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 PresentationTRANSCRIPT
Venous Thromboembolism In
PregnancyDr: Galila Zaher MRCPathConsultant hematologistAssistant ProfessorKAUH
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.
Pathogenesis of Venous Thromboembolism
Virchow’s Triad
Venous stasis Hypercoagulability
Vascular Damage
Platelet
Thrombin
VIIIa XIa
IXa TFVIIa
XaProthrombin
Fibroblast
Procoagulant factors: VWF ,FVIII & FV
Amplification
Activated platelets
XIaIXaXaProthrombin
Thrombin
Propagation
Factor IXa -FVIIIa
Factor Xa+FVa
Factor XIa Factor IIa(thrombin)
Fibrinogen Fibrin
TFPI
AntiThrombin
Protein C& Protein S
Tissue factor + Factor VIIa
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
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
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%
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%).
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%.
ULTRASOUND (Compression, Duplex, or Doppler)
Pro’s Quick, cheap, and non-invasive
Con’s highly operator dependent
negative in 10-30% distal DVT
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.
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.
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.
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
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.
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
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
Thrombo-Prophylaxis
Anticoagulant Heparin & LMWHWarfarinAspirin
Elastic compression
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
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
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
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)
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.
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
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
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
Secondary Thrombo-prophylaxis
Single episode Multiple (two or more) episodes
and/or receiving long-term anticoagulants
Thrombophilia & No prior VTE
VTE Thromboprophylaxis?
Yes
No
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)
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)
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.
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
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
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.
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.
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..