)

Oral estrogen 32 / 27 3.5 (1.8–6.8)

Transdermal estrogen 30 / 93 0.9 (0.5–1.6)

Scarabin, Lancet 2003


Risk of VTE during estrogen replacement

HR (95% CI)

Non-users 1.0 (ref.)

Micronized progesterone 0.9 (0.6-1.5)

Pregnane derivatives 1.3 (0.9-2.0)

Norpregnane derivatives 1.8 (1.2 -2.7)

Nortestosterone 1.4 (0.7–2.4)


Risk of VTE: effect of progestogens

Canonico, Arterioscler Thromb Vasc Biol 2010


• Female hormone intake increases the risk of VTE

• Risk related to dose and type of estrogen and route of

administration

• Increased by additional progestogens

• Related to type of progestogen

• Risk benefit ratio must be assessed in each woman

0 1 2 3 4 5 6 7

p<0.0001

Men

Women

10

20

30

40

Men vs. Women

Years after anticoagulation

Prob

abili

ty o

f re

curr

ence

%

Kyrle, N Engl J Med 2004

50

Risk of recurrent VTE

Risk of recurrence

Years after Discontinuation of Anticoagulation

Cum

ulat

ive

Prob

abili

ty o

f Re

curr

ence

(%

)

n = 145

n = 272

no combined contraceptive use

combined contraceptive usep < 0.001

*FV Leiden,, age and site of index VTE Eischer, J Thromb Haemost 2014

events/patients (n/n) RR* (95% CI)

Estrogen - 49/297 1

Estrogen + 22/333 0.4 (0.2-0.8)

CC - 27/145 1

CC + 14/272 0.4 (0.2-0.8)

HRT - 39/203 1

HRT + 8/57 0.7 (0.3-1.5)

* adjusted for age, site of VTE and F V Leiden

Risk of recurrence

Eischer, J Thromb Haemost 2014

Female hormone intake

Study Intervention Recurrence/100 pt. years

95% CI

ChristiansenJAMA 2005

OC continued OC discontinued

2.8%1.3%

1.6 – 5.00.8 – 2.1

HøibraatenThromb Hamost 2000

HRTPlacebo

8.5%1.1%

2.6 – 14.40 – 3.2

Risk of recurrent VTE

Risk of recurrence: route of administration

Olié, Menopause 2011


Cases / Controls OR (95% CI)

Non-users 93 / 261 1.0 (ref.)

Oral estrogen 32 / 27 6.4 (1.5 – 27.3)

Transdermal estrogen 30 / 93 1.0 (0.4 – 2.4)

Risk of recurrent VTE in men and women

• The risk of recurrent VTE is significantly lower in women than in men.• No specific predictor of recurrence with the exception of high FVIII

was found in men.• In women several distinct risk factors of recurrence could be

identified: high D-Dimer, high FVIII, high FIX, FII G20210A, overweight, high hematocrit

The difference between men and women - a conundrum!

Women Issues and Thrombosis -...

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