THROMBOPHILIA & THROMBOEMBOLISM DURING

PREGNANCY & PUERPERIUM-PREVENTION & MANAGEMENT

Dr. Jagannath Mishra Chair-Person-Dr. Sasmita Swain, Associate Prof. Dept. of O&G Co-chairperson-Dr. Utkal Naik, SR, Dept. of O&G

DEFINITIONS

• Homeostasis- Process that maintain blood in a fluid, clot-free state.

• Thrombosis- the formation of blood clot (thrombus) within vessels.

• Embolus- Dislodged thrombus within vessels.• Thrombophilia- Group of inherited and

acquired disorders that has increased risk of thrombosis.

The Three Factors……

Anticoagulant and Fibrinolytic Pathways

IX XI / platelets IXa VIIIa

Xa

X

TF/ VII

- (APC/S)

X

TFPI -

Va

II IIa - ( APC/S)

FDP

FXIII

Fibrin Fibrinogen

+tPAPlasmin

-

Antithrombin

PAI-1Antiplasmin

--

5

VTE in Pregnancy

Epidemilogy 1.Affects 1 in 100,000 women of child bearing

age.2.10 times more common in pregnancy.3.Age <35 = 1/1000 pregnancy4.Age >35 = 2.4/1000 pregnancy5.10%-20% of VTE are PE

Mortality

• PE remains third most common cause of maternal death after hypertension and hemorrhage.

• Most common direct cause maternal death in devloped countries.

• 62% of women with fatal VTE die in 1st trimester although highest risk is immediately after delivery.

Risk Factors…..

1. Pregnancy

Pregnancy-Associated Changes in Haemostatic and Fibrinolytic

Proteins 1. Increase in Clotting Factors: • 20 to 200% increase in levels of

fibrinogen,• factors II, VII, VIII, IX, X and• vWF • Progressive platelet activation

Pregnancy-Associated Changes in Haemostatic and Fibrinolytic

Proteins2. Decrease in Anticoagulant and Fibrinolytic

Activity:• Protein S levels (free and total) decrease by

60% to 70% • PAI-1 and PAI-2 levels increase two to three-fold in pregnancy

• Some women are at even higher risk during pregnancy because they have one or more additional risk factors

Additional risk factors for venous thromboembolism (VTE)

Pre-existing risk factors

• Previous recurrent VTE • Family history of VTE • Known thrombophilia

Pre-existing risk factors-contd..

• Medical co-morbidities(e.g. heart or lung disease, SLE, cancer, inflammatory conditions, nephritic syndrome, sickle cell disease, intravenous drug user, Surgical procedure,

• Age (> 35 years) • Obesity • Smoker • Gross varicose veins

Obstetric risk factors

• Parity ≥3 • Pre-eclampsia • Dehydration/ hyper emesis/ OHSS • Multiple pregnancy • Caesarean section in labor • Elective caesarean section • Prolonged labor (> 24 hours) • PPH (>1 liter or transfusion)

Acute presentation

DVT• Usually U/L, most commonly left leg.• a red and hot swollen leg.• swelling in entire leg or just part of it.• pain and/or tenderness• or it may just feel heavy.

PE • sudden unexplained difficulty in breathing• tightness in the chest or chest pain• Haemoptysis• Faintness or collapse• Tachypnoea• Raised JVP• ABG= Hypoxemia

Diagnosis

• Compression duplex ultrasound• Chest x-ray• Ventilation-perfusion lung scan• Computed tomography pulmonary angiogram Note: D-dimer testing was considered but not

recommended.

MANAGEMENT

Offer either:• proximal leg vein ultrasound scan (within 4 hours) or• if proximal leg vein scan not available within 4

hours, D-dimer test and an interim 24-hour dose of a parenteral anti-coagulant followed by proximal leg vein ultrasound within 24 hours .

NICE

• Repeat proximal leg vein ultrasound scan 6–8 days later for all patients with positive D-dimer test and negative proximal leg vein ultrasound scan.

NICE

FOR ACUTE PRESENTATION

Choice is LMWH- as soon as possible except in 1.Renal failure 2.High risk of bleeding3.Hemodynamic instability• In these conditions UFH is safer than LMWH NICE

For patients with hemodynamic unstability

• Urgent CTPA within one hour but t/t shouldn’t be delayed

• Thrombolysis if possible (Golden period=1st hour)

• IV UFH 5000iu bolus followed by 1000-2000iu/hr infusion with daily monitoring of aPTT

• Gradually switch over to LMWH

Confirmed PE or proximal DVT

Continue LMWH for remainder of pregnancy + 6 weeks post-partum.

NICE

Mechanical interventions

Temporary inferior vena caval filters:•offer to patients with proximal DVT or PE who cannot have anticoagulation treatment.•consider for patients with recurrent proximal DVT or PE despite adequate anticoagulation treatment.

NICE

Mechanical interventions

Offer below-knee graduated compression stockings (ankle pressure greater than 23 mmHg) to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently, and:•advise patients to continue wearing the stockings for at least 2 years •ensure that the stockings are replaced 2 or 3 times per year•advise patients that the stockings need to be worn only on the affected leg or legs. NICE

THROMBOPROPHYLAXIS

• Women at high risk of VTE, including those with previous

confirmed VTE, should be offered pre-pregnancy counseling with a

prospective management plan.

Pre-pregnancy Counseling

• Is important because thrombotic risk exists from the beginning of the first trimester and often the

antenatal booking visit is at the end of the first trimester.

• All women should undergo an assessment of risk factors for VTE in early pregnancy or

before pregnancy.

C

• A retrospective comparison of the overall risk of recurrence of VTE during pregnancy and the non-pregnant period revealed risks of 10.9% during and 3.7% outside pregnancy.

Evidence level III

• However, the risk was higher if the woman had thrombophilia or if the previous VTE was in an unusual site.

Evidence level III

scenarios1. Women with previous VTE and no

thrombophilia2. Women with previous VTE who have thrombophilia3. Women without previous VTE or thrombophilia

• Women with a previous VTE and no thrombophilia

Women with a previous VTE and no thrombophilia

• Women with single previous VTE and no thrombophilia should be offered prophylaxis with low molecular weight heparin (LMWH) for six weeks after delivery.

• Whether they also require antenatal thromboprophylaxis is controversial.

• Although pregnancy may be associated with a more than three-fold increase in the risk of recurrent VTE, the evidence is conflicting.

• It may be reasonable not to use antenatal thromboprophylaxis with heparin in women with a single previous VTE associated with a temporary risk factor that has now resolved.

C

Women who have had :

1. more than one previous episode of VTE,

2. who have had one episode and in addition have a family history of VTE in a first degree relative or

3. whose episode of VTE was in an unusual site

should be considered for antenatal thromboprophylaxis with LMWH and for at

least six weeks postpartum.

Women with a previousVTE who have thrombophilia

Women with a previous VTE who have thrombophilia

• Women with thrombophilias have an increased risk of VTE in pregnancy,

but this risk varies depending upon the specific

thrombophilia.

High Risk

• Antiphospholipid syndrome• Anti-thrombin deficiency

Medium Risk

• Protein C deficiency• Protein S deficiency• Homozygosity for Factor V Leiden

mutation• Homozygosity for PT G20210A mutation• Combined heterozygosity (Factor V

Leiden and PT 20210A)

Low Risk

• Heterzoygosity for Factor V Leiden mutation

• Heterozygosity for PT G20210A mutation

WHO DO WE SCREEN ?

• Studies suggests that all patients with a history of prior venous thrombotic events and those with adverse pregnancy events such as fetal loss, abruptions, severe intra-uterine growth restriction and early onset severe preeclampsia, should be evaluated for thrombophilias.

• Screening tests for inherited and acquired

thrombophilias

LABORATORY TESTS FOR TROMBOPHILIAS SCREENING

A. Acquired Thrombophilias

• Lupus anticoagulants

•Anticardiolipin antibodies

•ß2-glycoprotein antibodies

•Anti-nuclear antibodies

LABORATORY TESTS FOR TROMBOPHILIAS SCREENING

B. Inherited Thrombophilias•Activated protein C resistance (APCR)

•Protein S

•Protein C

•Ant thrombin III (AT III)

•Factor V Leiden mutation

•Prothrombin gene mutation

• Women should be stratified according to the level of risk associated with their thrombophilia.

• Since the risk of VTE is lower in women with no history of VTE,

antenatal thromboprophylaxis is not always necessary, except in:

1. those with combined defects, 2. those homozygous for defects or3. those with anti-thrombin deficiency.

Women with a previous VTE who Women with a previous VTE who have inherited thrombophiliahave inherited thrombophilia

Women with acquired

thrombophilia (antiphospholipid

syndrome)

Antiphospholipid syndrome (APS) is defined as:

the presence of lupus anticoagulant or anticardiolipin antibodies of medium–high titer on two occasions 12 weeks apart, found in association with a history of:

• Thrombosis (arterial or venous) or • Adverse pregnancy outcome :1. Three or more unexplained miscarriages before ten

weeks of gestation,

2. Fetal death after ten weeks of gestation or

3. Preterm birth {less than 34 weeks} due to severe pre-eclampsia or intrauterine growth restriction.

• The risk of recurrent thromboses in women with APS is up to 70% and may be even higher in pregnancy.

• Therefore, pregnant women with APS and previous thromboses should receive antenatal and postnatal thromboprophylaxis with LMWH.

• Low-dose aspirin has been shown to improve pregnancy outcome in APS and is recommended for all women with APS.

Women without previous VTE or thrombophilia

• The combination of either of (Age over 35 years and BMI greater than 30/body weight greater than 90 kg )with any other risk factor for VTE (such as pre-eclampsia or immobility) or

• The presence of two other persisting risk factors

should lead the clinician to consider the use of LMWH for three to five days

postpartum.GPP

Women without previous VTE or thrombophilia

Timing and duration of

thromboprophylaxis

Ante partum

• As VTE during pregnancy has an equal distribution throughout gestation , if a decision is made to initiate thromboprophylaxis antenatally, this should begin as early in pregnancy as practical.

• Once antenatal treatment is initiated it should continue until-

1.Labour pain occurs

2.Elective induction of labour starts

BEFORE LSCS

• last heparin injection should be 24 hours before the planned caesarean delivery.

• If by emergency caesarean section within 24 hours of last injection

Need general anesthesia

Very High Risk• Women with recurrent VTE associated

with either1. On long term oral anti-coagulation 2. Anti-thrombin deficiency or 3. Antiphospholipid syndrome

Requires antenatal prophylaxis with LMWH (high dose 40 mg 12-hourly)

High Risk• Women with

1. Single previous VTE witha)Thrombophilia or family historyb) Unprovoked/estrogen-related2. Previous recurrent VTE (> 1)

require thromboprophylaxis with LMWH antenatally

Intermediate RiskWomen with1.Single previous VTE with no family history

or thrombophilia2.Thrombophilia without VTE3.Medical co-morbidities LMWH prophylaxis can be considered antenatlly

• Age > 35 years, Obesity (BMI > 30kg/m2)• Parity ≥ 3, Pre-eclampsia• Smoker• Gross varicose veins, Immobility• Dehydration/hyper emesis/OHSS• Multiple pregnancy or ART

-More than 3 risk factors- consider LMWH antenatally-Less than 3 risk factors- do not require LMWH

antenatally ( mobilization & prevention of dehydration)

Postpartum

• Postpartum thromboprophylaxis should be given as soon as possible after delivery, provided that there is no postpartum hemorrhage.

• Those with postpartum hemorrhage should be fitted with thromboembolic deterrent stockings.

• If the woman has been given regional analgesia, LMWH should be withheld until four hours after insertion or removal of the epidural catheter (or six hours if either insertion or removal were traumatic).

Postpartum

• The combined oral contraceptive pill should not be prescribed during the first three months

postpartum for women with other risk factors for VTE.

High Risk

• Any previous VTE• Anyone requiring antenatal LMWH

At least 6 weeks postnatal prophylactic LMWH

Intermediate Risk• Caesarean section in labor• Asymptomatic thrombophilia• BMI > 40 kg/m2• Medical co-morbidities

At least 7 days postnatal prophylactic LMWH

• Age > 35 years, Obesity (BMI > 30kg/m2)• Parity ≥ 3, Pre-eclampsia• Smoker• Elective caesarian section• Gross varicose veins, Immobility• Prolonged labor (> 24 hours)• PPH > 1 liter or blood transfusion

-2 or more risk factors-At least 7 days postnatal prophylactic LMWH

-Less than 2 risk factors-Mobilization and avoidance of dehydration

Agents for thromboprophylaxis

• Regardless of their risk of VTE, immobilization of women during

pregnancy, labour and the puerperium should be minimized

and dehydration should be avoided.

Good Practice Point (GPP)

Low molecular weight heparin

• Low molecular weight heparins are the agents of choice for antenatal thromboprophylaxis.

• They are as effective as and safer than unfractionated heparin in pregnancy.

B

Advantages of LMWH over UFH

1. No need for laboratory monitoring- -Experience indicates that, provided that

the woman has normal renal function, monitoring of anti-Xa levels is not required when LMWH is used for thromboprophylaxis.

Continued……..

2.Higher bioavailability - 90% vs 30%3.Longer plasma half-life

– 4 to 6 hours vs 0.5 to 1 hour– renal (slower) vs hepatic clearance

4. Less inhibition of platelet function– potentially less bleeding risk, but not shown in

clinical use

Continued……

5.Lower incidence of thrombocytopenia and thrombosis (HIT syndrome)– less interaction with platelet factor 4– fewer heparin-dependent IgG antibodies

current guidelines still recommend checking the platelet count one week after starting LMWH

6. Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and fractures but this risk is low with LMWH.

Continued……

• Experience of enoxaparin in the puerperium reports no adverse effects on the baby resulting from breastfeeding.

Low molecular weight heparin

Thromboprophylactic doses for antenatal and postnatal LMWH

Weight (kg)EnoxaparinDalteparinTinzaparin <5020 mg daily2500U daily3500U daily

50-9040 mg daily5000U daily4500U daily

90-13060 mg daily7500U daily7000U daily

>13080 mg daily10,000U daily9000U daily

High prophylactic

40 mg 12-hourly

5000 units 12-hourly

4500 units 12-hourly

Treatment dose

1 mg/kg/12 hourly antenatal;1.5 mg/kg/daily postnatal

100 units/kg/12 hourly

175 u/kg/daily (antenatal and postnatal)

Low-dose aspirin

• Low-dose aspirin is safe in pregnancy, although its use for thromboprophylaxis in this setting has never been assessed by a controlled trial.

• The use of low-dose aspirin (75 mg daily) may be appropriate in situations where the risk of VTE is increased but is not deemed high

enough to warrant the use of antenatal LMWH.

Low-dose aspirin

Warfarin• Warfarin should be avoided if possible

during pregnancy, especially between 6 and 12 weeks of gestation, because it is associated with an up to :

1. 5% risk of teratogenesis and 2. increases the risk of miscarriage, 3. fetal and maternal hemorrhage, 4. neurological problems in the baby and

stillbirth.

• Warfarin is safe after delivery and for breastfeeding, although it requires :

1. Close monitoring, 2. Frequent visits to an anticoagulant

clinic

Warfarin

Warfarin carries an increased risk of:1. Postpartum hemorrhage and 2. Perineal hematoma compared with

LMWH.

Warfarin

Dextran

Dextran should not be used primarily because of the risk of anaphylaxis, which has killed fetuses by causing :

• Massive histamine release and • Uterine hyper tonus.

Graduated elastic compression stockings

• There are no trials to support such practice but the British Society for Hematology guidelines give a grade C recommendation (evidence level IV) that:

All women with previous VTE or a thrombophilia should be encouraged to wear class-II graduated elastic compression below knee stockings throughout their

pregnancy and for 6–12 weeks after delivery.