Transcript Women and Thrombosis

Women and Thrombosis
Ahmad Shihada Silmi
Msc, FIBMS
Staff Specialist in Hematology
Medical Technology Department
Islamic University of Gaza
2012
Thromboembolic Disease
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Venous system
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Deep venous thrombosis
Pulmonary embolism
Arterial system
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Stroke
Myocardial infarction
Widely Known Risk Factors for
Venous Thromboembolism (VTE)
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Age
Surgery or trauma
Immobilization
Cancer or myeloproliferative disorder
Pregnancy
Hormonal therapy
Increased body mass index > 24 kg/m2
History of idiopathic thrombosis
Thrombophilia
the tendency to
thrombosis
Thrombophilic Syndromes
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Inherited thrombophilia
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Protein C and S deficiency
Antithrombin deficiency
Dysfibrinogenemia
Factor V Leiden mutation
Prothrombin 20210 mutation
mutation in methylenetetrahydrofolate reductase
(MTHFR)
Acquired or mixed thrombophilia
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Hyperhomocysteinemia
Antiphospholipid syndrome
High levels of factors VIII, IX, XI, TAFI
Inherited Thrombophilia
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Recurrent or life-threatening VTE
Family history of VTE
Age less than 45 at presentation
No acquired risk factors (surgery, trauma,
immobilization, cancer, myeloproliferative
disorder, pregnancy, hormonal therapy)
History of multiple miscarriages or
stillbirths
Associated with:
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Recurrent miscarriage
Pre eclampsia
IUGR
Placental abruption
Still birth
Inherited Thrombophilia
three important inherited thrombophilias :
 mutation in factor V causing Resistance to activated
protein C (responsible of 20–30% of venous
thromboembolism events.)
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mutation in prothrombin (guanine 20210 adenine )
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mutation in methylenetetrahydrofolate reductase
(MTHFR) (cytosine 677 thymine (C677T) ) The
mutation is responsible for reduced MTHFR activity
and is the most frequent cause of mild
hyperhomocysteinemia and can be found in 5–15% of
the population.
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A high rate of protein S deficiency,
APCR, hyperhomocysteinemia and aCL
IgG or IgM was found in women with
severe preeclampsia .
Dekker et al Am J Obstet Gynecol 1995
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higher prevalence of FV Leiden mutation in
women with severe preeclampsia compared to
controls.
Nagy et al Clin genet 1998
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120 women with severe preeclampsia, (72%
nulliparous) and 101 healthy matched for age
and parity. 18.3% of preeclamptic women
were carriers of the FV Leiden mutation
compared to 3% in controls .
Rigo et al Hypertens Pregnancy 2000
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110 healthy women who had during pregnancy severe
preeclampsia, IUGR , severe abruptio placentae and
stillbirth were enrolled in the study. The control group
comprised 110 healthy matched women with normal
pregnancies. All 220 patients were tested for all
known thrombophilias at least 2 months after delivery.
The total prevalence of all thrombophilias detected in
the 110 women with complications was 65%
compared to 18% in controls.
Kupferminc et al N Eng J Med 1999
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in USA tested the genetic thrombophilic
mutations in 110 women with severe
preeclampsia and 97 controls. Most women
were nulliparous and 60% of them were
African Americans. No difference was found
in the prevalence of thrombophilias between
the women with severe preeclampsia and
control women groups, or in fetal genetic
thrombophilias.
Livingstone et al Am J Obstet Gynecol 2001
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tested 113 nulliparous women with
preeclampsia: 100 with severe disease, 13
with mild disease and 103 controls for the
C677T polymorphism of the MTHFR gene.
No difference in homozygosity for MTHFR
was found between the 2 groups
(preeclampsia 3% vs controls 6%)
Laivuori et al in Finland Obstet Gynecol 2000,
factor V Leiden(A506G) mutation
adenine 506 guanine (A506G) mutation in factor V
(factor V Leiden) (a substitution of glutamine for
arginine at amino acid 506 of factor V) Factor V
Leiden (FVL) is a mutation in the factor V
molecule, rendering it resistant to cleavage by
activated protein C. Factor V remains a
procoagulant and thus predisposes the carrier
to clot formation.
It has been linked with an increased risk for venous
thromboembolism due to Resistance to activated
protein C and is responsible of 20–30% of
venous thromboembolism events
factor V Leiden (A506G) mutation
The Factor V Leiden (FVL) mutation, present in 38% of the general population, leads to less than
normal anticoagulant response to activated
protein C resulting in an increased risk for venous
thrombosis.
Individuals with one copy of the FVL gene mutation
(heterozygotes) have a seven fold increased risk
for thrombosis compared to the general
population whereas homozygotes have an eighty
fold increase.
prothrombin (G20210A) mutation
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A change of G to A at position 20210 in
prothrombin (prothrombin 20210A)
elevates baseline prothrombin levels and
thrombin formation.
MTHFR (C677T) mutation
cytosine 677 thymine (C677T) mutation (a C to T
change at position 677 of MTHFR) is responsible for
reduced MTHFR activity results in decreased synthesis
of 5-methyltetrahydrofolate, the primary methyl donor
in the conversion of homocysteine to methionine and
the resulting increase in plasma homocysteine
concentrations
( Hyperhomocysteinemia ) is a risk factor for thrombosis
Dietary restriction of folate and vitamin B12 remains the
most common cause.
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MTHFR (C677T) mutation
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A homozygous methylenetetrahydrofolate
reductase (MTHFR) mutation, present in 14% of the general population, is associated
with a three fold increased risk for DVT or
PE, as well as preeclampsia and placental
abruption.
Protein S deficiency
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Protein S deficiency (PSD), present in up to
2% of the general population, is found in
approximately 15% of individuals with a
DVT or PE and 6% of women with obstetrical
complications including a relatively high risk
for stillbirth.
Protein C deficiency
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Protein C deficiency (PCD), present in about
1.5% of the general population, is associated
with a lower risk for obstetrical complications
than PSD and is found in 3-5% of individuals
with a DVT or PE.
Furthermore, PCD combined with a FVL
mutation is a relatively common cause of
DVTs and show a higher risk for thrombosis
compared to FVL alone.
Antithrombin III deficiency
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Antithrombin III deficiency (ATIII), present
in less than 0.5 % of the general population,
as with PSD and PCD, may rarely result from
mutational events
Because of its relative rarity, actual risks for
thrombotic events are difficult to estimate, but
without question this entity contributes to
thrombotic risks during pregnancy.
Hyperhomocysteinemia
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Amino acid formed during conversion of
methionine to cysteine
Induces endothelial cell desquamation,
oxidizes LDL, promotes monocyte
adhesion and thrombin generation
Either congenital or acquired
Risk factor for CAD, PVD, CVD, VTE
Oral Contraceptives and
Thrombosis
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Thromboembolic disease described soon
after introduction in early 1960’s
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Deep venous thrombosis
Pulmonary embolism
Stroke (ischemic, hemorrhagic)
Myocardial infarction
Procoagulant Effects of OCP
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Increased levels of factor VII, factor VIII, factor
X, prothrombin, and fibrinogen
Decreased levels of protein S and antithrombin
Decreased levels of factor V (cofactor in
inactivation of FVIIIa mediated by APC)
Acquired resistance to activated protein C
Fibrinolytic Effects of OCP
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Increased fibrinolytic activity
Increased levels of thrombin-activatable
fibrinolysis inhibitor (TAFI)
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Removes lysine residues from fibrin needed
for binding and activation of plasminogen
Elevated levels a risk factor for VTE
Overall clot-lysis time unchanged
Risk of VTE with Thrombophilia
and OCP Use
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Protein C and S, or antithrombin
deficiency: 6- to 8-fold increase over
baseline
Prothrombin 20210: 4- to 8-fold increase
over baseline
High factor VIII levels: 2-fold increase
over baseline
Screening for Factor V Leiden Mutation
1 DVT
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Not cost effective
Adverse
psychological
and insurance
effects
400 FVL
8000 Screened
More than 500,000 women would need to be screened to prevent 1 death from PE
Screening for Factor V Leiden
Mutation
? Selective screening of patients with 1st
and 2nd degree relatives with VTE
 Sensitivity 16%
 Positive predictive value 9%
BMJ 2001; 322:1024-5
Oral Contraceptives and MI
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Risk of myocardial infarction doubled by current
OCP use
3/100,000 woman-years
Low-dose estrogens carry lower risk
Third-generation OCP may be safer (wide
confidence interval)
Other risk factors play a major role – smoking,
HTN, DM, hypercholesterolemia, obesity
NEJM ‘01;345:1787-93
Cerebral Vein Thrombosis
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Potential causes – postpartum, infection,
oral contraceptives, thrombophilias
Factor V Leiden and prothrombin 21210
mutations play major role, especially in
association with OCP use
Relative risk with OCP alone
13-22
Relative risk with OCP + PT 21210
150
Relative risk with OCP + other thrombophilia 30
BMJ ‘98;316:589-92
NEJM ‘98; 338:1793-7
Pregnancy and Thrombosis
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Venous thromboembolism (VTE)
Placental infarction
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Miscarriage
Intrauterine growth retardation
Pre-eclampsia
Abruption
Intrauterine death
Pregnancy and Risk of VTE
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0.5-3/1000 pregnancies
Most common cause of maternal mortality
(2.1/100,000 live births or 11% of maternal
deaths)
Incidence same for all trimesters?
Incidence 5- to 10-fold higher after Cesarean
section than vaginal delivery
Greatest for left leg (90% vs. 10%) and
iliofemoral veins
Pregnancy and Virchow’s Triad
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Hypercoagulability
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Venous stasis
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Increased fibrinogen, factor VIII
Acquired resistance to APC
Decreased protein S
Increased plasminogen activator inhibitor
Platelet activation
Progesterone-related increase in venous capacitance
IVC compression by gravid uterus
Vascular damage
Pregnancy and VTE
Acquired
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Antiphospholipid antibody syndrome - 5-22% develop VTE
Hereditary
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Antithrombin deficiency - 50%
Protein C deficiency - 3-10% antepartum, 7-19% postpartum
Protein S deficiency - 0-6% antepartum, 7-22% postpartum
Factor V Leiden mutation – 2-6% heterozygotes, 17% homozygotes
Prothrombin 20210 mutation
Double heterozygote – 4-20%
Br J Haematol ’01;113(2):553-5
Haematologica ’01;86(12):1305-9
Thromb Haemost ’01;86(3):800-3
Pregnancy and Thrombophilia
Thrombophilia
OB/Gyn Clin ‘01; 28:1-17
Risk of VTE
AT III
++++
FVL + PT 20210
++++
FVL 2/2
+++
PT 20210 2/2
+++
FVL 1/2
++
PT 20210 1/2
++
Prot S
++
Prot C
++
MTHFR
+
Pregnancy and VTE Prophylaxis
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No data on primary prophylaxis in women with
known thrombophilia and no history of VTE
Do need secondary prophylaxis in women with
documented thrombophilia and VTE in a prior
pregnancy
No need for secondary prophylaxis in women
without thrombophilia and a single episode of
VTE in a prior pregnancy
Anticoagulation During Pregnancy
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ASA - safe in low doses (60-150 mg/day)
UFH
LMWH - less HIT and osteoporosis
Heparin-like agents (danaparoid, fondaparinux)
Coumarin derivatives – cross placenta
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Bleeding
Teratogenicity – 1st trimester nasal hypoplasia and
stippled epiphyses, any trimester CNS abnormalities
Direct thrombin inhibitors – cross placenta
Thrombophilia and Pregnancy Loss
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1st Trimester (failure of implantation)
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2nd Trimester (placental thrombosis)
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Antiphospholipid antibody syndrome
Hyperhomocysteinemia
Factor V Leiden mutation
Prothrombin 20210 gene mutation
Stillbirth (IUGR, preeclampsia, abruption)
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Antithrombin, protein C, or protein S deficiency
Hyperhomocysteinemia
Factor V Leiden mutation
Prothrombin 20210 gene mutation
Prophylaxis of Pregnancy Loss
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Antiphospholipid antibody syndrome – low-dose
aspirin + LMWH
Hyperhomocysteinemia – supplementation with
folic acid, vitamin B12, and vitamin B6
Congenital thrombophilias – unknown if
antithrombotic therapy beneficial but small
uncontrolled trials have resulted in higher
gestational ages and birth weights
Antiphospholipid Antibody
Syndrome and Pregnancy
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Increased risk of both VTE and pregnancy
loss
Primary prophylaxis - ? surveillance vs.
UFH/LMWH
Secondary prophylaxis
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ASA + prednisone of no benefit
ASA + heparin > ASA alone
Pregnancy and Prosthetic Heart
Valves
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Commonly used approaches
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Warfarin throughout
UFH from 6-12 weeks, warfarin otherwise except
near delivery
UFH throughout
? LMWH
Chan et al. 2000
Review of prospective and retrospective cohort studies
35.00%
30.00%
25.00%
Warfarin
Both
Heparin
Nothing
20.00%
15.00%
10.00%
5.00%
0.00%
Abortions
Anomalies
TEC
Death
LMWH for Heart Valve
Prophylaxis During Pregnancy
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Combined case reports of 15 patients
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12 delivered at term
3 fetal deaths
0 thromboembolic complications
Dosing of LMWH During Pregnancy
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Two options for therapeutic dosing:
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Change dose in proportion to weight change
Check anti-Xa level weekly 4 hours after morning
injection, adjust to keep 0.5-1.2 U/mL
Dalteparin 5000 U or enoxaparin 40 mg SQ once
daily for DVT prophylaxis
Discontinue 24 hours prior to elective induction
of labor
Anticoagulation When Breast
Feeding
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Heparin and LMWH – not secreted into
breast milk
Warfarin – does not induce an
anticoagulant effect in the breast-fed infant
Effect of Estrogen on CV System
1. Increases vasodilatation
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Smooth muscle relaxation occurs within 5-20
minutes (nongenomic)
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Ca-activated K channels opened through NOand cGMP-dependent pathways
NO released after activation of NO synthase
Increased expression of prostacyclin
synthase and NO synthase (genomic)
NEJM ‘99; 340:1801-11
Effect of Estrogen on CV System
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Inhibits response of blood vessels to injury
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Accelerated endothelial growth due to inc’d
expression of VEGF
Inhibition of migration and proliferation of
smooth muscle
Inhibits development of atherosclerosis
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Decreases total cholesterol, LDL, serum Lp(a)
lipoprotein
Increases HDL, triglyceride
NEJM ‘99; 340:1801-11
Effect of Estrogen on Coagulation
Procoagulant Effects
 Increased factor VII
levels and APC
resistance
 Decreased levels of
protein S and
antithrombin III
NEJM ‘99; 340:1801-11
Anticoagulant Effects
 Decreased fibrinogen
 Decreased PAI-1
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