Thromboembolic Disease in Pregnancy

1
Thromboembolic Disease in Pregnancy

• Alec Welsh
• MBBS MSc PhD MRCOG(MFM) FRANZCOG DDU CMFM
• Professor in Maternal-Fetal Medicine
• University of New South Wales
• alec.welsh_at_unsw.edu.au

Movember.com

• There is no universal truth regarding
  thrombophilias and
• thromboembolic disease
• uteroplacental disease

OG Perinatal Update 2008 Royal Hospital for
Women, Saturday November 8th 2008
2
Personal interest in Thromboprophylaxis

• Writing guidelines for screening and treatment
  at RPA Hospital and Central Sydney Area
• Participation in the NICS National
  Thromboprophylaxis initiative

3
Incidence

• 0.5 3 / 1000 pregnancies (mostly UK data)
• 10 fold increase in risk cf non pregnant
• Poor / insufficient Aust / NZ data

Significance?
4
Risk Factors

• General
• Specific

5
Prevalence and risk of VTE with different
thrombophilias Ref Handbook of Obstetric
Medicine 2006

• Thrombophilic disorder population RR VTE
• Inherited AT III 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
• Antiphospholipid antibody 2 9
• Lupus Anticoagulant
• Anticardiolipin antibodies
• Acquired APC resistance 8-11 2-4
• (without FVL)

6
Routine antenatal care

• Risk factor assessment all pregnancies

1. Hypercoagulability Increase in factors
II,V,VII,VIII,IX,X,XII and fibrinogen Increased
platelet aggregation Decreased protein S, tissue
plasminogen activator, factors XI,XIII Decreased
fibrinolytic activity Increased resistance to
activated protein C Antithrombin may be normal
or reduced 2. Stasis Increased venous
distensibility, decreased venous tone 50
decrease in venous flow in lower extremity by
third trimester Uterus mechanically impedes
venous return 3. Endothelial Vascular damage
(pelvic veins) at delivery
All components of Virchows Triad are
affected (coagulation, stasis, endothelium)
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Risk factors - individual
1. Pre-existing Previous VTE Thrombophilia
(i) Congenital Antithrombin deficiency Protein
C deficiency Protein S deficiency Factor V
Leiden mutation (5 population prevalence) Prothr
ombin gene mutation G20210A (2 population
prevalence) Antithrombin deficiency Hyperhomocys
teinemia - specifically MTHFR gene Plasminogen
deficiency (ii) Acquired Lupus
anticoagulant Anticardiolipin antibodies Nephrot
ic syndrome (decreased antithrombin levels)
8
Risk factors - individual

• 2. Current Risk Factors?
• Age gt35 years
• Obesity (BMI gt30) pre-pregnancy or early
  pregnancy
• Parity gt4
• Gross varicose veins
• Paraplegia
• Sickle cell disease
• Inflammatory disorders e.g. inflammatory bowel
  disease
• Some medical disorders e.g. nephritic syndrome,
  cardiac disease
• Myeloproliferative disorders e.g. essential
  thrombocythaemia, polycythaemia rubra vera

9
Risk factors - individual

• 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
• Immobility (gt4 days bedrest)
• Pre-eclampsia
• Excessive blood loss
• Long-haul travel
• Prolonged labour
• Operative instrumental delivery
• Immobility after delivery

10
Routine care

• General advice effects of long-haul travel,
  immobility, dehydration etc.
• 2 current or transient risk factors consider
  prophylactic TPX for 3-5 days postpartum.
• 3 or more current or transient risk factors as
  shown in Table consider prophylactic TPX
  antenatally and for at least 3-5 days postpartum

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Previous VTE 1

• 10-12 recurrence of VTE during pregnancy and
  3.7 outside pregnancy
• RR in pregnancy 3.5 (95 CI 1.6-7.8).
• Single previous thrombosis no known
  thrombophilia, risk of recurrence 2.0-3.0.
• higher in the presence of thrombophilia or the
  clot is in an unusual site or is unprovoked
• History
• Screening should be performed for inherited and
  acquired thrombophilias (considering the effects
  of pregnancy on thrombophilia screen).

12
Previous VTE 2

• Family history, with or without previous VTE.
• Who to test on family history?
• No previous VTE, women with a first-degree
  relative with an AT-III deficiency or homozygous
  factor V Leidin or prothrombin G20210A mutation
  may benefit from testing.
• Strong family history may mean coexistence of
  multiple inherited risk factors.
• History of thrombosis, recurrent fetal loss,
  early or severe preeclampsia or severe
  unexplained IUGR requires testing for?

13
The Thrombophilia Screen

• Lupus anticoagulant
• Anticardiolipin antibodies
• Factor V Leiden mutation
• Prothrombin G20210A mutation
• Antithrombin-III antigen activity levels
• Fasting homocysteine levels or MTHFR C677T
  mutation
• Protein C antigen activity levels
• Protein S antigen activity levels

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Thromboprophylactic Agents
What can we use?
15
Low molecular weight Heparin (LMWH)

• Effective and safe
• Why are these now agents of choice?
• Enhanced ratio of anti-Xa (antithrombotic) to
  anti-IIa (anticoagulant) activity reducing the
  risk of bleeding.
• Less binding to platelet factor 4 substantially
  reducing the risk of heparin-induced
  thrombocytopaenia.
• Less osteoporosis

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Low molecular weight Heparin (LMWH)

• No need for monitoring of peak antifactor Xa
• No reported adverse effects on breastfeeding
• Incidence of significant bleeding does not seem
  to be increased compared to background population.

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Unfractionated Heparin

• Accelerates ability of antithrombin to inactivate
  thrombin (factor IIa), factor Xa and factor IXa
• Larger molecular weight heparins catalyse
  inhibition of both factors IIa and Xa
• IV injection results in immediate anticoagulant
  activity, subcutaneous injection results in a 1-
  to 2-hour delay
• Significant side effects in pregnancy include
  thrombocytopaenia, osteoporosis and bleeding

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Unfractionated Heparin

• 2 forms of heparin-induced thrombocytopaenia.
• Nonimmune form within first few days of therapy,
  resolves by 5 days.
• Immune (IgG) seen in 3 within 5 14 days.
• Osteoporosis is dose dependent. Mean bone loss
  5, approximately 1/3 suffering gt/ 10 decrease
  in bone density.
• There is a risk of major bleeding episodes in
  2-10. Platelets should be checked on day 5 and
  then periodically for the first two weeks of
  therapy.

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Low dose Aspirin (50-100mg)

• Efficacy in pregnancy not demonstrated in an RCT
  but safe
• May be more beneficial for arterial rather than
  venous

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Warfarin

• Crosses the placenta!!!
• Avoid if possible during pregnancy.
• Up to 6.4 risk of teratogenesis and increased
  risk of miscarriage, fetal and maternal
  haemorrhage, neurological problems in the baby
  and stillbirth.
• Warfarin embryopathy (1st Trimester)
• nasal hypoplasia, chondrodysplasia punctata, eye
  abnormalities, short proximal limbs, growth
  restriction and developmental delay)
• CNS risks can come at any stage of pregnancy.

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Warfarin

• Some cases of metal prosthetic heart valves, may
  be more efficacious, start after 20 weeks
  gestation, discontinue prior to delivery, in
  close consultation with cardiologist.
• Safe postpartum and for breastfeeding
• Anticoagulant clinic care
• Increased risk of haemorrhage and haematoma.
• If chosen over LMWH postnatally, initiate on day
  2 or 3, with LMWH continued until INR gt2.0 for 5
  days.

22
Agents available for thromboprophylaxis TED
Stockings

• Above knee (full length) TEDS significantly
  decrease the risk of DVT in hospitalised post
  operative patients. TEDS on their own are
  effective, but are more effective when used with
  other methods.

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Management of Thromboprophylaxis in Pregnancy (4
categories)
Note no universally agreed rule significant
local variation In practice
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1. Previous VTE and no thrombophilia

• Prophylaxis with LMWH or warfarin for 6 weeks
  after delivery for all cases.
• 1. Single previous VTE - temporary risk factor
• Usually no need for antenatal TPX
• 2. Previous VTE idiopathic, related to pregnancy
  or OCP or additional risk factors exist such as
  obesity?
• Antenatal prophylactic dose LMWH
• 3. gt 1 previous VTE, unusual site or FH in 1st
  degree relative
• Antenatal prophylactic LMWH.

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2a. Previous VTE and inherited thrombophilia
Antenatal, intrapartum and postpartum TPX should
be given (LMWH). Specialist obstetric and / or
haematological advice should be sought

• 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

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2b. Previous VTE and acquired thrombophilia
(antiphospholipid syndrome)

• Up to 70 recurrent thrombosis, even higher in
  pregnancy.
• Some of these women will be on long-term warfarin
  outsided pregnancy.
• Antenatal, intrapartum and postnatal prophylactic
  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

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3. Known inherited thrombophilia without previous
VTE

• Risk of VTE
• Antithrombin III deficiency 30-70 all
  trimesters
• Protein S or C deficiency 18-20 mostly
  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 III TPx
  antenatally and postpartum
• Protein S or C TPx 6-12 weeks postpartum
• All others TPx postpartum ? Aspirin antenatally

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4. Known acquired thrombophilia without previous
VTE

• If true APS by definition, antenatal treatment
  with aspirin and at least 3-5 days postpartum
  LMWH
• (n.b. evidence that aspirin and LMWH useful for
  other risks of true APS in pregnancy)

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5. Other clinical conditions e.g. artificial
heart valves

• Manage with Cardiologist Haematologist
• Higher prophylactic dose LMWH or Warfarin
• Rh H Dx with current AF TPX prophylaxis.
• Recurrent Thromboembolism High Risk TPx
  Antenatally, Intrapartum Postpartum

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Intrapartum Care for women on thromboprophylaxis
- Obstetric
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Intrapartum Care for women on
thromboprophylaxis - Obstetric

• DETAILS IN HANDOUT
• Stop Heparin when labour commences
• May need TPx for high risk cases during labour or
  delivery
• Balance risks of ceasing TPx versus neuraxial
  anaesthesia (PPH not generally a major issue)

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Intrapartum Care for women on
thromboprophylaxis - Obstetric

• DETAILS IN HANDOUT
• Therapeutic Anticoagulation Consider
  Unfractionated (may be neutralised with protamine
  sulphate and more manageable)

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Intrapartum Care for women on thromboprophylaxis
- Anaesthetic
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Intrapartum Care for women on
thromboprophylaxis Anaesthetic 1

• DETAILS IN HANDOUT
• Epidurals are safe and risk of epidural haematoma
  is negligible, but it is hard to convince
  anaesthetists of this fact
• They are the ones who take responsibility, so
  ultimately its their call

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Intrapartum Care for women on
thromboprophylaxis Anaesthetic 2

• WHEN TO GIVE REGIONAL TECHNIQUES
• At least 10-12 hours after previous prophylactic
  dose of LMWH.
• At least 24 hours after previous therapeutic or
  high prophylactic dose of LMWH (e.g. Clexane 1mg
  / kg bd)
• LMWH should not be given for at least 4 hours
  after epidural catheter inserted or removed (6
  hours if insertion or removal were traumatic) and
  the catheter should not be removed within 10-12
  hours of most recent injection.

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Intrapartum Care for women on
thromboprophylaxis Anaesthetic 4

• El LSCS HOW TO MANAGE ANAESTHETIC RISKS?
• Thromboprophylactic dose of LMWH day before
  delivery
• Day of delivery, omit mornings dose
• Thromboprophylactic dose of LMWH should be given
  by 4 hours postoperatively or 4 hours after
  insertion or removal of epidural catheter.
• 2 risk of wound haematoma following caesarean
  section with LMWH and unfractionated heparin.

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Postpartum / Puerperial Care

• Heparin may be resumed 4-12 hours postpartum.
• Warfarin / Heparin / LMWH OK

38
Thromboprophylaxis following LSCS

• (unadjusted RR 3.8 95 CI 2.0-4.9)
• 1 2 DVT after caesarean section
• Most comprehensive guidelines are those of the
  RCOG.
• Low risk mobilisationm, hydration, TEDS
• Moderate risk prophylaxis if single risk
  factors, plus measures above
• High risk prophylaxis must be given with leg
  stockings until 5th postoperative day or fully
  mobile. Consideration should also be given to 6
  weeks LMWH postpartum

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RCOG Guideline LSCS (handout!)

• LOW-RISK
• Elective LSCS with uncomplicated pregnancy and
  no other risk factors
• Early mobilisation and hydration, TEDS
• MODERATE-RISK (two of the following)
• Agegt35 years
• Obesity (gt80kg)
• Para 4 or more
• Gross varicose veins
• Current infection
• Pre-eclampsia
• Immobility prior to surgery (gt4 days)
• Major current illness e.g. heart or lung
  disease, cancer, inflammatory bowel disease,
  nephritic syndrome
• Emergency caesarean section in labour
• Early mobilisation and hydration, TEDS, Consider
  prophylactic measures such as LMWH or
  unfractionated heparin for 3 5 days
• HIGH-RISK
• 3 or more of the moderate risk factors listed
  above
• Extended major pelvic or abdominal surgery, e.g.
  caesarean hysterectomy
• Personal or family history of DVT, PE or
  thrombophilia, paralysis of lower limbs
• Antiphospholipid antibody or syndrome

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Diagnosis and Management of VPE
41
Diagnosis and Management of VPE

• Most DVTs iliofemoral or calf veins (90 left)
• Clinical diagnosis unreliable
• Leg oedema common
• High index of suspicion
• Puerperium highest risk.
• Objective testing ASAP to reduce inappropriate
  anticoagulation.

42
Estimated radiation to fetus associated with
investigations for thromboembolism

• Investigation Radiation (µGy) 1 rad 10,000 µGy
  
• CXR lt10
• Limited venography lt500
• Unilateral venography 3140
• without abdo shield
• Perfusion scan (technetium) 60-120
• VQ scan
• Xenon 40-190
• Technetium 10-350
• CTPA 60-1000
• Pulmonary angiography
• Brachial lt500
• Femoral 2210-3740

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DVT

• Venography gold standard for DVT, though it
  requires radiation.
• Limited venography with lead shielding decreases
  radiation exposure to the fetus to lt0.05rads,
  though the iliacs may not be clearly seen
• Doppler sonography 95 correlation with
  venography in the non-pregnant patient for
  popliteal and femoral thromboses
• Sensitivity and specificity limited in pregnancy
• Calf vein DVTs may be more difficult to predict

44
PE

• Pulmonary angiography gold standard but
  invasive with significant morbidity.
• CXR and V/Q scan are primary tools with low
  radiation to the fetus (lt1.0 rads for the
  latter), though CXR is often normal.
• ECG may be hard to interpret and may appear
  normal for pregnancy.
• Probability on V/Q should be combined with
  clinical suspicion to make the diagnosis

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PE

• Hypoxaemia and hypercapnia on ABG
• Spiral CT may be useful, though may not reliably
  identify emboli below the segmental level. MRI
  may also be diagnostic.
• D-dimer often elevated in pregnancy due to the
  physiological changes in the coagulation system,
  particularly in the presence of pre-eclampsia.
  Low level or negative may help to exclude VTE

46
Initiation of Therapy later reading

• Prior to anticoagulation, blood should be taken
  for a full thrombophilia screen, full blood count
  and coagulation screen, as well as urea,
  electrolytes and liver-function tests
• If there is a high level of clinical suspicion of
  DVT or PE, the patient should be admitted and
  treatment doses of i.v. heparin or s.c. LMWH
  should be commenced prior to confirmatory
  diagnostic tests.
• For DVT, if ultrasound is negative and there is a
  low level of clinical suspicion, anticoagulant
  therapy can be discontinued. If ultrasound is
  negative and a high level of suspicion exists,
  anticoagulation should continue and ultrasound
  should be repeated in one week, with venography
  considered. If repeat testing is negative,
  discontinue anticoagulation.
• For PE perform both V/Q scan and bilateral
  Doppler ultrasound leg studies. Treatment should
  be continued for a medium or high risk
  probability of PE on V/Q. If there is a high
  index of suspicion but probability is low then
  continue treatment and repeat imaging in one
  week. Consider pulmonary angiography or MRI if
  clinical probability high

Details in Handout
47
Unfractionated Heparin Therapy treatment of
choice later reading

• Initial therapy should be with unfractionated
  heparin as a bolus of 4,000 IU followed by an
  infusion of 15 units / kg / hour to achieve
  therapeutic range within 24 hours. Measure APTT
  six hours after bolus and adjust to keep to local
  (RPA) therapeutic level (1.5-2.5 times control).
  Refer to CSAHS policy document for dose
  adjustment chart. Repeat aPTT every 6 hours for
  first 24 hours. Once therapeutic, daily APTT or
  anti-Xa monitoring is recommended.
• Platelet counts should be monitored every 2nd
  day. It they fall to less than 50 of their
  original baseline or below 100, consult a
  haematologist.
• Subcutaneous unfractionated heparin has also been
  shown to be safe and efficacious, with dosage of
  5000 IU initially, followed by 15,000-20,000 IU
  12 hourly.
• Intravenous anticoagulation should be maintained
  for at least 5-7 days then changed to
  subcutaneous (t.d.s.) dosing. In the postpartum
  period, Warfarin may be commenced on day 1 or 2
  and overlapped for a minimum of 5 days after the
  INR is therapeutic.
• APTT cannot gauge adequacy of anticoagulation
  with therapeutic heparin in APS for which small
  amounts of heparin may markedly increase APTT
  need to use antifactor Xa instead.

Details in Handout
48
Therapy LMWH and other methods later reading

• In 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 Clexane is 1mg/kg twice
  daily based upon the early pregnancy weight. If
  diagnosis is confirmed then peak anti-Xa activity
  should be measured three hours post-injection
  aiming for a range of 0.6-1.0 units/ml. Reduce
  the dosage if the peak anti-Xa level is above
  this upper limit.
• Leg elevation with full length graduated elastic
  compression stockings to reduce oedema.
• A temporary vena caval filter may be required in
  those with recurrent PE despite satisfactory
  anticoagulation.
• With massive PE, CPR, thrombolytic therapy,
  percutaneous catheter thrombus fragmentation or
  surgical embolectomy may be required.

Details in Handout
49
Maintenance Therapy later reading

• Unfractionated Heparin
• Dosage should be adjusted to keep aPTT
  therapeutic six hours post injection (1.5-2.5
  times control or heparin level of 0.1-0.2 IU/ml)
• LMWH
• Dose should be chosen to achieve an antiXa
  heparin level of 0.4-1.0 Units/ml four hours
  post-injection. A single subsequent measurement
  of the antiXa level in the third trimester should
  be performed to check in therapeutic range.
• Overall, the regime is more simplified, requiring
  less testing, and platelet count monitoring may
  be performed monthly.
• Six months therapy is usual. If very early in
  pregnancy could consider reducing to prophylactic
  levels after consulting with the caring
  haematologist.
• TPX should be continued for three months
  postpartum. At three months an assessment should
  be made of the ongoing risk for VTE by a
  haematologist.
• Graduated elastic compression stockings should be
  worn on the affected leg for two years after the
  acute event to reduce the risk of post-thrombotic
  syndrome.

Details in Handout
50
Summary of risk and TPx for VTE Details in
Handout
51
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 Party Report on Prophylaxis against
  Thromboembolism
• National Collaborating Centre for Womens and
  Childrens Health (NHS/NICE UK). Caesarean
  Section. Clinical Guideline April 2004.
• SOGC Clinical Practice Guideline No. 95.
  Prevention and Treatment of Venous
  Thromboembolism (VTE) in Obstetrics. September
  2000.
• ACOG practice bulletin No.19. Thromboembolism in
  Pregnancy. August 2000.
• Low-molecular weight heparins for
  thromboprophylaxis and treatment of venous
  thromboembolism in pregnancy a systematic review
  of safety and efficacy. Ian A. Greer and
  Catherine Nelson-Piercy. Blood. 2005106401-407
• Neuraxial Anesthesia and Anticoagulation. Terese
  T. Horlocker. Jobson Symposium RPA Anaesthetics
  Sydney 2001.
• Prophylaxis 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. Issue 3. 2005
• Regional Anesthesia in the Anticoagulated
  Patient Defining the Risks (The Second ASRA
  Consensus Conference on Neuraxial Anesthesia and
  Anticoagulation). Horlocker TT et al. Regional
  Anesthesia and Pain Medicine, 2003 28172-197.