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Venous Thromboembolism In Pregnancy Dr: Galila Zaher MRCPath Consultant hematologist Assistant Professor KAUH

Venous Thromboembolism In Pregnancy

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Venous Thromboembolism In Pregnancy. Dr: Galila Zaher MRCPath Consultant hematologist Assistant Professor KAUH. Epidemiology of venous thromboembolism. Incidence with pregnancy is unknown PE is leading cause of MM second only to bleeding - PowerPoint PPT Presentation

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Page 1: Venous Thromboembolism In Pregnancy

Venous Thromboembolism In

PregnancyDr: Galila Zaher MRCPathConsultant hematologistAssistant ProfessorKAUH

Page 2: Venous Thromboembolism In Pregnancy

Epidemiology of venous thromboembolism

Incidence with pregnancy is unknown PE is leading cause of MM second only to bleeding Pregnancy & puerperium are thrombophilic

condition Risk of VTE in pregnancy is 4 - 6 X > non pregnant No preponderance to any trimester Predisposition for DVT in left leg (90%) Increased risk persists postpartum Mayo Clinic,

Over the 30-year study period, the highest risk period for VTE and PE in particular is during the postpartum period (57% after delivery)

Risk is higher after CS (esp. emergency CS) Additional risk factors.

Page 3: Venous Thromboembolism In Pregnancy

Pathogenesis of Venous Thromboembolism

Virchow’s Triad

Venous stasis Hypercoagulability

Vascular Damage

Page 4: Venous Thromboembolism In Pregnancy

Platelet

Thrombin

VIIIa XIa

IXa TFVIIa

XaProthrombin

Fibroblast

Procoagulant factors: VWF ,FVIII & FV

Amplification

Activated platelets

XIaIXaXaProthrombin

Thrombin

Propagation

Page 5: Venous Thromboembolism In Pregnancy

Factor IXa -FVIIIa

Factor Xa+FVa

Factor XIa Factor IIa(thrombin)

Fibrinogen Fibrin

TFPI

AntiThrombin

Protein C& Protein S

Tissue factor + Factor VIIa

Page 6: Venous Thromboembolism In Pregnancy

Pregnancy is a “physiological” hypercoagulation state

Acquired Resistance APC & Protein S Imparied fibrinolysis : Venous stasis end of 12w & peaks at 36w Raised progeterone levels reduced venous flow Endothelial damage to pelvic vessels during delivery

Special Risk Factors Age > 35 yrs (doubled) Mortality from PE x100 in preg

women > 40 years • Parity 3 • Prolonged immobility• Obesity• Operative delivery - 2-8 fold increase

GA > epidural block Emergency CS elective CS• Inherited thrombophilia

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Page 8: Venous Thromboembolism In Pregnancy

Venous Thrombosis During Pregnancy

Diagnostic Challenge Symptoms & signs of DVT & PE :

physiologic changes Concern about diagnostic

procedures : radiation exposure Thrombophilia testing Safety of anti-coagulant during pregnancy

Page 9: Venous Thromboembolism In Pregnancy

Inherited Prothrombotic State

Defect Incidence % of hypercoagulabe States

Factor V Leiden 2 – 8 % 40-60%

Prothtombin Gene Mutation

1-2 % ?10%

Protein C deficiency

1: 200 5-10%

Protein S deficiency

1: 5,000 5-10%

Antithrombin III deficiency

1: 2- 5000 1-3%

Dysfibrinogenemia rare 1%

Page 10: Venous Thromboembolism In Pregnancy

Impact of Unconfirmed Diagnosis of VTE in Pregnancy:

Risk of anticoagulant therapy Future pregnancy (ies): Thromboprophylaxis or

not? No large scale trials Empirical recommendations based on

extrapolation from studies in non-pregnant and small observational ones

Clinical Diagnosis Physiological changes mimicing symptoms of VTE Clinical diagnosis (pre test probability) lakes both the sensitivity & specificity(20-40%).

Page 11: Venous Thromboembolism In Pregnancy

D-DIMER (ELISA)

Highly sensitive, nonspecific screening test 95-99% NPV Elevated in pregnancy, inflammation, advanced age and

cancer In pregnancy because its specificity was deemed too poor. Sensitivity and specificity of SimpliRED assay in pregnant

women Prospective study. Sensitivity :100%, specificity 60%, and NPV value was 100%

Normal result excludes DVT Initial screen it reduce the imaging workload by 35% Clin

Radiol 2000Jul:55(7):525-7 Normal D-dimer level in low –inermediate clinical probability

excludes DVT. Semin Thromb Hemos2000:26(6):65767 Normal D-dimer test + normal CUS has a NPV of 99%.

Page 12: Venous Thromboembolism In Pregnancy

ULTRASOUND (Compression, Duplex, or Doppler)

Pro’s Quick, cheap, and non-invasive

Con’s highly operator dependent

negative in 10-30% distal DVT

Page 13: Venous Thromboembolism In Pregnancy

V/Q SCAN

Diagnosis based on pre-test probability

Rarely diagnostic (i.e. high or intermediate probability)

Unreliable in the setting of concomitant lung disease (e.g. pneumonia, cancer, COPD) or significant cardiac disease.

Page 14: Venous Thromboembolism In Pregnancy

High-Res CT SCAN

Quick, accurate, available, and relatively non-invasive. Sensitivity(79%)Specificity(91%)

Valid only for main, lobar, or segmental artery occlusions.

Not an option in renal insufficiency.

Page 15: Venous Thromboembolism In Pregnancy

MRI for Diagnosis of PE

MRI Godolinium contrast crosses placenta

FDA “Safety of MRI devices when imaging the foetus has not been established”. Therefore, informed consent is required throughout pregnancy.

Page 16: Venous Thromboembolism In Pregnancy

ANGIOGRAPHY

Gold Standard for the diagnosis of VTE

It is invasive and has associated risksReserved when diagnosis of VTE

cannot be established by less invasive tests

In indeterminate V-Q scan

Page 17: Venous Thromboembolism In Pregnancy

Estimated Radiation absorbed by foetus

CXR* < 10 Gy V/Q*10 – 50 GyTc-99 m sulphur colloid PA* < 500 Gy brachial route Total* < 50,000 Expose of foetus to radiation <50,000

Gy (i.e. 5 rads) has not been associated with seg risk of foetal injury in most studies.

Page 18: Venous Thromboembolism In Pregnancy

Algorithm for the investigation of suspected DVT during pregnancy

Suspected DVT

CUS of proximal veins

Clearly abnormal

Treat

Normal

Isolated Iliac DVT Suspected

Yes

Pulsed Doppler with direct visualization of iliac vein

Abnormal

Venography or MRISerial CUS

Normal Abnormal

No treatmentSerial CUS Treat or Confirm with

Vernography or MRV

Treat

Equivocal

Venography or MRI

Normal

No treatment Treat

No

Normal AbnormalNormal Abnormal

No treatmentTreat

Blood, 2002; 100: 3470-8

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Indications For Anticoagulant Therapy

Prevention and treatment of VTEPrevention of pregnancy

complications in APLAs Prevention of pregnancy

complications in thrombophilia Recommendations are based largely

on extrapolations from non pregnant patients

Page 20: Venous Thromboembolism In Pregnancy

Thrombo-Prophylaxis

Anticoagulant Heparin & LMWHWarfarinAspirin

Elastic compression

Page 21: Venous Thromboembolism In Pregnancy

Warfarin—Mechanism of Action

Vitamin KVitamin K

WarfarinWarfarin

Vitamin K Utilization Reduced

ProteinProtein Half-LifeHalf-Life

Factor VIIFactor VII 4–6 4–6 hourshours

Factor IXFactor IX 24 24 hourshours

Factor IIFactor II 60 60 hourshours

Factor XFactor X 48–72 48–72 hourshours

Protein CProtein C 8 hours8 hours

Protein SProtein S 30 30 hourshours

Page 22: Venous Thromboembolism In Pregnancy

Elimination Half-Lives of Vitamin K-Dependent Proteins

ProteinProtein Half-Half-LifeLife

Factor VIIFactor VII 4–6 4–6 hourshours

Factor IXFactor IX 24 24 hourshours

Factor IIFactor II 60 60 hourshours

Factor XFactor X 48–72 48–72 hourshours

Protein CProtein C 8 8 hourshours

Protein SProtein S 30 30 hourshours

Page 23: Venous Thromboembolism In Pregnancy

Warfarin Therapy

Cross placenta Safe during first 6 ws of gestation Embryopathy 6- 12 ws of gestation CNS abnormalities : any trimester Fatal or non-fatal hemorrhage Necrosis of skin and other tissues Less frequently include:

cholesterol microembolization Alopecia Purple toes syndrome, urticaria, dermatitis

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Long-term Heparins

UFH Dose not cross placenta Major bleeding 2% (non

pregnant) Inconvenient :frequent

monitoring aPTT response to heparin is

attenuated Painful to administer Osteoporosis Heparin-induced

thrombocytopenia (HIT)

LMWH Dose not cross placenta Major bleeding 2% Monitoring usually is not

required : longer T1/2 Weight-adjusted dose BID

preferable to OD Less Osteoporosis

Less HIT As effective & safe as

UFH Non-pregnant Expensive Anti- Xa 3 - 4 h post dose

( 0.5 - 1.2 U/mL)

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Nursing Mother

Heparin & LMWHs are not secreted into breast milk can be safe

Warfarin does not induce anticoagulant effect in breast-fed infant is also safe.

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Dose Definitions

UFH SC BID Minidose UFH 5,000 U Moderate-dose adjusted anti-Xa 0.1

- 0.3 U/mL. Adjusted-dose mid-interval aPTT 1.5-

2.5 X controlLMWH Enoxaparin Prophylactic : 40 mg SC OD Intermediate-dose 40 mg SC BID Adjusted-dose weight-adjusted, 1

mg/kg OD or BID

Page 28: Venous Thromboembolism In Pregnancy

Treatment of VTE During Pregnancy Many randomized trials & meta-analyses : in

non-pregnant . LMWH is at least as safe and effective as

UFH. Enoxaparin 1 mg/kg BID OR UFH 80 IU/Kg X 5 d Enoxaparin 1 mg/kg BID OR Adjusted-dose UFH

SC BID mid-interval aPTT 1.5-2.5 Delivery : DC heparin 24 h before elective

induction Postpartum 4-6 ws Warfarin INR 2-3 Graduated elastic stocking :ante &post-natal All are 1C except GES 2C

Page 29: Venous Thromboembolism In Pregnancy

Long-term Oral Anticoagulant Therapy Attempting pregnancy

Replacement with UFH or LMWHwhen pregnancy is achieved

Replacement with UFH or LMWH

before conception is attempted.

Adjusted-dose UFH Or LMWH

Assumes warfarin is safe first 4 - 6 ws

Reliable patientIncreases heparin exposure Is costlyHigher osteoporosis

(Grade 2C)

mid-interval aPTT 1.5-2.5 X control1 mg/kg OD or BID

Page 30: Venous Thromboembolism In Pregnancy

Secondary Thrombo-prophylaxis

Single episode Multiple (two or more) episodes

and/or receiving long-term anticoagulants

Thrombophilia & No prior VTE

Page 31: Venous Thromboembolism In Pregnancy

VTE Thromboprophylaxis?

Yes

No

Page 32: Venous Thromboembolism In Pregnancy

Single Episode

Transient risk factor

o Antepartum clinical surveillance (Grade 1C) OR Graduated elastic compression o Postpartum warfarin 4- 6 W INR 2.5 (1C)Pregnancy / estrogen-related or

additional risk factors (obesity) o Antepartum anticoagulant prophylaxis ( 2C) OR LMWH enoxaparin 40 mg SC ODOR UFH Minidose 5,000 U SC q12hOR Graduated elastic compression o Postpartum warfarin 4- 6 Ws INR 2.5(1C)

Page 33: Venous Thromboembolism In Pregnancy

Single Episode

Idiopathic Or Strong Family History o Ante-partum o LMWH Prophylactic Or Intermediate-dose

enoxaparin 40 mg SC OD Or BIDo UFH Minidose Or Moderate-dose 5,000 U SC

BID Or adjusted to anti-Xa 0.1 -0.3 U/mL. o Clinical surveillance & aggressive investigation

with S&S of DVT or PE.o Ante-natal & postpartum GES o Postpartum warfarin 4 - 6 ws INR 2- 3 with initial

heparin overlap until INR is 2.5 (All are 2C)

Page 34: Venous Thromboembolism In Pregnancy

Single episode VTE Thrombophilia confirmed by lab & not on long-term

anticoagulants Or strong family history of VTE High Risk :AT-deficient , compound heterozygotes &

homozygotes :i. History of VTE Antipartum & Postpartum moderate

dose ii. No prior VTE Prophylactic dose LMWH Enoxaparin 40

mg SC All are 2C Low Risk :i. Surveillance ii. Enoxaparin 40 SC mg OD OR Minidose UFH 5000 IU

SC BIDiii. Postpartum warfarin 4 - 6 ws INR of 2- 3, with initial

UFH or LMWH overlap until INR is 2.0

UFH: anti-Xa 0.1 - 0.3 U/mL or

Enoxaparin 40 mg SC BID.

Page 35: Venous Thromboembolism In Pregnancy

Secondary prophylaxis Multiple episodes of VTE

Or women receiving long-term anticoagulants Antepartum i. UFH SC BID adjusted mid-interval aPTT 1.5-2.5ii. LMWH weight-adjusted, enoxaparin 1 mg/kg

BID Delivery DC heparin 24 h before elective

induction Postpartum warfarin 4-6W INR 2-3 Antepartum & postpartum :Graduated elastic

compression All are Grade 2C

Page 36: Venous Thromboembolism In Pregnancy

Thrombophilia &VTEFVL heterozygous

FVLhomozygous

Pro-thrombin G20210A.9 heterozygous

C677T MTHFR Homozygous

Double heterozygotes

PS /PC deficiency

AT deficiency

VTE 1:5004.5*

9-16% 1:2004.4* 0.45*

4:100 1:2.8

OR or RR (95% CI)

3.4 – 22.5 (8.7)

0.6 – 5.4 (1.8)

5.0 – 34.5 (13.1)

3.4 – 22.5 (8.7)

5.0 – 34.5 (13.1)

fetalLoss

1.73 2.15 7.39

Preeclampsia

No association

No association

*McColl et al73 Retrospective case control

Page 37: Venous Thromboembolism In Pregnancy

Labor & Adjusted-dose Heparin

Heparin be discontinued 24 h prior to elective induction or CS

Spontaneous labor careful monitoring of aPTT Markedly prolonged near delivery, protamine

sulfate Bleeding complications very uncommon with

LMWH Very high risk of recurrent VTEi. Proximal DVT within 2 weeks DC 4- 6 h prior to

expected time of delivery &Temporary IVC filter ii. Postpartum anticoagulants for at least 6 weeks.

Page 38: Venous Thromboembolism In Pregnancy

Recurrent deep venous thrombosis

In order to estimate the rate of recurrent deep venous thrombosis

Retrospectively :1104 women with previous VTE

Recurrences during pregnancy 7.5% if first VTE was unprovoked, related to pregnancy or to oral contraceptive use

No recurrence occurred if the first VTE was related to other transient risk factors.

In puerperium, the rate of recurrence was 15.5% Mannuccio : Br J Haematol. 2006 Nov;135(3):386-91.

Page 39: Venous Thromboembolism In Pregnancy

Combined oral contraceptives

The risk of VTE in women taking combined oral contraceptives (COCs) is attributed to changes in coagulation and fibrinolysis.

Women with hereditary deficiencies of PS,PC , or AT are at high risk of VTE during use of COCs, particularly when other thrombophilic defects are present..

Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of FVL Martinelli2003 Semin Vasc Med. 2003 Feb;3(1):47-60.

Presence of inherited thrombophilia increases the risk for VTE due to OCCs up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years De Stefano V, Rossi E, Leone G..

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