thrombophilia in pregnancy rukset attar, md, phd obstetrics and gynecology department

THROMBOPHILIA IN PREGNANCY

Rukset Attar, MD, PhDRukset Attar, MD, PhDObstetrics and Gynecology Obstetrics and Gynecology

DeparDeparttmentment

Hypercoagulability in PregnancyHypercoagulability in Pregnancy

During pregnancy, there is a marked increase in the procoagulant activity by elevation of fibrinogen, factors II, V, VII, VIII, IX, X, XII and the von Willebrand factor.

Fibrinogen levels increase up to two fold. It is unclear why factor XI decreases. The physiological anticoagulant system becomes less

efficient because of an increased resistance to activated protein C in the second and third trimester and a reduced protein S activity, due to estrogen induced decreases in total protein S.

higher concentrations of plasminogen activator inhibitors (PAI), and an increased tendency to platelet aggregation

Overall fibrinolytic activity is impaired during pregnancy

Risk factors for thrombotic complications

Pregnancy-related risk factors for VTE include increasing maternal age (35 years), Caesarean section (especially emergency sections), thrombophilia, a family or personal history of thrombosis and obesity The puerperium itself is a risk factor (the most

probable trigger for that is delivery itself, because vessel trauma can cause thrombosis, and systemic coagulation activation in the mother’s circulation can easily occur.

Immobilisation after delivery can substantially add to this risk.

Risk factors for thrombotic complications

An individual assessment of the thrombotic risk should be undertaken, ideally before or in early pregnancy.

There is an increased risk of thrombosis in pregnant patients with thrombophilia depending on the severity of thrombophilia

Thrombophilia in Pregnancy

Inherited thrombophilias Acquired thrombophilias Non-thrombotic pregnancy complications and

thrombophilias

Inherited thrombophilias

genetic conditions with an increased thrombotic risk depending on additional risk factors

frequent causes of inherited thrombophilia are heterozygosity for Factor V Leiden (FVL) and G20210A mutation of the prothrombin gene;

rarer are antithrombin, protein C and S deficiency Hyperhomocysteinemia due to genetic defects

(homozygosity for a thermolabile mutant of methylenetetrahydrofolate reductase MTHFR) is controversially discussed as a cause of hereditary thrombophilia.

Inherited thrombophilias

Rare thrombophilic mutations, such as gene polymorphisms of plasminogen activator inhibitor-1, factor XIII or apolipoprotein B do not generally transfer an independent risk for thrombosis

Acquired thrombophilias

Antiphospholipid antibodies, such as the lupus anticoagulant or anticardiolipin and b-2-glycoprotein I antibodies are directed against glycoproteins in concert with phospholipids and are associated with thromboembolism and/or obstetrical complications.

Antiphospholipid antibodies (aPL) are found in about 5% of the reproductive population and antiphospholipid syndrome (APS) in 15–17% of women with recurrent pregnancy loss

Non-thrombotic pregnancy complications and thrombophilias

Maternal thrombophilias are not associated with pregnancy loss prior to 8–10 weeks of gestation , explained by the embryogenetic development of the vascular system

Before 8 weeks of gestation in the embryo there is only yolk sac vasculature, and thereafter a contact between the maternal and fetal circulation develops.

Therefore, it seems unlikely, that maternal thrombophilia can impair embryonic development at that earliest gestational stage.

Non-thrombotic pregnancy complications and thrombophilias

Women with thrombophilia show an increased risk for pregnancy loss at the end of the first and in the second trimester

those with FVL or prothrombin gene variant show a higher risk of late pregnancy loss (24 weeks)

Recurrent pregnancy loss has been linked to inherited thrombophilia particularly with protein C and S deficiency,FVL and a prothrombin gene variant

A significant association with increased risk for placental abruption was only observed with heterozygous FVL and the prothrombin gene variant

IUGR Pre-eclampsia

Management of thrombotic disorders during pregnancy

Risk-assessment for VTE Major known risk factors for VTE in pregnancy and in the

postpartum period are C-section, obesity, Prolonged bed rest, immobility, pre-eclampsia, Nephrotic syndrome, current infection and recent surgery previous VTE and thrombophilia.

In women at high risk LMWH prophylaxis should be continued for 4–6 weeks postpartum


Anticoagulan Therapy coumarin-derivates Unfractionated heparin (UFH) low-molecular-weight heparins (LMWH) and aspirin

The choice of the anticoagulant depends on the maternal or fetal complications.

UFH and LMWH do not cross the placenta and are safe for the fetus.

Maternal bleeding complications appear to be uncommon with LMWH.


Prevention of VTE LMWH is the prophylaxis of choice in pregnancies at

risk for VTE No laboratory monitoring is required. All women with previous VTE or a thrombophilia

should be additionally encouraged to wear elastic compression stockings throughout their pregnancy and for 6–12 weeks after delivery.


Women with prior VTE These women should have a postpartum prophylaxis

for 6 weeks Two options have been proposed:

no routine prophylaxis during pregnancy, but clinical surveillance and immediate investigation in cases with clinical suspicion of VTE- due to transient risk factor

prophylaxis starting during the first trimester (ideally before 10 gestational weeks) in women with an increased risk for VTE (thrombophilia or a history of a severe thrombotic event like PE or extended deep vein thrombosis, VTE during previous pregnancy, or during HRT)-ACCP Guidelines, Chest 2008ACCP Guidelines, Chest 2008


Treatment of VTE Acute DVT or PE during pregnancy should be

managed initially as in non-pregnant women UFH or LMWH have to be given until the diagnosis is

confirmed. The first line treatment remains intravenous UFH (70

IU/kg as bolus, followed by 350 IU/kg/24 h as continuous infusion) to rapidly achieve an aPTT at 1.5–2.5 times the control value.

Therapeutic doses of LMWH may be started once the patient is hemodynamically stable


Weight-adjusted subcutaneous LMWH is to be preferred and administered once daily at a therapeutic dose (200 IU/kg/d) throughout pregnancy.

Twice-daily administration (100 IU/kg q12 h) might be preferable for obese patients to achieve more stable factor Xa-levels in plasma,

Therapeutic anticoagulation should be continued throughout pregnancy and for at least 6 month after thrombosis

• Patients with recurrent trombosis attacks without Patients with recurrent trombosis attacks without trombophilia shoud be on life-long anticoagulan therapytrombophilia shoud be on life-long anticoagulan therapy

• ProProphylaxis with UFH/LMWH during pregnancy and + with UFH/LMWH during pregnancy and + postpartum period is advised for these patients (Grade postpartum period is advised for these patients (Grade 1A)1A)


APS Pregnant women with APS and previous thrombosis

should receive antepartum and postpartum thromboprophylaxis with LMWH in a therapeutic dose

UFH combined with ASS significantly reduced pregnancy loss compared to ASS alone

A typical combined treatment regimen includes A typical combined treatment regimen includes aspirin aspirin (75–85 mg/day), (75–85 mg/day), beginning with attempts at beginning with attempts at conception, and conception, and unfractionated heparin (5,000–unfractionated heparin (5,000–10,000 subcutaneous twice daily), 10,000 subcutaneous twice daily), beginning at first beginning at first indication of pregnancyindication of pregnancy..

• Operations not related to malignancies, lasting Operations not related to malignancies, lasting no longer than 30 minutes don’t require any no longer than 30 minutes don’t require any prophylaxis unless there is another risk factor. prophylaxis unless there is another risk factor. Early mobilisation and IPC is advised for them Early mobilisation and IPC is advised for them (Grade 1A)(Grade 1A)

• No prophylaxis for laparoskopic procedures No prophylaxis for laparoskopic procedures unless there is another risk factor (Grade 1B) unless there is another risk factor (Grade 1B)

• Routin trombosis prophylaxis must be done in Routin trombosis prophylaxis must be done in major gynecologic operations (Grade 1A)major gynecologic operations (Grade 1A)• With no other risc factor and not related to With no other risc factor and not related to

malignancy- malignancy- LMWH (Grade 1A) or LMWH (Grade 1A) or unfractunated heparin (Grade 1A) or IPC unfractunated heparin (Grade 1A) or IPC (Grade 1B) (Grade 1B)

• With another risk factor or operation for With another risk factor or operation for malignancy- malignancy- heparin + IPC (Grade 1C)heparin + IPC (Grade 1C)

SectioSectio• One risk factor besides pregnancy and sectio - One risk factor besides pregnancy and sectio -

heparin prophylaxis or (IPC, GCS) during heparin prophylaxis or (IPC, GCS) during hospital stay (Grade 2C)hospital stay (Grade 2C)

• multipl risk factors- heparin prophylaxis or (IPC, multipl risk factors- heparin prophylaxis or (IPC, GCS) (Grade 2C)GCS) (Grade 2C)

• patients with high risk - prophylaxis for 6 weekspatients with high risk - prophylaxis for 6 weeks

• Routin trombosis prophylaxis should be started Routin trombosis prophylaxis should be started before the major gynecologic operationsbefore the major gynecologic operations

• Should continue during hospital stay (Grade 1A)Should continue during hospital stay (Grade 1A)• İf it was a cancer surgery or if the patient had a İf it was a cancer surgery or if the patient had a

VTE before LMWH should be continued for 28 VTE before LMWH should be continued for 28 days after discharge from the hospital (Grade days after discharge from the hospital (Grade 2C)2C)

Acute trombosis in pregnancyAcute trombosis in pregnancy

• UFH heparin UFH heparin (IV bolus, then infusion, aPTT (IV bolus, then infusion, aPTT measurement every 4 hours) or measurement every 4 hours) or LMWH LMWH ( twice a ( twice a day, s.c.) at least forday, s.c.) at least for 5 days 5 days (Grade 1A) (Grade 1A)

• Then prophylactic dosageThen prophylactic dosage• Should continue thoroughout pregnancy (Grade Should continue thoroughout pregnancy (Grade

1B) and 6 weeks postpartum (Grade 2C)1B) and 6 weeks postpartum (Grade 2C)• Should be stopped 24 hours before delivery Should be stopped 24 hours before delivery

(Grade 1C) if delivered at therapeutic dosage (Grade 1C) if delivered at therapeutic dosage

Unfractunated HeparinUnfractunated Heparin

• 3000- 30.000 Da3000- 30.000 Da• Binds to antitrombin, FIX, FX, FXI ve FXII Binds to antitrombin, FIX, FX, FXI ve FXII • Also binds to beta tromboglobulin, PF4, histidin Also binds to beta tromboglobulin, PF4, histidin

rich protein, vitronektin, platelets, osteoblasts rich protein, vitronektin, platelets, osteoblasts and endothelial cellsand endothelial cells

• IV IV • followed with aPTT measurements x1.5-2.5followed with aPTT measurements x1.5-2.5• neutralised with Protaminneutralised with Protamin

LMWHLMWH

• 2000- 9.000 Da2000- 9.000 Da• Exreacted from UH via chemical and enzimatic Exreacted from UH via chemical and enzimatic

proceduresprocedures• İnhibits Fxaİnhibits Fxa• Low affinity for endothelial cells, osteoblasts and PLTLow affinity for endothelial cells, osteoblasts and PLT• Sc Sc • monitorised via antiXa- anti-Xa level should be 0.5-monitorised via antiXa- anti-Xa level should be 0.5-

1.2 U/ml1.2 U/ml• neutralisation with Protamin is lowneutralisation with Protamin is low

Whom should receive prohylaxis with Whom should receive prohylaxis with heparin during pregnancy?heparin during pregnancy?

• Those with valvular dieases or ritm disorders Those with valvular dieases or ritm disorders who are already on anticoagulation therapy who are already on anticoagulation therapy

• Recurrent VTE attacks- who are already on Recurrent VTE attacks- who are already on anticoagulation therapy anticoagulation therapy

• Patients with one VTE + trombophiliaPatients with one VTE + trombophilia• Patients with VTE during previous pregnancy or Patients with VTE during previous pregnancy or

HRTHRT

Trombosis risksTrombosis risks

FVFV LLeiden heterozigoteiden heterozigot x 4-7x 4-7FV Leiden homozigotFV Leiden homozigot x 80x 80P-20210 AP-20210 A x 2-5x 2-5HiperhomosisteinemiaHiperhomosisteinemia x 2-6x 2-6OC OC x 4x 4FVL+ P-20210 AFVL+ P-20210 A x 20x 20FVL+ hiperhomosisteinemiaFVL+ hiperhomosisteinemia x 21.6x 21.6FVL+ OCFVL+ OC x 35x 35FVL+ smoking FVL+ smoking x 30x 30

• FV Leiden mutationFV Leiden mutation• Protrombin G20210AProtrombin G20210A• Protein C activityProtein C activity• Protein S activityProtein S activity• AT activityAT activity• Fasting homosistein levelFasting homosistein level• Lupus anticoagulantLupus anticoagulant• ACA IgG ve IgMACA IgG ve IgM• Anti-B2 GPI IgG ve IgMAnti-B2 GPI IgG ve IgM• ANA, anti-DNAANA, anti-DNA

thrombophilia in pregnancy rukset attar, md, phd obstetrics and gynecology department

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