Preventing venous thromboembolism during pregnancy and ... · ash-sap 2010, Rosendaal, Lancet 1999, 353: 1167-1173. Threshold model of thrombotic risk •10. th. ... •Antepartum

Preventing venous thromboembolism

during pregnancy and postpartum

Prof. Anne Angelillo-Scherrer

Department and Central Laboratory of Hematology

Inselspital, Bern University Hospital

Bern, Switzerland

SAOA 2019 - SPRING MEETINGNEUCHATEL

Saturday – March 16th, 2019

http://www.unibe.ch/

Overview

• Introduction

•Risk assessment and patient’s perspective

•Choice of the anticoagulant

•Bleeding risk under anticoagulation duringpregnancy

•Thrombophilia

•Antiphospholipid syndrome

•Take home message

Venous thromboembolism (VTE) and pregnancy

• VTE may manifest as:− Pulmonary embolism (PE)

− Deep vein thrombosis (DVT)

• VTE complicates 0.5-2.2 per 1000 deliveries

• During pregnancy, the risk of VTE increases 5- to 10-fold (comparedto non-pregnant women)

• The risk is higher in postpartum− greatest during the first 3-6 weeks

− Daily-risk is increased 15- to 35-fold (compared to non-pregnant women)

• VTE, an important cause of maternal morbidity and mortality

Adapted from Merli G. Clin Geriatr Med 2006; 22: 75-92

Virchow’s triad

ash-sap 2010, Rosendaal, Lancet 1999, 353: 1167-1173

Threshold model of thrombotic risk

• 10th week of pregnancy

• Past history of DVT 10 days after hip and pelvis surgery(post-traumatic) 3 years ago

• No risk factor

• No thrombophilia testing

• No current anticoagulation

What is your proposition for the current pregnancy?

Case # 1: 35 year-old woman

Risk assessment for VTE (1)

Royal College of Obstetricians and Gynaecologists 2015, Green-top Guideline N° 37a







Other guidelines

•Pregnant women with prior VTE who are not receiving long-term anticoagulation should receive6 weeks of postpartum prophylaxis

•Antepartum prophylaxis should be considered in pregnancy women with prior unprovoked VTE orpregnancy- or oestrogen-related VTE not receivinglong-term anticoagulation

Obstet Gynecol 2011, 118:718-729; J Obstet Gynaecol 2014, 36:527-53; Chest2012, 141:e419S-e3494S


• Past history of DVT 1 month after starting with oral contraception11 years ago

• No current anticoagulation

• No family history of VTE

What is your proposition for the current pregnancy?


Perzborn, E. et al., Nature Reviews Drug Discovery, 10: 61-75, 2011

Development of anticoagulants over the pastcentury

Perzborn, E. et al., Nature Reviews Drug Discovery, 10: 61-75, 2011

Target of anticoagulants

Anticoagulant Passes placenta

Passesontobreastmilk

Evidence based summary

Heparins - + Safe during pregnancy & breastfeeding

Aspirin up to 100 mg/day

+ + Safe during pregnancy & breastfeeding

Vitamin K antagonists

+ + Restricted to special situations duringpregnancy, safe during breastfeeding

Direct oral anticoagulants

+ + Not recommended (limited evidence)

Danaparoid - - Safe during pregnancy & breastfeeding

Fondaparinux + ? Restricted to special situations: based on limited available, it does not seem to beharmful for the fetus

Argatroban + ? Restricted to special situations

Hirudins + - Not recommended (limited evidence)

+, passes; -, does not pass; ?, unknown

Anticoagulant passage of the placenta and into breast milk


• Past history of bilateral, central PE 2 years ago

• Risk factor: oral contraception

• Current anticoagulation: Lixiana® (Edoxaban) 60 mg/day

What is your recommendation for the anticoagulation duringpregnancy?

What would you have been proposed during the pre-conception counseling?


• Pre-conception counseling on the risk for both woman and fetus is key

• If using DOACs switch to VKA pre-pregnancy

• Perform pregnancy test immediately after missed menstrual period, re-assess frequently if negative

• If pregnancy test positive: switch to LMWH immediately and prescribe oral vitamin K

Preconception management of women alreadyusing anticoagulants when planning pregnancy

• Heparins

• Aspirin up to 100 mg/day

• Danaparoid

• Fondaparinux

Which anticoagulants/antithrombotics are safe in pregnancy ?

• Vitamin K antagonists (VKA)

• Direct oral anticoagulants (DOACs)

Which anticoagulants are not safe in pregnancy?

•7th week of pregnancy

•Past history of bilateral, central PE 2 years ago

•Risk factor: oral contraception

•Current anticoagulation: Lixiana® (Edoxaban) 60 mg/day

•Past history of heparin-induced thrombocytopenia

What is your recommendation for theanticoagulation during pregnancy?


•At suspicion, switch to non-heparin anticoagulantdrug: first choice = danaparoid

•Consider or rule out the diagnosis, and manage appropriately

•Possible other non-heparin anticoagulant drugs, depending on the clinical situation−Fondaparinux−Argatroban

Heparin-induced thrombocytopenia & pregnancy

• Inform all women about measures to be taken regarding theiranticoagulant therapy and discuss delivery options (spontaneaousdelivery, induction, elective caesarean section, CS)

• Discontinue LMWH when contractions start or membranes rupture

• Last dose of low prophylactic dose LMWH at least 12h prior toplanned delivery/CS

• Last dose of higher doses LMWH at least 24h prior to planneddelivery

• Blood analysis: CBC, creatinin, PT, aPTT, TT, fibrinogen, anti-Xa activity

• Unfractionated heparin IV, therapeutic dosage in cases with high riskfor VTE recurrence, to be interrupted 4h before delivery; startprogressive anticoagulation 6-8h after delivery with preferentiallyLMWH

Peripartal management

• Low

• Increases with the intensity of the anticoagulation

• Highest at the time of delivery

• Be carefull in case of thrombocytopenia

Bleeding risk under anticoagulation during pregnancy

Classification of thrombophilias

INHERITED THROMBOPHILIASDeficiency of natural inhibitors of coagulation(loss of function mutations)

-Antithrombin, Protein C, Protein S

Abnormal functions/elevated levels of coagulation factors(gain of function mutations)

-Factor V Leiden (G1691A mutation)-Prothrombin gene mutation (G20210A mutation)-Elevated factors VIII, IX, XI, or fibrinogen

ACQUIRED THROMBOPHILIASAntiphospholipid syndromeMyeloproliferative neoplasmsParoxysmal nocturnal hemoglobinuriaNephrotic syndromeOccult malignancy

The American College of Obstetricians and Gynecologists, Practice Bulletin Number197, 2018, 132:e18-e34

Context

Thrombophilia

Provoked VTE Unprovoked

VTE

Asymptomatic

first degree

relatives

Asymptomatic first degree

females pregnant or

considering OC, HRT or

pregnancy

OC/HRT Pregnancy

Antithrombin

deficiency

Protein C deficiency

Protein S deficiency

ICS 2013 ICS 2013 ICS 2013 ICS 2013 ICS 2013

FCG 2009 FCG 2009 FCG 2009 FCG 2009 FCG 2009

BCSH 2010 BCSH 2010 BCSH 2010 BCSH 2010 BCSH 2010

EGAPP 2011 EGAPP 2011 EGAPP 2011 EGAPP 2011 EGAPP 2011

NICE 2012 NICE 2012 NICE 2012 NICE 2012 NICE 2012

ACCP 2012 ACCP 2012 ACCP 2012 ACCP 2012 ACCP 2012

Factor V Leiden

Prothrombin G20210A

mutation







Antiphospholipid

syndrome







Statements from several guidelines regarding whether to screen for specific thrombophilia

Indications for thrombophilia testing (1)

NOT RECOMMENDED

• Adult patients with venous thromboembolism occurring in the setting of major transient risk factors (surgery, trauma, or prolonged immobility)1

• Testing at the time of acute VTE

• Upper-extremity thrombosis

• Central-catheter-related thrombosis

• Retinal vein thrombosis

• Arterial thrombosis

• Asymptomatic relatives in most thrombosis-prone families

• Asymptomatic relatives starting hormonal/contraceptive therapy

• Women with early pregnancy loss (inherited thrombophilia)2

1ASH Choosing Wisely® Campaign (2013)2Canadian Choosing Wisely campaign (2015)


MAY BE CONSIDERED

• VTE and strong family history of unprovoked VTE

No recommendations on which patients to test

• Asymptomatic relatives in selected thrombosis-prone families

No recommendations on which patients to test

Test AT, PC, PS

• Cerebral vein thrombosis

By consensus


RECOMMENDED

• Patients who develop skin necrosis while on AVKTest PC and PS only, after AVK is discontinued

• Intra-abdominal vein thrombosisScreening for MPN (JAK2 mutation, calreticulin) recommended, other testing may beconsidered

• Patients with clinical clues of antiphospholipid syndromeTest for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2 glycoprotein I antibodies)

What to test ?

Risk factors Screening testsConfirmation

tests

CBC, PT and aPTT are performed together with the thrombophilia screning. PTT-LA, PTT lupus sensitive; dRVVT, diluted Russel viper venom time.

Antithrombin deficiency Antithrombin activity Antithrombin antigen Unfractionated heparin, LMWH, liver

insufficiency, DIC, nephrotic syndrome

Protein C deficiency Protein C activity Chromogenic and

antigenic protein C

VKA, vitamin K deficiency, liver insufficiency,

DIC

Protein S deficiency Free protein S Total and coagulant

protein S

VKA, vitamin K deficiency, liver insufficiency,

DIC

pregnancy, estrogen

Factor V Leiden Factor V Leiden (PCR)

Prothrombin mutation Prothrombin mutationG20210A (PCR)

Lupus anticoagulant 2 tests: for ex.: PTT-LA

and dRVVT. Lupus

anticoagulant is present

when one of the test is

positive.

Resistance to activated

protein C (APCR)

Anticoagulants: heparin inlfuences PTT-LA and

VKA prolong dRVVT ; before12 weeks

after an acute thromboembolic event

Anticardiolopin

antibodies

ELISA (isotypes IgG &

IgM)

Prothrombin mutation

(PCR)

Before12 weeks


Anti-2-glycoprotein 1

antibodies

ELISA (isotypes IgG &

IgM)

Before12 weeks


Hyperhomocysteinemia Fasten homocystein level

To avoid in the

following conditions

• Suggest postpartum prophylaxis only:− Heterozygous Factor V Leiden or prothrombin mutation and 1st degree VTE family

history

− Protein S, C or antithrombin deficiency and 1st degree VTE family history

− Homozygous Factor V Leiden or homozygous prothrombin mutation without VTE family history

• Recommend antepartum and postpartum prophylaxis:− Homozygous Factor V Leiden or homozygous prothrombin mutation and 1st degree

VTE family history

• Consider antepartum and postpartum prophylaxis:− Combined inherited thrombophilia regardless of VTE family history

Is there an indication for antepartum and/or postpartum thrombosis prophylaxis in women withinherited thrombophilia (without personal history of VTE)?

• Consider and discuss in women at high VTE risk, i.e. those withsimilar risk factors as considered for antepartum prophylaxis

• Recommend to use prophylaxis dose LMWH for 3 months in severeovarian hyperstimulation syndrome

Is there an indication for antepartum and/or postpartum thrombosis prophylaxis in womenundergoing assisted reproductive technology?

Garcia, D. & Erkan, D. , NEJM, 2018, 378:2010-21

Overview of the initial pathogenesis

Ruiz-Irastorza, G. et al., Lancet, 2010, 376:1498-1509

Pathogenesis of thrombosis in APS

Myakis. S. et al., J Thromb Haemost, 2006, 4:295-306Ruiz-Irastorza, G. et al., Lancet, 2010, 376:1498-1509

Revised classification criteria for APS:Clinical criteria

Revised classification criteria for APS:Laboratory criteria

• I > 1 criteria

• IIa LA alone

• IIb ACL alone

• IIc anti-2GP1alone

Classification

Minimum 12 weeks betweenclinical symptoms and laboratory tests

Do not perform laboratory test >5 years after clinicalmanifestations

Myakis. S. et al., J Thromb Haemost, 2006, 4:295-306Ruiz-Irastorza, G. et al., Lancet, 2010, 376:1498-1509

Associated with APS but not diagnostic criteria

• Heart valves pathology:

11,6% of patients with APS, independently from SLE

• Livedo:

increased prevalence if SLE, sexe F

• Thrombocytopenia (platelets < 100 G/l, confirmed 12 weekslater):

− prevalence 20-40% in ref. 1 (in ref. 2, prevalence 6% in triple positive patients and 100% in CAPS patients)

− for diagnosis and treatment cf. ITP

− ITP + APL: more thrombotic events, 5 years follow-up

− exclusion of other causes of thrombocytopenia

• Nephropathy

1Myakis, S. et al., J. Thromb Haemost, 2006, 4:295-306

2Pontara E. et al., JTH 2018, 16:529-532

Diagnostic criteria of catastrophic APS (CAPS)

CAPS criteria

1. Evidence of involvement of ≥ 3 organs, system, and/or tissues

2. Development of manifestation ≤ 1 week

3. Confirmation by histopathology of small vessel occlusion in ≥ 1 organ or tissue

4. Laboratory confirmation of the presence of APL

Definite CAPS

All 4 criteria

Probable CAPS

A. All 4 criteria, except for 2 organs, system, and/or tissue involvement

B. All 4 criteria, except 0 for the absence of laboratory confirmation ≥ 6 weeksapart due to the death of a patient never previously tested for APL prior to the CAPS event

C. 1,2 and 4

D. 1, 3 and 4 and the development of a 3rd event in more > 1 week but < 1 month, despite anticoagulation

N Engl J Med 358:275-89, 2008

1. Lupus anticoagulant (LA) present in plasma detected according to the SSC on Lupus Anticoagulant/Phospholipid Antibodies recommendations2

2. β2GPI-dependent anticardiolipin antibodies (ACL) of IgG/IgM isotype in plasma or serum, present at higher levels (>99th percentile of normal controls), measured by solid phaseassays (ELISA or automated systems), according to the SSC on Lupus Anticoagulant/Phospholipid Antibodies recommendations3

3. β2GPI-antibodies (Aβ2GPI) of IgG/IgM isotype in plasma or serum, present at higherlevels (> 99th percentile), measured by solid phase assays (ELISA or automated systems), according to the SSC on Lupus Anticoagulant/Phospholipid Antibodies recommendations2

4. LA, ACL and Aβ2GPI should be positive on ≥ 2 occasions at least 12 weeks apart2-4

5. Laboratory results need to be reviewed and interpreted in a collaboration between a clinical pathologist and a clinician who is skilled at interpreting the data

6. Comprehensive APL antibody testing (LA, ACL and Aβ2GPI IgG and IgM) should be carriedout as triple APL-positive patients are at high risk of thrombosis or APL-related pregnancymorbidity

7. Other APL antibody tests are not recommended yet

Recommended laboratory testing for the APS1

1Devreese KMJ et al. JTH, 2018, 16:809-8132Pengo V et al. JTH, 2009, 7:1737-17403Devreese KMJ JTH, 2014, 12:792-7954Myakis S et al., JTH, 2006, 4:295-306

Cohen D et al. BMJ 2010;340:bmj.c2541

Situations when you should test for APL antibodies

Thrombosis• Arterial thrombosis before the age of 50• Unprovoked VTE before the age of 50• Recurrent thrombosis• Thrombosis at an usual site• Patients with both arterial and venous thrombotic events• Any patient admitted with thrombotic microangiopathy of unknown

etiologyObstetric manifestations• One or more unexplained fetal loss after 10 week’s gestation• Unexplained severe intrauterine growth restriction• Early or severe preeclampsia• Three or more spontaneous miscarriages before 10 wees’ gestationPatients with SLE• At baseline• Repeat testing before pregnancy, surgery, transplantation, the use of

oestrogen containing treatments, or in the presence of a new neurological, vascular or obstetric event

Proposed primary thrombosis prophylaxis algorithm for patients withclinically significant APL profiles

Barbhaiya, M. et al., Curr Rheumatol Rep, 2011, 13:59-69

Clinical setting Recommendation Comments

1st VTE in APS Anticoagulation (AC) with VKA (INR 2-3) Insufficient data to support routineDOAC use

Arterial thrombosis in APS ASA + standard intensity AC with VKA (INR 2-3) or high intensity VKA AC (INR 3-4) in high risk patients

One study showed no benefit of ASA + VKA over ASA in APS with stroke;results are not generalizable sinceAPLA tested onyl at baseline and lower target INR

Recurrent thrombosis in APS Confirm that therapeutic INR is maintainedMay consider LMWH or high intensity AC with VKAConsider adjunctive hydroxychloroquine, statins

No clinical trials. Based on clinicalobservation and expert opinion.

Treatment recommendations for APS and APL antibodies (2)

Clinical setting Recommendation Comments

1st VTE in APS Anticoagulation (AC) with VKA (INR 2-3) Insufficient data to support routineDOAC use

Obstetric APS without prior thrombosis ASA + LMWHProphylactic dose LMWH continued until6 weeks post-partum

Obstetric APS with prior thrombosis ASA + therapeutic LMWH. After pregnancy may be transitioned back toVKA to continue AC indefinitively

Start LMWH (and stop VKA) at diagnosis of pregnancy

Catastrophic APS UFH + high dose steroids Observational data supports the use ofeculizumab, rituximab, plasmapheresisand defibrotide

Treatment recommendations for APS and APL antibodies (2)

• ITP diagnosed 3 years ago (platelet count 80 G/L)

• Spontaneous abortion 10th week of gestation 4 years ago

• Death in utero (16th week of pregnancy) 2 years ago

• Placenta: increase of fibrin (subchorial, peri-villeous)

• Currently: pregnancy 10th week of gestation

• Triple-positivity for APL antibodies, current platelet count 30 G/L

What is your diagnosis? What do you suggest?

Case 4: 31-year old woman

Take home message (1)

• Assess the VTE risk

• Importance of preconception management of women already usinganticoagulants when planning pregnancy

• Importance of providing in advance a detailed plan for the management of the anticoagulation around delivery

• Identify and manage carefully patients with antiphospholipid syndrome (importance of a multidisciplinary approach)

• Importance of well informating the patient and considering patient choices


• Thrombophilia testing does not predict anticoagulation failure and does not alter the initial treatment for VTE.

• No studies have shown that management strategies based on thrombophiliatesting affect patients risk of recurrence.

• The strongest predictor for recurrence is whether the initial VTE event was unprovoked.

Cohn et al., Cochrane Database of Systematic Reviews 2012; American College of Chest

Physicians Evidence-Based Clinical Practice Guidelines, Chest 2012; Baglin, T. et al., Br J

Haematol 2010


• Routine screening for inherited thrombophilia is not recommended in patients with unprovoked VTE

→ no major impact on the duration of anticoagulation.

• In selected patients, testing for thrombophilia may assist in their counseling about prognosis ; the implications of test results should be discussed withpatients before testing is done.

Cohn et al., Cochrane Database of Systematic Reviews 2012; American College of Chest

Physicians Evidence-Based Clinical Practice Guidelines, Chest 2012; Baglin, T. et al., Br J

Haematol 2010

Thank you for your attention

Documents

Preventing venous thromboembolism during pregnancy and ... · ash-sap 2010, Rosendaal, Lancet 1999, 353: 1167-1173. Threshold model of thrombotic risk •10. th. ... •Antepartum