ThromboemboIic Disease in

Pregnancy
Done by:
Dr. AIia AbduIIah Shoib
Movember.com
ncidence
0.5 - 3 / 1000 pregnancies (mostIy UK data)
10 - foId increase in risk cf non pregnant
#isk Factors
GeneraI
Specific
PrevaIence and risk of VTE with
different thrombophiIias
- #ef Handbook of Obstetric Medicine 2006
ThrombophiIic disorder % popuIation ## VTE
nherited AT deficiency 0.07 10-20
Pr C deficiency 0.3 6-8
Pr S deficiency 0.2 2-6
Factor V Leid (heteroz) 5-8 4-10
Factor V Leid (homoz) 0.06 80
Prothrombin gene mutation
(heterozygous) 2-3 2-4
Acquired
AntiphosphoIipid antibody 2 9
Lupus AnticoaguIant
AnticardioIipin antibodies
Acquired APC resistance 8-11 2-4
(without FVL)
#outine antenataI care
#isk factor assessment - aII pregnancies:
1. HypercoaguIabiIity:
ncrease in factors ,V,V,V,X,X,X and fibrinogen
ncreased platelet aggregation
Decreased protein S, tissue plasminogen activator, factors X,X
Decreased fibrinolytic activity
ncreased resistance to activated protein C
Antithrombin may be normal or reduced
2. Stasis:
ncreased venous distensibility, decreased venous tone
50% decrease in venous flow in lower extremity by third trimester
Uterus mechanically impedes venous return
3. EndotheIiaI:
Vascular damage (pelvic veins) at delivery
All components
of Virchow's Triad
are affected
(coagulation, stasis, endothelium)
All components
of Virchow's Triad
are affected
(coagulation, stasis, endothelium)
#isk factors - individuaI
1. Pre-existing:
!revious VTE
Thrombophilia:
(i) Congenital:
Antithrombin deficiency
!rotein C deficiency
!rotein S deficiency
Factor V Leiden mutation (5% population prevalence)
!rothrombin gene mutation G20210A (2% population prevalence)
Antithrombin deficiency
Hyperhomocysteinemia - specifically MTHFR gene
!lasminogen deficiency
(ii) Acquired:
Lupus anticoagulant
Anticardiolipin antibodies
Nephrotic syndrome (decreased antithrombin levels)
#isk factors - individuaI
2. Current #isk Factors?
Age >35 years
Obesity (BM >30) pre-pregnancy or early pregnancy
!arity >4
Gross varicose veins
!araplegia
Sickle cell disease
nflammatory disorders e.g. inflammatory bowel disease
Some medical disorders e.g. nephritic syndrome,
cardiac disease
Myeloproliferative disorders e.g. essential
thrombocythaemia, polycythaemia rubra vera
#isk factors - individuaI
3. New onset or transient?
Surgical procedure in pregnancy or puerperium e.g. LSCS,
evacuation of retained products of conception, postpartum
sterilisation
Hyperemesis
Dehydration
Ovarian hyperstimulation syndrome
Severe infection e.g. pyelonrphritits
mmobility (>4 days bedrest)
!re-eclampsia
Excessive blood loss
Long-haul travel
!rolonged labour
Operative instrumental delivery
mmobility after delivery
#outine care
GeneraI advice: effects of Iong-hauI traveI,
immobiIity, dehydration etc.
2 current or transient risk factors: consider
prophyIactic TPX for 3-5 days postpartum.
3 or more current or transient risk factors as shown
in TabIe: consider prophyIactic TPX antenataIIy and
for at Ieast 3-5 days postpartum
Previous VTE 1
10-12% recurrence of VTE during pregnancy and
3.7% outside pregnancy
## in pregnancy 3.5 (95% C 1.6-7.8).
SingIe previous thrombosis no known
thrombophiIia, risk of recurrence 2.0-3.0%.
[ higher in the presence of thrombophiIia or the cIot
is in an unusuaI site or is unprovoked ]
History
Screening shouId be performed for inherited and
acquired thrombophiIias (considering the effects of
pregnancy on thrombophiIia screen).
Previous VTE 2
FamiIy history, with or without previous VTE.
Who to test on famiIy history?
No previous VTE, women with a first-degree
reIative with an AT- deficiency or homozygous
factor V Leidin or prothrombin G20210A mutation
may benefit from testing.
Strong famiIy history may mean coexistence of
muItipIe inherited risk factors.
History of thrombosis, recurrent fetaI Ioss, earIy or
severe preecIampsia or severe unexpIained UG#
requires testing for?
The ThrombophiIia Screen
Lupus anticoaguIant
AnticardioIipin antibodies
Factor V Leiden mutation
Prothrombin G20210A mutation
Antithrombin- antigen activity IeveIs
Fasting homocysteine IeveIs or MTHF#
C677T mutation
Protein C antigen activity IeveIs
Protein S antigen activity IeveIs
ThromboprophyIactic Agents
What can we use?
Low moIecuIar weight Heparin (LMWH)
Effective and safe
Why are these now agents of choice?
Enhanced ratio of anti-Xa (antithrombotic) to anti-
a (anticoaguIant) activity reducing the risk of
bIeeding.
Less binding to pIateIet factor 4 substantiaIIy
reducing the risk of heparin-induced
thrombocytopaenia.
Less osteoporosis
Low moIecuIar weight Heparin (LMWH)
No need for monitoring of peak antifactor Xa
No reported adverse effects on breastfeeding
ncidence of significant bIeeding does not seem to
be increased compared to background popuIation.
Unfractionated Heparin
AcceIerates abiIity of antithrombin to inactivate
thrombin (factor a), factor Xa and factor Xa
Larger moIecuIar weight heparins cataIyse
inhibition of both factors a and Xa
V injection resuIts in immediate anticoaguIant
activity, subcutaneous injection resuIts in a 1- to
2-hour deIay
Significant side effects in pregnancy incIude
thrombocytopaenia, osteoporosis and bIeeding
Unfractionated Heparin
2 forms of heparin-induced thrombocytopaenia.
Nonimmune form within first few days of therapy,
resoIves by 5 days.
mmune (gG) seen in 3% within 5 - 14 days.
Osteoporosis is dose dependent. Mean bone Ioss
5%, approximateIy 1/3 suffering >/= 10% decrease in
bone density.
There is a risk of major bIeeding episodes in 2-10%.
PIateIets shouId be checked on day 5 and then
periodicaIIy for the first two weeks of therapy.
Low dose Aspirin (50-100mg)
Efficacy in pregnancy not demonstrated in an #CT
but safe
May be more beneficiaI for arteriaI rather than
venous
Warfarin
Crosses the pIacenta!!!
Avoid if possibIe during pregnancy.
Up to 6.4 % risk of teratogenesis and increased risk
of miscarriage, fetaI and maternaI haemorrhage,
neuroIogicaI probIems in the baby and stiIIbirth.
Warfarin embryopathy (1
st
Trimester):
nasaI hypopIasia, chondrodyspIasia punctata, eye
abnormaIities, short proximaI Iimbs, growth
restriction and deveIopmentaI deIay)
CNS risks can come at any stage of pregnancy.
Warfarin
Some cases of metaI prosthetic heart vaIves, may be
more efficacious, start after 20 weeks gestation,
discontinue prior to deIivery, in cIose consuItation
with cardioIogist.
Safe postpartum and for breastfeeding
AnticoaguIant cIinic care
ncreased risk of haemorrhage and haematoma.
f chosen over LMWH postnataIIy, initiate on day 2 or
3, with LMWH continued untiI N# >2.0 for 5 days.
Agents avaiIabIe for thromboprophyIaxis
- TED Stockings
Above knee (fuII Iength) TEDS significantIy
decrease the risk of DVT in hospitaIised post
operative patients. TEDS on their own are
effective, but are more effective when used
with other methods.
Management of ThromboprophyIaxis in
Pregnancy (4 categories)
!revious VTE No !revious
VTE
Thrombophilia
No
Thrombophilia
Note: no "universally agreed rule significant local variation
n practice
1. Previous VTE and no
thrombophiIia
ProphyIaxis with LMWH or warfarin for 6 weeks after deIivery for
aII cases.
1. SingIe previous VTE - temporary risk factor
UsuaIIy no need for antenataI TPX
2. Previous VTE idiopathic, reIated to pregnancy or OCP or
additionaI risk factors exist such as obesity?
AntenataI prophyIactic dose LMWH
3. > 1 previous VTE, unusuaI site or FH in 1
st
degree
reIative
AntenataI prophyIactic LMWH.
2a. Previous VTE and inherited
thrombophiIia
[ Precise relative risk depends upon the specific thrombophilia (note these
are risks with previous VTE):
Thrombophilia: Risk: (x background):
Factor V Leidin mutation 7.0 - 9.1
Prothrombin G2021A mutation 2.9 - 9.5
Antithrombin III deficiency 10.0 - 13.1
Factor V L plus Prothrombin 107
Deficient Protein C or S 13.1 ]
AntenataI, intrapartum and postpartum TPX shouId be given
(LMWH).
SpeciaIist obstetric and / or haematoIogicaI advice shouId be
sought
2b. Previous VTE and acquired thrombophiIia
(antiphosphoIipid syndrome)
Up to 70% recurrent thrombosis, even higher in pregnancy.
Some of these women wiII be on Iong-term warfarin outsided
pregnancy.
AntenataI, intrapartum and postnataI prophyIactic TPX
Antiphospholipid syndrome (APS) is defined as the presence of lupus anticoagulant or
anticardiolipin antibodies of medium-high titre on two occasions eight weeks apart, in
association with a history of thrombosis (arterial or venous) or adverse pregnancy outcome
(three or more unexplained miscarriages before 10 weeks gestation, fetal death after 10 weeks
gestation or a premature (less than 35 weeks) birth due to severe pre-eclampsia or intrauterine
growth restriction). It is not defined solely by the presence of lupus anticoagulant or
anticardiolipin antibodies ]
3. Known inherited thrombophiIia without
previous VTE
#isk of VTE:
Antithrombin deficiency 30-70% aII trimesters
Protein S or C deficiency 18-20% mostIy postpartum
Homozygous Factor V Leidin 15.8% to 17.0%.
Heterozygous Factor V Leidin 1.2%.
Heterozygous Prothrombin G2021A 0.2%
Combined defects, homozygous or AT : TPx antenataIIy and
postpartum
Protein S or C: TPx 6-12 weeks postpartum
AII others: TPx postpartum ? Aspirin antenataIIy
4. Known acquired thrombophiIia without
previous VTE
f true APS by definition, antenataI treatment with
aspirin and at Ieast 3-5 days postpartum LMWH
(n.b. evidence that aspirin and LMWH usefuI for
other risks of true APS in pregnancy)
5. Other cIinicaI conditions e.g. artificiaI
heart vaIves
Manage with CardioIogist + HaematoIogist
Higher prophyIactic dose LMWH or Warfarin
#h H Dx with current AF: TPX prophyIaxis.
#ecurrent ThromboemboIism = High #isk: TPx
AntenataIIy, ntrapartum + Postpartum
ntrapartum Care for women on
thromboprophyIaxis - Obstetric
ntrapartum Care for women on
thromboprophyIaxis - Obstetric
DETALS N HANDOUT:
Stop Heparin when Iabour commences
May need TPx for high risk cases during Iabour or
deIivery
BaIance risks of ceasing TPx versus neuraxiaI
anaesthesia (PPH not generaIIy a major issue)
ntrapartum Care for women on
thromboprophyIaxis - Obstetric
DETALS N HANDOUT:
Therapeutic AnticoaguIation: Consider
Unfractionated (may be neutraIised with protamine
suIphate and more manageabIe)
ntrapartum Care for women on
thromboprophyIaxis -
Anaesthetic
ntrapartum Care for women on
thromboprophyIaxis - Anaesthetic 1
DETALS N HANDOUT:
EpiduraIs are safe and risk of epiduraI haematoma is
negIigibIe, but it is hard to convince anaesthetists of
this fact
They are the ones who take responsibiIity, so
uItimateIy it's their caII
ntrapartum Care for women on
thromboprophyIaxis - Anaesthetic 2
WHEN TO GVE #EGONAL TECHN"UES:
At Ieast 10-12 hours after previous prophyIactic dose of LMWH.
At Ieast 24 hours after previous therapeutic or high
prophyIactic dose of LMWH (e.g. CIexane 1mg / kg bd)
LMWH shouId not be given for at Ieast 4 hours after epiduraI
catheter inserted or removed (6 hours if insertion or removaI
were traumatic) and the catheter shouId not be removed within
10-12 hours of most recent injection.
ntrapartum Care for women on
thromboprophyIaxis - Anaesthetic 4
EI LSCS - HOW TO MANAGE ANAESTHETC #SKS?
ThromboprophyIactic dose of LMWH day before
deIivery
Day of deIivery, omit morning's dose
ThromboprophyIactic dose of LMWH shouId be
given by 4 hours postoperativeIy or 4 hours after
insertion or removaI of epiduraI catheter.
2% risk of wound haematoma foIIowing caesarean
section with LMWH and unfractionated heparin.
Postpartum / PuerperiaI Care
Heparin may be resumed 4-12 hours postpartum.
Warfarin / Heparin / LMWH OK
ThromboprophyIaxis foIIowing LSCS
(unadjusted ## 3.8 95% C 2.0-4.9)
1 - 2% DVT after caesarean section
Most comprehensive guideIines are those of the
#COG.
Low risk: mobiIisationm, hydration, TEDS
Moderate risk : prophyIaxis if singIe risk factors,
pIus measures above
High risk : prophyIaxis must be given with Ieg
stockings untiI 5th postoperative day or fuIIy mobiIe.
Consideration shouId aIso be given to 6 weeks
LMWH postpartum
#COG GuideIine - LSCS (handout!)
LOW-#SK:
EIective LSCS with uncompIicated pregnancy and no other risk factors
EarIy mobiIisation and hydration, TEDS
MODE#ATE-#SK (two of the foIIowing):
Age>35 years
Obesity (>80kg)
Para 4 or more
Gross varicose veins
Current infection
Pre-ecIampsia
mmobiIity prior to surgery (>4 days)
Major current iIIness e.g. heart or Iung disease, cancer, infIammatory boweI disease,
nephritic syndrome
Emergency caesarean section in Iabour
EarIy mobiIisation and hydration, TEDS, Consider prophyIactic measures such as LMWH or
unfractionated heparin for 3 - 5 days
HGH-#SK
3 or more of the moderate risk factors Iisted above
Extended major peIvic or abdominaI surgery, e.g. caesarean hysterectomy
PersonaI or famiIy history of DVT, PE or thrombophiIia, paraIysis of Iower Iimbs
AntiphosphoIipid antibody or syndrome
AntenataI LMWH prophyIaxis, TEDS untiI 5th postoperative day or fuIIy mobiIe +/- 6 weeks LMWH
Diagnosis and Management of
VPE
Diagnosis and Management of VPE
Most DVTs iIiofemoraI or caIf veins (90% Ieft)
CIinicaI diagnosis unreIiabIe
Leg oedema common
High index of suspicion
Puerperium highest risk.
Objective testing ASAP to reduce inappropriate
anticoaguIation.
Estimated radiation to fetus associated with
investigations for thromboemboIism
nvestigation #adiation (Gy) 1 rad = 10,000 Gy
CX# 10
Limited venography 500
UniIateraI venography 3140
without abdo shieId
Perfusion scan (technetium) 60-120
V" scan
Xenon 40-190
Technetium 10-350
CTPA 60-1000
PuImonary angiography
BrachiaI 500
FemoraI 2210-3740
DVT
Venography = goId standard for DVT, though it
requires radiation.
Limited venography with Iead shieIding decreases
radiation exposure to the fetus to 0.05rads, though
the iIiacs may not be cIearIy seen
DoppIer sonography = 95% correIation with
venography in the non-pregnant patient for popIiteaI
and femoraI thromboses
Sensitivity and specificity Iimited in pregnancy
CaIf vein DVTs may be more difficuIt to predict
PE
PuImonary angiography - goId standard but
invasive with significant morbidity.
CX# and V/" scan are primary tooIs with Iow
radiation to the fetus (1.0 rads for the Iatter),
though CX# is often normaI.
ECG may be hard to interpret and may
appear normaI for pregnancy.
ProbabiIity on V/" shouId be combined with
cIinicaI suspicion to make the diagnosis
PE
Hypoxaemia and hypercapnia on ABG
SpiraI CT may be usefuI, though may not
reIiabIy identify emboIi beIow the segmentaI
IeveI. M# may aIso be diagnostic.
D-dimer often eIevated in pregnancy due to
the physioIogicaI changes in the coaguIation
system, particuIarIy in the presence of pre-
ecIampsia. Low IeveI or negative may heIp to
excIude VTE
nitiation of Therapy - Iater reading
Prior to anticoaguIation, bIood shouId be taken for a fuII thrombophiIia
screen, fuII bIood count and coaguIation screen, as weII as urea,
eIectroIytes and Iiver-function tests
f there is a high IeveI of cIinicaI suspicion of DVT or PE, the patient
shouId be admitted and treatment doses of i.v. heparin or s.c. LMWH
shouId be commenced prior to confirmatory diagnostic tests.
For DVT, if uItrasound is negative and there is a Iow IeveI of cIinicaI
suspicion, anticoaguIant therapy can be discontinued. f uItrasound is
negative and a high IeveI of suspicion exists, anticoaguIation shouId
continue and uItrasound shouId be repeated in one week, with
venography considered. f repeat testing is negative, discontinue
anticoaguIation.
For PE perform both V/" scan and biIateraI DoppIer uItrasound Ieg
studies. Treatment shouId be continued for a 'medium' or 'high' risk
probabiIity of PE on V/". f there is a high index of suspicion but
probabiIity is 'Iow' then continue treatment and repeat imaging in one
week. Consider puImonary angiography or M# if cIinicaI probabiIity high
Details
in
Handout
Details
in
Handout
Unfractionated Heparin Therapy -
treatment of choice - Iater reading
nitiaI therapy shouId be with unfractionated heparin as a boIus of 4,000 U
foIIowed by an infusion of 15 units / kg / hour to achieve therapeutic range
within 24 hours. Measure APTT six hours after boIus and adjust to keep to IocaI
(#PA) therapeutic IeveI (1.5-2.5 times controI). #efer to CSAHS poIicy
document for dose adjustment chart. #epeat aPTT every 6 hours for first 24
hours. Once therapeutic, daiIy APTT or anti-Xa monitoring is recommended.
PIateIet counts shouId be monitored every 2nd day. t they faII to Iess than 50%
of their originaI baseIine or beIow 100, consuIt a haematoIogist.
Subcutaneous unfractionated heparin has aIso been shown to be safe and
efficacious, with dosage of 5000 U initiaIIy, foIIowed by 15,000-20,000 U 12
hourIy.
ntravenous anticoaguIation shouId be maintained for at Ieast 5-7 days then
changed to subcutaneous (t.d.s.) dosing. n the postpartum period, Warfarin
may be commenced on day 1 or 2 and overIapped for a minimum of 5 days
after the N# is therapeutic.
APTT cannot gauge adequacy of anticoaguIation with therapeutic heparin in
APS for which smaII amounts of heparin may markedIy increase APTT - need
to use antifactor Xa instead.
Details
in
Handout
Details
in
Handout
Therapy - LMWH and other methods
- Iater reading
n a review of 64 studies reporting 2777 pregnancies with
LMWH in pregnancy, the risk of recurrence of VTE was 1.5%
when treatment doses were used to treat VTE in pregnancy.
A suggested dosage for CIexane is 1mg/kg twice daiIy based
upon the earIy pregnancy weight. f diagnosis is confirmed then
peak anti-Xa activity shouId be measured three hours post-
injection aiming for a range of 0.6-1.0 units/mI. #educe the
dosage if the peak anti-Xa IeveI is above this upper Iimit.
Leg eIevation with fuII Iength graduated eIastic compression
stockings to reduce oedema.
A temporary vena cavaI fiIter may be required in those with
recurrent PE despite satisfactory anticoaguIation.
With massive PE, CP#, thromboIytic therapy, percutaneous
catheter thrombus fragmentation or surgicaI emboIectomy may
be required.
Details
in
Handout
Details
in
Handout
Maintenance Therapy - Iater reading
Unfractionated Heparin
Dosage shouId be adjusted to keep aPTT therapeutic six hours post injection
(1.5-2.5 times controI or heparin IeveI of 0.1-0.2 U/mI)
LMWH
Dose shouId be chosen to achieve an antiXa heparin IeveI of 0.4-1.0 Units/mI
four hours post-injection. A singIe subsequent measurement of the antiXa IeveI
in the third trimester shouId be performed to check in therapeutic range.
OveraII, the regime is more simpIified, requiring Iess testing, and pIateIet count
monitoring may be performed monthIy.
Six months therapy is usuaI. f very earIy in pregnancy couId consider reducing
to prophyIactic IeveIs after consuIting with the caring haematoIogist.
TPX shouId be continued for three months postpartum. At three months an
assessment shouId be made of the ongoing risk for VTE by a haematoIogist.
Graduated eIastic compression stockings shouId be worn on the affected Ieg
for two years after the acute event to reduce the risk of post-thrombotic
syndrome.
Details
in
Handout
Details
in
Handout
Risk Previous VTE and/or thrombophilia
status
Prophylaxis
Very high Previous VTE ( thrombophilia) on long-
term warIarin
Antenatal high prophylactic or
therapeutic dose LMWH
and at least six weeks oI postnatal
warIarin
High Previous recurrent VTE not on long-term
warIarin
Previous VTE thrombophilia
Previous VTE Iamily history oI VTE
Asymptomatic thrombophilia
(Antithrombin deIiciency, combined
deIects, homozygous Iactor V Leiden or
prothrombin gene deIect)
Antenatal and six weeks postnatal
prophylactic LMWH
Moderate Single previous provoked VTE without
thrombophilia, Iamily history or other risk
Iactors
Asymptomatic thrombophilia (except
antithrombin deIiciency,combined deIects,
homozygous FVL or prothrombin gene
deIect
Antenatal and six weeks postnatal
prophylactic LMWH /- antental
low dose aspirin
Summary of risk and TPx for
VTE:
Details
in
Handout
Summary of risk and TPx for
VTE:
Details
in
Handout
References
RCOG Guideline No. 37. Thromboprophylaxis during pregnancy, labour and after
vaginal delivery. January 2004
RCOG Guideline No. 28. Thromboembolic disease in pregnancy and the puerperium:
acute management. April 2001.
RCOG Working !arty Report on !rophylaxis against Thromboembolism
National Collaborating Centre for Women's and Children's Health (NHS/NCE UK).
Caesarean Section. Clinical Guideline April 2004.
SOGC Clinical !ractice Guideline No. 95. !revention and Treatment of Venous
Thromboembolism (VTE) in Obstetrics. September 2000.
ACOG practice bulletin No.19. Thromboembolism in !regnancy. August 2000.
Low-molecular weight heparins for thromboprophylaxis and treatment of venous
thromboembolism in pregnancy: a systematic review of safety and efficacy. an A. Greer
and Catherine Nelson-!iercy. Blood. 2005;106:401-407
Neuraxial Anesthesia and Anticoagulation. Terese T. Horlocker. Jobson Symposium
R!A Anaesthetics Sydney 2001.
!rophylaxis for VTE in pregnancy and the early postnatal period. Gates. Brocklehurst.
Cochrane review 2005.
Elastic compression stockings for prevention of deep vein thrombosis. Amaragiri SV.
Lees TA. Cochrane review. ssue 3. 2005
Regional Anesthesia in the Anticoagulated !atient: Defining the Risks (The Second
ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Horlocker
TT et al. Regional Anesthesia and !ain Medicine, 2003; 28:172-197.