1. Women Issues and Thrombosis
Sabine Eichinger
Dept. of Medicine I
Medical University of Vienna/Austria

2. 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)
per1000persons

4. Risk conditions / risk factors of VTE
Advancing 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

5. • Sex related differences in hemostasis
Women issues and thrombosis

6. Coagulation factors in women compared to men
Sex-related differences
Fibrinogen
F VII, VIII, IX
Lowe, Br J Haematol 1997

7. Anticoagulant system
Antithrombin
Protein S
Protein C (except older age)
Sex-related differences
Lowe, Br J Haematol 1997

8. F1+2
TAT
(D-Dimer)
Coagulation activation
Sex-related differences
Lowe, Br J Haematol 1997

9. • Sex related differences in hemostasis
• Specific hormone-related issues
– Pregnancy
Women issues and thrombosis

10. 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

11. Altered Rheology
Pregnancy
Vascular Injury
Altered Hemostasis
Prothrombotic State

12. Coagulation factors
Hemostasis during pregnancy
Fibrinogen
F VII, VIII, IX, X, XII
vWF
F V, XIII
F XI

13. Anticoagulant system
Hemostasis during pregnancy
Thrombomodulin
TFPI
Protein S
APC-ratio
Protein C
Antithrombin

14. Fibrinolytic system
Hemostasis during pregnancy
Plasminogen
tPA
PAI-1
PAI-2
TAFI

15. F1+2
TAT
FPA
Soluble fibrin
D-Dimer
Plasmin-antiplasmin complexes
Coagulation activation
Increased fibrin generation Increased fibrinolysis
Hemostasis during pregnancy

16. 12 24 34
week of gestation
1000
3000
500
D-Dimer(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

17. 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

18. 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

19. Approach to a patient with suspicion of VTE
Clinic ImagingLab
Diagnostic issues of VTE in pregnancy
Not validated for pregnant women

20. • 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
Diagnostic issues of VTE in pregnancy

21. • D-Dimer 0.74 µg/ml ( < 0.5 µg/ml)
36 year old woman

22. 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

23. • 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

24. Chan, Ann Intern Med 2009
Potential predictive variables for DVT in pregnancy

25. Chan, Ann Intern Med 2009
Pretest probability and performance of LEFt variables

26. Approach to a woman with suspicion of VTE
Imaging
Diagnostic issues of VTE in pregnancy
DVT
compression ultrasound
phlebography
PE
ventilation/perfusion scan
computed tomography

27. Compression ultrasound to exclude DVT
Chan, CMAJ 2013

28. • 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
Diagnostic issues of VTE in pregnancy

29. 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

30. • 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
Diagnostic issues of VTE in pregnancy

31. 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
Diagnostic issues of VTE in pregnancy
consider clinic, risks, D-Dimer

32. 36 year old woman
• Week 7  proximal deep vein thrombosis 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

33. 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) .

34. 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

35. Recurrent miscarriage
~ 50% explained
• Chromosomal abnormalities in the fetus
• Abnormal karyotype in the parents
• Cervical incompetence
• Endometrial infections
• Endocrine disorders
• Thrombophilia?

36. Thrombophilia and pregnancy complications
Rey, Lancet 2003; Robertson, Br J Haematol 2006; Nelen, Fertil Steril 2000
Thrombophilia Sporadic miscarriage
OR
Recurrent miscarriage
OR
IU fetal death
OR
Lupus anticoagulant 3.0 7.8 2.4
Anticardiolipin antibodies 3.4 3.6 - 5.1 3.3
AT deficiency 1.5 0.9
7.6 (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

37. 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

38. Scenario 1: PLA +, previous miscarriage
Phospholipidantibodies during pregnancy

39. Relevance
LAC ACA ß2GP-AK
Recurrent pregnancy loss ++ + ?
Late pregnancy loss ++ + ?
Preeclampsia +/- +/- ?
Placental abruption +/- +/- ?
IUGR +/- +/- ?
Opatrny, J Rheumatol 2006
Phospholipidantibodies during pregnancy

40. 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
Phospholipidantibodies during pregnancy

41. Pregnancy complications and PLA
Pregnancy loss
HR (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

42. Empson, Cochrane Database of Systematic Reviews 2005
Aspirin and pregnancy loss
Phospholipidantibodies during pregnancy

43. Empson, Cochrane Database of Systematic Reviews 2005
Heparin and pregnancy loss
Phospholipidantibodies during pregnancy

44. Mak, Rheumatology 2010
RR 1.3 (95% CI 1.04 - 1.6)
Live births: metaanalysis
Phospholipidantibodies during pregnancy

45. 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
Phospholipidantibodies during pregnancy

46. ALIFE Study
Kaandorp, N Eng J Med 2010

47. 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)

48. HAPPY Trial
Martinelli, Blood 2012
N=63
N=65

49. 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

50. 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

51. Scenario 2: PLA +, previous VTE
Phospholipidantibodies during pregnancy

52. 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

53. • 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
Phospholipidantibodies during pregnancy

54. • Sex related differences in hemostasis
• Specific hormone-related issues
– Pregnancy
– Hormone use
• Oral contraceptives
• Hormone replacement therapy
Women issues and thrombosis

55. Coagulation factors during oral contraceptives
Fibrinogen
F II, VII, VIII, X
Lowe, Br J Haematol 1997; Middeldorp, Thromb Haemost 2000
Hormone contraceptives
F V

56. Anticoagulant system
APC-ratio
Protein S
Hormone contraceptives
Lowe, Br J Haematol 1997; Rosing, Lancet 1999; Tans, Thromb Haemost 2000
Antithrombin
Protein C

57. Estimated annual incidence of venous thrombosis
OC –
Vandenbroucke, Lancet 1994
all > 70 yrs OC +
1/100
1/10 000 3-4/10 000

58. 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)

59. Risk of venous thrombosis
Van Hylckama Vlieg, BMJ 2009
Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis Study
(MEGA)

60. Thrombosis risk according to oestrogen dose
Van Hylckama Vlieg, BMJ 2009
Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis Study
(MEGA)

61. Risks with use of combined contraceptives
van Hylckama Vlieg, J Thromb Haemost 2011
MEGA
case-control study
OR (95% CI)
Danish national
cohort study
RR (95% CI)
Combined oral contraceptives
Estrogen 30 µg + noresthisterone
Estrogen 30 µg + levonorgestrel
Estrogen 37.5 µg + lynestrenol
Estrogen 30 µg + norgestimate
Estrogen 30 µg + desogestrel
Estrogen 30 µg + gestodene
Estrogen 30 µg + drospirenone
Estrogen 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)

62. Risks with use of progestin-only contraceptives
Mantha, Br Med Journal 2012
Oral preparations

63. Risks with use of progestin-only contraceptives
Mantha, Br Med Journal 2012
Injectables

64. 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

65. Estimated annual incidence of venous thrombosis
OC –
FVL –
Vandenbroucke, Lancet 1994
all > 70 yrs OC + OC +
FVL +
FVL +
1/100
0.8/10 000
3/10 000
5.7/10 000
28.5/10 000

66. Family history and the risk of a first VTE
Family history Odds Ratio (95% CI)
negative 1.0 (ref.)
All
Any 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

67. 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

68. Hormone replacement therapy
• 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

69. = FVIII, AT, PC, PS, F1+2, TAT
 Fibrinogen, FVII, FIX
Menopause
Effect on hemostatic parameters
Lowe, Br J Haematol 1997

70. Effect on hemostatic parameters
Hormone replacement therapy
Teede, ATVB 2000

71. 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
Hormone replacement therapy

72. Risk of VTE according to dose
HRT exposure Rate ratio (95% CI)
Oral estrogen
Low dose
High dose
Very 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)
Hormone replacement therapy
Renoux, J Thromb Haemost 2010

73. Risk of VTE according to dose
HRT exposure Rate ratio (95% CI)
Oral estrogen
Low dose
High dose
Very 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)
Patch
Low dose
High dose
1.00 (0.89–1.12)
0.99 (0.87–1.12)
1.05 (0.81–1.36)
Hormone replacement therapy
Renoux, J Thromb Haemost 2010

74. 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
Hormone replacement therapy
Risk of VTE during estrogen replacement

75. 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)
Hormone replacement therapy
Risk of VTE: effect of progestogens
Canonico, Arterioscler Thromb Vasc Biol 2010

76. Hormone replacement therapy
• 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

77. 0 1 2 3 4 5 6 7
p<0.0001
Men
Women
10
20
30
40
Men vs. Women
Years after anticoagulation
Probabilityofrecurrence%
Kyrle, N Engl J Med 2004
50
Risk of recurrent VTE

78. Risk of recurrence
Years after Discontinuation of Anticoagulation
CumulativeProbabilityofRecurrence(%)
n = 145
n = 272
no combined contraceptive use
combined contraceptive use
p < 0.001
*FV Leiden,, age and site of index VTE Eischer, J Thromb Haemost 2014

79. 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

80. Female hormone intake
Study Intervention Recurrence/
100 pt. years
95% CI
Christiansen
JAMA 2005
OC continued
OC discontinued
2.8%
1.3%
1.6 – 5.0
0.8 – 2.1
Høibraaten
Thromb Hamost 2000
HRT
Placebo
8.5%
1.1%
2.6 – 14.4
0 – 3.2
Risk of recurrent VTE

81. Risk of recurrence: route of administration
Olié, Menopause 2011
Hormone replacement therapy
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)

82. 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

83. The difference between men and women - a conundrum!