Download Thrombotic Disease in Pregnancy

Venous Thrombosis in
Pregnancy
Vicky Tagalakis, MD MSC
General Internal Medicine
Academic Rounds
September 8, 2009
Objectives
1.
2.
3.
4.
5.
Facts about VTE in pregnancy
VTE diagnostic modalities in pregnancy
Treatment of VTE in pregnancy
Thrombophilia in pregnancy?
Thromboprophylaxis during pregnancy?
VTE in pregnancy


Pregnant women are at an increased risk for venous
thromboembolic disease (VTE)
 1 in 1000 pregnancies
 2-4 fold increase compared to non-pregnant state
 Cesarian delivery > vaginal delivery
 2/3 of DVT occur antepartum (equally distributed
among all three trimesters)
 43-60% of PE occur 4-6 weeks after delivery
 Daily risk of PE and DVT highest following delivery than
antepartum
PE is the major non-obstetric cause of maternal
mortality
 2/100 000 pregnancies
Case scenario #1
34 year old woman 24 weeks pregnant who reports
non-productive cough, SOBOE, and pleuritic
chest pain of 3 days duration. Sick 2 year old at
home. She has had 2 prior uncomplicated
pregnancies. She has a history of a prior DVT post
surgery for an ankle fracture repair.
DVT facts

90% of DVT during pregnancy occurs on
the left side.

A significant proportion of DVT in
pregnancy occurs in the pelvic veins and
therefore, may not be picked up by routine
testing.

Ovarian vein thrombosis can also occur.
Why is the risk greater in
pregnancy?

Pathopsysiology
 Increased venous capacity (estrogen)
 Increased plasma volume
 Compression of IVC
 Increased levels of coagulation factors
(fibrinogen, factor VII)
 Decreased levels of natural anticoagulants
(protein S)
 Acquired protein C resistance
Independent risk factors of a
higher VTE risk in pregnancy?






Bed rest
Multiparity
Advanced maternal age (>35 yo)
Overweight
Personal or family history of VTE
Preeclampsia
Case scenario #1
34 year old woman 14 weeks pregnant who reports nonproductive cough, SOBOE, and pleuritic chest pain. Sick 2 year
old at home.She has a history of a prior DVT post surgery for an
ankle fracture repair.
Physical exam
BP 105/80, HR 95, O2 Sat 91% on RA, T 37.8°C
Mild bilateral leg swelling
Decreased a/e at bases
VTE presentation in
pregnancy

Leg symptoms, chest pain, and dyspnea are
common in pregnancy.
Swelling, tenderness, skin discoloration, warm to
touch, unusual firmness/hardness, cord, pain on
dorsiflexion

Tachycardia may be a normal physiologic
response.
 ABG and A-a gradient are often normal.

Diagnosis of VTE in
pregnancy: challenges




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Clinical diagnosis by itself is unreliable.
In symptomatic pregnant patients, DVT and PE are
less prevalent than in non-pregnant patients.
Anticoagulant treatment is highly effective but carries
risks.
Untreated VTE can result in fatal and non fatal PE.
Hence, when VTE is suspected, it is essential to
diagnose it when present and exclude it when
absent.
Diagnosis of VTE in
pregnancy: challenges

The common diagnostic tests have not been studied
in pregnant women, and hence not appropriately
validated for this population

D-dimer assays and DVT/PE clinical prediction rules
have not been validated in the pregnant population

…..and what about the issue of both radiation
exposure to the fetus with diagnostic testing???
Diagnosis of VTE in
pregnancy: challenges

It is important to avoid ionizing radiation
exposure whenever possible during
pregnancy, but the risks of undiagnosed PE
are much greater than any theoretical risk to
the fetus from diagnostic testing
DVT and PE - Investigation

CUS, IPG, and venography can be done safely and with
reliable results in pregnancy.

Ventilation perfusion scans and pulmonary angiograms
can be done safely during pregnancy.

Pelvic vein ultrasound, CT scan and MRI are all tests that
can be used to look for pelvic clot.

CT angiography can be done in pregnancy (risk of
congenital hypothyroidism in first trimester)

IVC filters can be placed in pregnancy.
Risk of radiologic procedures to the
fetus

Radiation exposure of up to 0.05 Gy (5 rad) in
utero:
 Oncogenicity



Relative risks of 1.2-2.4
Absolute risk of malignancy (baseline) in fetus
is estimated to be 0.1%.
Tetratogenicity

No increase in pregnancy loss, growth or
mental retardation
CT angiography: 0.013- 0.0026 (rads)
Techniques to lower radiation
exposure during



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Circumferential screening of the abdomen and pelvis (CTPA)
Duration of scanning reduced (CTPA)
Half-dose (perfusion) techniques (VQ scan)
If perfusion is normal, then ventilation scan unnecessary (PE
excluded)
***Please note that even if a pregnant woman underwent a CXR,
followed by a VQ scan, then CTPA, and then pulmonary
angiogram, the combined fetal radiation dose would still be less
than that obtained via background radiation during the nine
months of pregnancy!
Case scenario #1
WBC 14 with neutrophilia.
Platelets are normal.
CXR: RLL atelectatic changes
ABG shows an increased aA gradient.
CTPA
Fig. 2. Algorithm for clinically suspected pulmonary embolism in pregnancy. PE, pulmonary
embolism; CT, computed tomography; PA, pulmonary angiography; HP, high probability; CUS,
compression ultrasonography. *ND, non-diagnostic result. Non-diagnostic results are those that
indicate an intermediate or low-probability of pulmonary embolism, or that do not indicate a high
probability.
Nijkeuter et al, JTH 2008
Scarsbrook et al, Clinical Radiology, 2007
Diagnosis of DVT: Algorithm
VTE Treatment
VTE treatment

LMWH preferred based on better safety profile,
reliable pharmacokinetics, more practical, and as
effective as UFH

Largely based on studies in non-pregnant population

Widespread use over the last 10-15 years in pregnant women
have shown that LMWHs are as effective and safer than UFH
(less HIT and less osteoporosis than UFH)

Does not cross placenta!
VTE treatments: other options

UFH

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Initial IV UFH therapy followed by UFH bid sc dosing
(adjusted weekly to achieve target PTT (60-80 sec) 6H after
injection). Weekly surveillance
VKA



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Teratogenicity (coumarin embryonopathy: nasal hypoplasia and/or stippled
epiphyses); observed only duirng 6-12 weeks of gestation (Chan et al, studied 549
live births; VKA through out preg vs. UFH 6-12 weeks then VKA vs. UFH
throughout pregnancy)
CNS abnormalities during any trimester (corpus callosum agenesis; midline
cerebellar atrophy); very rare and questionable association
Fetal hemorrhagic complications especially at delivery due to prolonged
anticoagulant effect of warfarin as a result of fetal liver being immature and hence
fetal levels of vit K dependent coag factors are low.
?role in pregnant women with mechanical prosthetic valves at high risk for
embolization (i.e. previous CVA)
VTE treatments: other options

Fondaparinux
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Danaproid
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Anti Xa activity found in plasma umbilical cord of 6 women
treated with fondaparinux
For now, avoid general use and reserve for pregnant women
with HIT or a history of HIT who cannot receive danaproid
In vitro data shows placenta crossing but…
No detectable anti Xa activity in plasma umbilical cord of the
few women wolr-wide that have been treated with danaproid.
DTIs

No human data!
DVT and PE – Treatment


CHEST 2008 recommendations:
Treatment of acute DVT/PE in pregnancy
 Adjusted dose LMWH thru pregnancy
OR (but less preferred)

weight-based intravenous UFH protocol for 5
days, then adjusted dose UFH (PTT mid-interval
of 60-80 secs; weekly surveillance).
LMWH: adjust dose during pregnancy?

LMWH requirements may alter as pregnancy progresses ( volume of
distribution of LMWH changes and GFR increases in second trimester)

Hence, some suggest that dose should change as weight changes
(based on small studies that support dose escalation to achieve
“therapeutic anti Xa levels”)

Adjusted dose LMWH thru pregnancy


adjust as weight , or adjust to anti Xa level 0.5-1.2 U/ml (every 1-3
months blood test, 4 hrs after last dose) (bid vs qd dosing)
Others have demonstrated that few women require dose adjustment
when therapeutic LMWH doses are given
Controversial; ACCP does not give any recommendations
At time of delivery

D/C LMWH (or UFH sc) 24 hrs. prior to elective
induction

If very high risk of recurrence (eg, PE or DVT within 2-4
weeks of expected delivery), IV UFH can be initiated
and d/c 4-6 hours prior to delivery; in addition, a
temporary IVC filter can be inserted

If spontaneous labour occurs while receiving adjusteddose SC UFH, monitor PTT and if prolonged give
protamine

If spontaneous labor occurs while receiving LMWH,
anticoagulant effect depends on timing of last dose.
 Avoid epidural
 Protamine can be considered
Postpartum management

Re-start anticoagulation within 8-12 hours of
delivery (consult with obstetrician)

LMWH or coumadin for 6 weeks after delivery

For a minimum total duration of 6 months
Fetal complications during
pregnancy

Heparins and LMWH
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Heparins and UFH do not cross placenta
Uteroplacental bleeding possible but very rare
Warfarin
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Risk of embryopathy (nasal hypoplasia) (6-12
weeks of gestation)
CNS abnormalities in any trimester
Anticoagulant effect in fetus (**at delivery)
Maternal complications of
anticoagulant therapy

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Bleeding
 2% risk with UFH
 Very uncommon with LMWH
Heparin induced osteoporosis
 2.2% incidence of vertebral fracture with UFH (>1
month)
 Uncommon with LMWH
HIT
 3% risk with UFH
 suspect HIT if platelets <100 or 50% of baseline
value 5-15 days after commencing UFH
 Uncommon with LMWH
Nursing mother

Heparin and warfarin not secreted into breast milk.

LMWH: small amounts may be secreted into breast milk but not
absorbed by infant and no anticoagulant effect in breast-fed
infant

Danaproid: case reports +/- passage into breast milk; no
anticoagulant effect in infant

Fondaparinux and DTIs: unknown
Prevention of VTE during
pregnancy

How do we evaluate women with an
increased risk of VTE?

Prior history of VTE

Thrombophilia without a prior history of
VTE
Case scenario #2
28 year old woman who is 10 weeks pregnant is
referred to you to assess the need for DVT
prophylaxis. She has a history of a prior DVT. She
is currently not on any anticoagulants. She feels
well otherwise.
Thromboprophylaxis during
pregnancy and postpartum
How we manage pregnant women who
have a high risk of VTE

Women with a history of VTE have a higher risk of recurrence with
subsequent pregnancy (1-13% risk of recurrence)

Risk dependent on nature of VTE risk factor, presence or absence of
thrombophilia, and (number of previous VTEs).
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N=125 women with a single previous VTE who only received
prophylaxis in ppp for 4-6 weeks (Brill-Edwards, NEJM 2000)
3/125 had antepartum recurrence (2.4%, 95% CI 0.2-6.9%) and
3/125 had ppp VTE recurrence
Post hoc analysis: women without thrombophilia and a VTE
associated with a temporary risk factor were at low risk for
recurrence (0%)
Single prior VTE
1.
VTE associated with transient risk factor: clinical
surveillance and pp prophylaxis for 6 weeks
2.
VTE associated with pregnancy or estrogen-related or
there are additional risk factors (eg. obesity) clinical
surveillance and pp prophylaxis for 6 weeks OR antenatal
with pp prophylaxis for 6 weeks


LMWH (dalteparin 5000u q24 hrs or enoxaparin 40mg sc q24hrs)
Mini-dose UFH SC (5000 U SC bid) vs intermediate dose UFH
SC (10 000 sc bid)
Single prior VTE
3.
Idiopathic VTE: antenatal and pp prophylaxis (4-6 weeks
pp) OR clinical surveillance and pp prophylaxis

Prophylactic dose LMWH

Mini- or moderate-dose UFH SC
4.
With thrombophilia: antenatal and pp prophylaxis (4-6
weeks pp) OR clinical surveillance and pp prophylaxis

Prophylactic dose LMWH (eg. dalteparin 5000u q12
hours)

Mini- or moderate-dose UFH SC
Single prior VTE
5.
With “higher risk” thrombophilia: antenatal and pp
prophylaxis (4-6 weeks pp)

Prophylactic dose LMWH (eg. dalteparin 5000u q12
hours)

Mini- or moderate-dose UFH SC
APLA, ATIII deficiency, compound heterozygote PT/FVL,
or homozygosity for FVL or PT
Multiple episodes of VTE
(or those on long-term anticoagulation)

Prophylactic, vs. intermediate, vs. adjusted dose
LMWH (or UFH)

PP prophylaxis for 6 weeks, consider long-term
anticoagulants, or resumption of long-term
anticoagulants
For all women with prior DVT..

Consider compression stockings during
pregnancy and ppp
 reduce risk of PTS
Do you adjust LMWH prophylaxis
dosing in pregnancy?

The need to adjust according to anti-Xa levels is
very controversial
 Appropriate “therapeutic range” for
prophylaxis is not known
 It has not been shown that dose adjustment to
attain specific anti-Xa level increases safety or
efficacy.
Thrombophilia with no history
of prior VTE

50% of gestational VTEs occur in women with an underlying
thrombophilic disorder
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AT 3 deficient: OR = 8-13.1
FVL Homozygote: OR = 6.9-8.7
PT Homozygote: OR 1.8-9.5
Double FVL/PT mutations: OR=15
Antenatal and pp prophylaxis is recommended in women
without a prior VTE and with any of the above disorders.
For women without prior VTE and who have less
thrombogenic thrombophilias, clinical surveillance and pp
prophylaxis
Antiphospholipid Antibodies
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Lupus anticoagulant/non-specific inhibitor
Anticardiolipin antibodies
Convincing evidence of an association with increased
risk of thrombosis and pregnancy loss (less so with
preeclampsia, abruptio, IUGR)
But how to manage during pregnancy…not clear?
 Prednisone not useful
 ASA with LMWH (UFH) is likely the best
combination (outcomes: fetal loss, pregnancy
complications, VTE)
Management of pregnant women with
APLAs

Positive APLAs and hx of 2 or more early pregnancy losses or
one or more late pregnancy losses, IUGR, preeclampsia, or
abruptio
 Antepartum ASA plus prophylactic LMWH
 Antepartum ASA plus minidose or moderate dose UFH

Positive APLAs and hx of VTE are usually receiving long-term
anticoagulation bc of high risk of recurrence
 Antepartum adjusted dose LMWH (or UFH) plus ASA
 Long-term oral anticoagulation postpartum

Positive APLAs and no hx of pregnancy complications or VTE
 Clinical surveillance
 Minidose UFH
and/or asa?
 Prophylactic LMWH
Prevention of pregnancy complications in
women with non-APLA thrombophilia?

Data support weak associations between
thrombophilias (FVL, PT mutation) and adverse
pregnancy outcomes (early (recurrent) preg loss,
preeclampsia, IUGR)

But, clinical studies with LMWH or UFH vs. placebo
(no drug) in women with a history of adverse
pregnancy outcomes and non-APLA thrombophilias do
not show improved pregnancy outcomes.
C-section and the risk of VTE?

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Risk 0.4/1000 (c-section) vs. 0.2/1000 (vaginal
delivery)
Not standard of care to thromboprophylax
Thrombosis risk assessment to determine need for
prophylaxis (grade 2C)


If no additional thrombosis risk factor, no prophylaxis
If additional risk factors (eg. prior VTE, lower limb
paralysis, thrombophilia, extended surgery such as
hysterectomy, preeclampsia, obesity, increased age,
heart failure), then…
C-section and the risk of VTE?

Prophylaxis doses of LMWH or UFH +/stockings while in hospital following
delivery (grade 2C) and perhaps for 6 weeks
pp if important risk factors persist (grade
2C).