Conception Vs. Thrombosis The Risk and Controversy of Hormonal Therapy in Adolescent Women - PowerPoint PPT Presentation

1 / 62
About This Presentation
Title:

Conception Vs. Thrombosis The Risk and Controversy of Hormonal Therapy in Adolescent Women

Description:

Identification of risk factors and proposed mechanisms of action for further study ... Effect of 1995 pill scare on rates of venous thromboembolism among women taking ... – PowerPoint PPT presentation

Number of Views:209
Avg rating:3.0/5.0
Slides: 63
Provided by: lifebrid
Category:

less

Transcript and Presenter's Notes

Title: Conception Vs. Thrombosis The Risk and Controversy of Hormonal Therapy in Adolescent Women


1
Conception 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

2
Case 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

3
Case 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

4
Case 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

5
(No Transcript)
6
(No Transcript)
7
Case 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

8
Goals 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

9
Statement 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

10
Statement 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

11
The 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
12
Teen 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
13
Oral 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)

14
Combination 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.
15
Use 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
16
Use 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
17
Use 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
18
Use 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
19
Hemostasis
  • 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

20
Hemostasis
21
Activation of the Coagulation System
22
Thrombophilia
  • 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

23
Outcome 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

24
Outcome 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.
25
Familial 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.

26
Effectiveness 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

27
Incidence 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

28
(No Transcript)
29
Female Hormones and ThrombosisRosendaal FR, et
al. Arterioscler Thromb Vasc Biol. Feb 2002
30
Proposed 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

31
Higher 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
32
Oral Contraceptives and the Risk of Thrombosis
Vandenbroucke JPN Engl J Med, Vol. 344, No.
20May 17, 2001
33
Third generation oral contraceptives and risk of
venous thrombosis metaanalysis
Jeanet M Kemmeren, et al BMJ VOLUME 323 21 JULY
2001
34
Third generation oral contraceptives and risk of
venous thrombosis metaanalysis
Jeanet M Kemmeren, et al BMJ VOLUME 323 21 JULY
2001
35
Combination EstrogenProgestin Oral
Contraceptives


Petitti DB. NEJM 20033491443-50.
36
Effect 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
37
The 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
38
The 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
39
Combination EstrogenProgestin Oral
Contraceptives (Petitti DB. NEJM
20033491443-50.)
40
Factor 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

41
Mechanism of the Interaction of Factor V and
Activated Protein C (APC)
42
Factor 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

43
Factor 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

44
Factor 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

45
Oral Contraceptives and the Risk of Thrombosis
Vandenbroucke JP, et al N Engl J Med, Vol. 344,
No. 20May 17, 2001
46
Female Hormones and ThrombosisRosendaal FR, et
al. Arterioscler Thromb Vasc Biol. Feb 2002
47
High 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
48
High 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
49
Effect 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
50
Effect 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
51
Prothrombin 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

52
High 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
53
Elevated 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.

54
HIGH PLASMA LEVELS OF FACTOR VIII AND THE RISK OF
RECURRENTVENOUS THROMBOEMBOLISMKyrle, PA, et al
N Engl J Med 2000343457-62
55
Elevated Plasma Factor VIII and d -Dimer
Levelsas Predictors of Poor Outcomes of
Thrombosisin Children (Goldenber NA, et al N
Engl J Med 20043511081-8)
56
Venous 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
57
Oral 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
58
Summary- 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

59
Summary
  • 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

60
(No Transcript)
61
Effects 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
62
Effects 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
Write a Comment
User Comments (0)
About PowerShow.com