Title: Conception Vs. Thrombosis The Risk and Controversy of Hormonal Therapy in Adolescent Women
1Conception Vs. ThrombosisThe Risk and
Controversy of Hormonal Therapy in Adolescent
Women
- Joseph M. Wiley, MD
- Chief, Division of Pediatric Hematology/Oncology
- Chairman, Department of Pediatrics
- The Childrens Hospital at Sinai
2Case Report
- 15 yr old AAF recently placed on the transdermal
patch for contraception - Admitted for Tonsillectomy
- No Family History Obtained
- Patch removed at the day of surgery
3Case Report
- Tonsillectomy goes well with minimal bleeding
- Postoperatively develops lower extremity swelling
- Renal output reduces dramatically
- Imaging demonstrates occlussive clot from the
femoral vein all the way up the inferior vena
cava past the renal vein
4Case Report
- Spiral CT demonstrates pulmonary embolus
- Treated with an IVC filter, local tPA and
subsequent heparinization - Improves over the course of a week and is
discharged. - Remains on warfarin therapy 18 months later
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7Case Report
- Family Hx for 2 members with VTE
- Thrombophilia workup
- Factor V Leiden negative
- Prothrombin Gene 2 normal copies
- ATIII, Protein CS Normal
- Homocysteine, APL Normal
- Factor VIIIc 292
8Goals and Objectives
- Presentation of the epidemiology of
estrogen-progestin use in adolescents - Brief review of hemostasis and thrombophilia
pertinent issues (significant sleep risk!) - Review of the thrombosis data for OCPs
- Identification of risk factors and proposed
mechanisms of action for further study
9Statement of Purpose
- Hypothesis 1
- The use of oral contraceptives (OCPs) is
sufficiently high in adolescent females to
warrant pediatricians to become familiar with
their use and risk/benefit ratio - Hypothesis 2
- Thrombosis risk is higher in OCP users, the risk
of thrombosis is highest in the first year of use
of OCPs and can be ascribed, largely, to genetic
factors
10Statement of Purpose
- Hypothesis 3
- Large case control studies originally targeting
3rd generation OCPs as a higher risk were flawed
and the VTE risk is identical to 2nd generation
OCPs - Hypothesis 4
- The Protein C Factor V regulation of thromboses
may be central to the mechanism of thrombosis but
other factors are emerging
11The Public Health issue of Adolescent
Contraception Use
- 2003- 820,000 teen pregnancies in the US
- US rates 2-3x Canada 7-8x Netherlands
- 1970-2003- slow but gradual decline in teen
pregnancy - Babies of teen pregnancies more likely to be
- Born premature
- Poorly educated
- Abused/neglected/incarcerated
Taube O. Personal Communication
12Teen ContraceptionThe Taube Principles
- Every method of contraception is SAFER than
pregnancy - There is no ideal contraception
- Health care providers need to be able to match
the needs of the patient with choices available - Non- contraceptive benefits of birth control
should be considered when selction is made
Taube O. Personal Communication
13Oral Contraceptive Use
- First introduced in the USA in 1960
- Combines ethinyl estradiol or, uncommonly,mestrano
l with a progestin - Initial formulations had 2-10 times as much
estrogen- reduced over the years due to the risk
of cardiovascular disease etc. - Classified into generations (1st-4th)
14Combination EstrogenProgestin Oral
ContraceptivesGeneration Designation by
Progestin Compound
- First or Second
- Chlormadinone acetate
- Ethynodiol diacetate
- Medroxyprogesterone acetate
- Norethindrone
- Norethynodrel
- Norgestrel
- Lynestrenol
- Third
- Desogestrel
- Norgestimate
- Gestodene
Never marketed in the USA
Petitti DB. NEJM 20033491443-50.
15Use of Contraception and Use of Family Planning
Services in the United States 19822002
Mosher WD, et al Advance Data for Vital Health
Statistics No. 350 - December 10, 2004
16Use of Contraception and Use of Family Planning
Services in the United States 19822002
Mosher WD, et al Advance Data for Vital Health
Statistics No. 350 - December 10, 2004
17Use of Contraception and Use of Family Planning
Services in the United States 19822002
Mosher WD, et al Advance Data for Vital Health
Statistics No. 350 - December 10, 2004
18Use of Contraception and Use of Family Planning
Services in the United States 19822002
Mosher WD, et al Advance Data for Vital Health
Statistics No. 350 - December 10, 2004
19Hemostasis
- Process which maintains flowing blood in a fluid
state and confined to the circulatory system - The manifestations of deficiencies are common
(hemophilia/thrombophilia) and usually
independent of the individual factor
20Hemostasis
21Activation of the Coagulation System
22Thrombophilia
- Denotes the prothrombotic state
- Patient coagulation cascade tilted in the
direction of clotting - Risk for thrombosis may vary from 2-3 fold higher
in single mild defects to as high as 100-1000
fold in multiple defects - Much more common (up to 25-30 of the population)
than hemophilia
23Outcome of Pediatric Thromboembolic Disease A
Report from the Canadian Childhood Thrombophilia
Registry
Monagle P, et al Pediatr Res 47 763766,2000
-
- Figure 1. Age distribution of total cohort of 405
children
24Outcome of Pediatric Thromboembolic Disease A
Report from the Canadian Childhood Thrombophilia
Registry
Monagle P, et al Pediatr Res 47 763766,2000
N52
N119
N56
N110
N68
Figure 2. Patient age at time of diagnosis of
initial thrombosis for patients with recurrence
(yellow bars) and with PPS (red bars). Multiple
ages have been grouped to improve clarity.
25Familial Thrombophilia
- Important Features in FHx
- Venous thromboembolism before the age of 40 - 45
years. - Recurrent venous thrombosis or thrombophiebitis.
- Thrombosis in an unusual site, e.g. mesenteric
vein, cerebral vein. - Unexplained neonatal thrombosis.
- Arterial thrombosis before the age of 30.
- Relatives of patients with thrombophilic
abnormality. - Patients with recurrent fetal loss, ITP or SLE.
26Effectiveness of Family History and Screening
- Cosmi, et al BMJ 3221024-5, 2001
- Prospectively screened 324 women aged 15-49
eligible for OCPs - Complete FHx done
- 34 (10) had a FHx
- 3 had defects (2 FVLeiden, 1 PTG)
- 290 (90) had a FHX
- 16 (6) had defects (8 FVL, 8PTG)
- FHx screening had a low ppv (9)
- Better results obtained in the Leiden Study
27Incidence of Thrombophila Syndromes
- General Patients with Thrombophilic
- Population a Single VTE Families
- Factor V Leiden 3-7 20 50
- PTG20210A 1-3 6 18
- ATIII Deficiency 0.02 1 4-8
- Protein C Deficiency 0.2-0.4 3 6
- Protein S Deficiency N/A 1-2 3-13
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29Female Hormones and ThrombosisRosendaal FR, et
al. Arterioscler Thromb Vasc Biol. Feb 2002
30Proposed Mechanisms of Increased thrombosis by
OCPs
- Direct Effects of Estrogens on clotting factors
- Increases in Factors VII, VIII, X, XII
- Increased APC Resistance
- Decreases in activity of Protein CS
- Decreased fibrinolytic activty
- Effects on Platelet Aggregation
31Higher Risk of Venous Thrombosis During Early Use
of Oral Contraceptives in Women with Inherited
Clotting Defects
- Data from the Leiden Thrombophilia Study
- Risk of thrombosis early versus late
- Odds Ratio
- 1st 6 Months 1st Year
- Overall Group 3.0 (0.6-14.8) 2.0 (0.6-6.1)
- Thrombophilia 19.0 (1.9-175.7) 11.0 (2.1-57.3)
- Defects found
Bloemenkamp KWM, et al. Arch Intern Med
16049-52, 2000
32Oral Contraceptives and the Risk of Thrombosis
Vandenbroucke JPN Engl J Med, Vol. 344, No.
20May 17, 2001
33Third generation oral contraceptives and risk of
venous thrombosis metaanalysis
Jeanet M Kemmeren, et al BMJ VOLUME 323 21 JULY
2001
34Third generation oral contraceptives and risk of
venous thrombosis metaanalysis
Jeanet M Kemmeren, et al BMJ VOLUME 323 21 JULY
2001
35Combination EstrogenProgestin Oral
Contraceptives
Petitti DB. NEJM 20033491443-50.
36Effect of 1995 pill scare on rates of venous
thromboembolism among women taking combined oral
contraceptives Analysis of General Practice
Research Database
Farmer RTD, et al BMJ VOLUME 321 1926 AUGUST
2000
37The differential risk of oral contraceptives the
impact of full exposure historyRevision of The
Transnational Study Data
Lewis MA, et al Human Reproduction vol.14 no.6
pp.14931499, 1999
38The differential risk of oral contraceptives the
impact of full exposure historyRevision of The
Transnational Study Data
Lewis MA, et al Human Reproduction vol.14 no.6
pp.14931499, 1999
39Combination EstrogenProgestin Oral
Contraceptives (Petitti DB. NEJM
20033491443-50.)
40Factor V
- Factor V- Va activation is a key step in the
modulation of thrombosis - Excessive Va activity promotes thrombin
production and clotting - Protein C becomes activated (APC) and binds to
Va downregulating its function - APC resistance causes increased risk of thrombosis
41Mechanism of the Interaction of Factor V and
Activated Protein C (APC)
42Factor V/ V Leiden
- V-Leiden refers to a G-A substitution of at the
nucleotide 1691 in the gene for Factor V - The substitution causes a single amino acid
substitution in one of the APC binding sites - V-Leiden is inactivated 10 times slower than V
and results in longer half life and increased
thrombin formation - Heterozygous state results in mild thrombophilia
43Factor V/ V Leiden
- Most common form of inherited thrombophilia
- Prevalence is 3-8 of all US and European
population - 15 of patients with thromboembolism and 50 of
recurrent or resistant VTE
44Factor V/ V Leiden
- Diagnosis suspected in families where the history
of venous thrombosis exists - Homozygous state results in a much greater risk
of thrombosis - Diagnosis best made by DNA testing though second
generation APC assays can be used for screening
45Oral Contraceptives and the Risk of Thrombosis
Vandenbroucke JP, et al N Engl J Med, Vol. 344,
No. 20May 17, 2001
46Female Hormones and ThrombosisRosendaal FR, et
al. Arterioscler Thromb Vasc Biol. Feb 2002
47High Risk of Thrombosis in Patients Homozygous
for Factor V Leiden (Activated Protein C
Resistance)
- Age Range GG AG AA
-
- 0-29 yrs 0.6 5.1 78.4
- 30-49 yrs 1.8 11.8 176.2
- 50 yrs 2.1 16.4 110.0
- Incidence Rates/10-4 yrs.
Rosendaal FR, et al Blood, Vol 85, No 6 (March
15). 1995 pp 1504-1508
48High Risk of Thrombosis in Patients Homozygous
for Factor V Leiden (Activated Protein C
Resistance)
- Age Range ORGA (CI) ORAA (CI)
- 0-29 yrs 6.5 (1.8-23) 140 (9.5-2049)
- 30-49 yrs 7.2 (3.0-17) 98 (15-652)
- 50 yrs 8.0 (3.1-21) 30 (2.2-428)
Rosendaal FR, et al Blood, Vol 85, No 6 (March
15). 1995 pp 1504-1508
49Effect of second- and third-generation oral
contraceptives on the protein C system in the
absence or presence of the factor V-Leiden
mutationa randomized trial Kemmeran JM, et al
Blood.2004103927-933
50Effect of second- and third-generation oral
contraceptives on the protein C system in the
absence or presence of the factor V-Leiden
mutationa randomized trial Kemmeran JM, et al
Blood.2004103927-933
51Prothrombin G 20210 Mutation
- Mutation in the 3 untranslated portion of the
prothrombin gene - Occurs in 2 of the population
- Occurs in 6 of patients with first thrombosis
- Up to 18 of patients with history (personal or
family history) - Co inherited with V-Leiden in 1/1000 and in 2
of patients with thrombosis
52High Risk of Cerebral Vein Thrombosis in Carriers
of a Prothrombin Gene Mutation and in users of
Oral Contraceptives
Martinelli I, et al N Engl J Med 19983381793-7
53Elevated Factor Levels
- Elevated plasma concentrations of factors VIII,
IX and factor XI are linked to an approximately
two-five fold increased risk of venous
thromboembolism.
54HIGH PLASMA LEVELS OF FACTOR VIII AND THE RISK OF
RECURRENTVENOUS THROMBOEMBOLISMKyrle, PA, et al
N Engl J Med 2000343457-62
55Elevated Plasma Factor VIII and d -Dimer
Levelsas Predictors of Poor Outcomes of
Thrombosisin Children (Goldenber NA, et al N
Engl J Med 20043511081-8)
56Venous Thrombosis, Oral Contraceptives and High
Factor VIII Levels
- Leiden Thrombophilia Study
- 155 premenopausal women compared with DVT vs. 169
controls, aged 15-49 - Odds Ratio
(95CI) - No OCP/nl FVIII 1
- OCP/nl FVIII 3.8 (2.4-6.0)
- No OCP/High FVIII 4.0 (2.0-8.0)
- OCP/High FVIII 10.3 (3.7-28.9)
Bloemenkamp KW, et al Thrombosis Hemostasis
82(3) 1024-7, 1999
57Oral Contraceptives, Hormone Replacement Therapy,
Thrombophilias and Risk Of Venous
Thromboembolism a Systematic Review
- Meta analysis of all studies to identify
relationships between thrombophilia and OCP/HRT - Significant Interactions Found
- Odds Ratio
- Factor V Leiden 15.62 (8.66-28.15)
- Antithrombin III 12.60 (1.37-115.79)
- Protein C 6.33 (1.68-23.87)
- Protein S 4.88 (1.39-17.10)
- Factor VIIIc 8.80 (4.13-18.75)
Wu O, et al Thromb Haemost 2005 9417-25
58Summary- Interaction of Oral Contraceptives and
Thrombosis
- OCP use is common in adolescents
- Thrombosis risk is low but the Odds Ratio is
highest for familial thrombophilia and in the
first year of use - 3rd generation OCPs pose no greater VTE risk
than 2nd generation compounds - The Protein C- Factor V interaction may be a clue
to the differences in thrombosis susceptibility
in OCP users
59Summary
- OCP use is safe and effective but poses a
significant albeit small increase in risk for
some adolescents - Screening of patients with thrombophilia panels
is NOT cost effective or useful - Even though Family History is not very efficient,
counseling is key regarding possible side effects - Future study mechanistically may yield some
insight and possible screening strategies
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61Effects of different progestin regimens in
hormone replacement therapy on blood coagulation
factor VII and tissue factor pathway inhibitor
- Compared effects of Hormone Replacement Therapy
(HRT) in post menopausal women - Measured effects of various strategies on
activated Factor VII and Tissue Factor Pathway
Inhibitor (TFPI) - Major Findings
- Unopposed Estrogens caused increases in activated
Factor VII - Progestin use countered the estrogen induced
increase in Factor VII - All combinations of HRT and strategies led to
decreases in TFPI - Conclusion- HRT induces decreases in TFPI which
increase the risk of thrombosis
Bladbjerg EM, et al Human Reproduction Vol.17,
No.12 pp. 32353241, 2002
62Effects of different progestin regimens in
hormone replacement therapy on blood coagulation
factor VII and tissue factor pathway inhibitor
Long Cycle
Cont Oral
Cont Oral IUD
Short Cycle
Controls
Plt0.001
Bladbjerg EM, et al Human Reproduction Vol.17,
No.12 pp. 32353241, 2002