Thrombophilias

Definition

Special tendency to thrombosis as a result of inherited or acquired haemostatic disorders.

embarazada_felizThe risk of a pregnant woman suffering a thrombotic event or gestational complications increases if she has a thrombophilia.

Classification of thrombophilias
  • Inherited (or hereditary) thrombophilia includes:
Genetic thrombophilia Due to permanent changes in coagulation (or clotting) related to genetic defects in the genes that codify the plasmatic protein components of coagulation factors.
Plasma thrombophilia due to deficiency of physiological anticoagulants that regulate the formation of thrombin. Plasma defects are considered hereditary after ruling out an acquired origin due to pregnancy, associated diseases, recent or acute thrombosis, anticoagulant treatment or other drugs.
  • Acquired thrombophilia
These are thrombophilias associated with the presence of antiphospholipid antibodies (APA). APAs may increase in diseases such as lupus, Behcet syndrome, infections and drugs and sometimes with no justifying cause.
It is called Antiphospholipid Syndrome (APS) when 1 clinical criterion, such as arterial or venous thrombosis, is satisfied, or there are gestational vascular complications (GVC), plus 1 analytical criterion, determined with the positivity of an APA test and confirmed within 12 weeks.
Thrombophilia classificationThrombophilia defects
Inherited due to plasma deficiency AT deficiency
APCR
Protein C
Protein S
Inherited due to genetic mutationsMutation G1691A of the Factor V Leiden (FVL)
Mutation G20210A of the Prothrombin gene (FII)
Acquired by Antiphospholipid antibodiesLupus anticoagulant (LA)
Anticardiolipin antibodies or ACA
Anti-β2 GPI antibodies
Antiphospholipid Syndrome 2006 Sydney Classification Criteria
Clinical Criteria
Vascular thrombosisVenous
Arterial
Small vessel
Obstetric pathology1 or more foetal deaths at or beyond the 10th week.
3 or more consecutive miscarriages before the 10th week.
Premature birth (<34 weeks) due to eclampsia, pre-eclampsia or placental insufficiency.
Laboratory Criteria
2 determinations 12 weeks apart
Lupus anticoagulant
Anticardiolipin antibodies IgG or IgM
Anti-B2 GP1 antibodies IgG or IgM
APS Diagnosis = 1 Clínical Criterion + 1 Laboratory Criterion
Indications for study of Thrombophilia
Venous thromboembolic disease (VTE), before the age of 50, idiopathic or recurrent.
Venous thromboembolic disease (VTE), with atypical location (hepatic, mesenteric, portal, cerebral).
Asymptomatic women with a family history of VTE (first-degree relatives <50 years) if the event was idiopathic and / or related to pregnancy or hormonal contraceptive treatment or associated with a lower risk factor.

  • With known thrombophilia, it is recommended to study only the known congenital thrombophilia factor.

In gestational vascular complications (GVC) request the study of antiphospholipid antibodies (APA). With a personal or family history of VTE, assess hereditary thrombophilia (there is no scientific evidence):

  • Early recurrent abortions (2 or more before 10 weeks), one or more in the second trimester (> 10 weeks) of a fetus without malformations, having ruled out maternal anatomical, maternal hormonal, and maternal or paternal genetic causes.

  • Placental abruption, late fetal loss, intrauterine growth restriction, and severe eclampsia or preeclampsia.

  • There is no evidence to date regarding the usefulness of the thrombophilia study in patients with implantation failure.

1.-Favaloro EJ. Laboratory Investigation of Thrombophilia: the good, the bad, and the ugly. Semin Thromb Hemost 2009;35: 695-710.
2.-Baglin T. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149:209-220.
3.-Bates SM. ACCP Evidence -Based Clinical Practice Guidelines 2012;141: e691S-e736S.
4.-Royal College of Obstetricians and Gynaecologists Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium.Green-top Guideline No. 37a.April 2015.
5.- Altuna D,Ceresetto J,Fassi D,Ferro H,Fondevila C,Giumelli C et al.Trombofilias.2017.Guías de diagnóstico y tratamiento .Sociedad Argentina de Hematología(SAH). p 229-237.

a.- Early recurrent abortions (2 or more before 10 weeks), one or more in the second trimester (> 10 weeks) of a fetus without malformations, having ruled out maternal anatomical, maternal hormonal, and maternal or paternal genetic causes.
b.- Placental abruption, late fetal loss, intrauterine growth restriction, and severe eclampsia or preeclampsia.

Risk of thromboembolism according to Thrombophilia


High Risk
Antithrombin deficiency
Homozygote mutation Factor V Leiden or of prothrombin 20210A
Double homozygote Factor V Leiden and prothrombin 20210A
Combined defects
Protein C or Protein S deficiency
Antiphospholipid syndrome (APS)
Moderate Risk
Protein C / Protein S deficiency
Low Risk
Heterozygote mutation Factor V Leiden
Heterozygote mutation prothrombin G20210A
Lecumberri R, Casellas M, Fontcuberta J, et al. La Trombosis en embarazo y parto .Madrid. Acción Médica. 2008
Lecumberri R. Enfermedad tromboembólica venosa y embarazo. Trombosis update. vol 4, 8 Enero 2011
Altuna D,Ceresetto J,Fassi D,Ferro H,Fondevila C,Giumelli C et al.Trombofilias.2017 .Guías de diagnóstico y tratamiento.SAH. p 229-237
When should the thrombophilia study be conduced?
Study of inherited genetic thrombophilia: at any time, it does not interfere with the pregnancy situation.
Study of inherited plasma thrombophilia: this can be carried out at any time, outside the acute or recent episode of thrombosis. In the case of pregnancy or puerperium, bear in mind that protein S can be reduced physiologically during pregnancy (up to levels of 30-24% in the second and third trimester, respectively) . In the event of a deficiency of any protein, the determination must be repeated for confirmation. The AT and PC levels do not decrease but the APCR can be modified during the pregnancy.
Study of acquired thrombophilia: the antiphospholipid antibodies (LA, ACA, antiβ2GPI) can be requested during pregnancy. Positivity must be verified by repeating the determination within a 12-week interval. If negative, and the clinical suspicion persists due to bad obstetric result, the determination should be repeated.
ThrombophiliaTesting Method¿Reliable during pregnancy?¿Reliable during acute Thrombosis?¿Reliable with anticoagulation?
Factor V Leiden MutationActivated Protein C resistance assay (secont generation)
YesYesNo
If abnormal: DNA analysisYesYesYes
Prothrombin G20210A Mutation DNA AnalysisYesYesYes
Protein C deficiencyProtein C activity (<60%)YesNoNo
Proteina S deficiencyFunctional assay (<55%)No*NoNo
Antithrombin deficiencyAntithrombin activity (<60%)YesNoNo
*if Screening in pregnancy is necessary cutoff values for free protein S antigen levels in the second and third trimesters have been identified at less than 30% and less than 24%, respectively.
ACOG Inherited Thrombophilias in Pregnancy .Practice Bulletin 138 September 2013.
How to test for Thrombophilia
ThrombophiliaTesting methodReliable
during pregnancy?
Reliable during acute thrombosis??Reliable with anti-coagulation?
Factor V Leiden mutationGenetic and/or
Coagulation (APCR)
YesYesYes
Prothrombin mutationGenetic YesYesYes
Protein C activity (<60%)Coagulation YesNoNo
Protein S functional (<55%)*CoagulationNo*NoNo
Antithrombin activity (<60%)CoagulationYesNoNo
APCR (ratio<2)CoagulationYesYesNo
APA**(LA,ACA,B2GPI)Coagulation immunological LAYesYesNo coagulation tests
*Protein S can be reduced physiologically during pregnancy (up to levels of 30-24% in the second and third trimester, respectively.
**antiphospholipid antibodies (LA, ACA, antiβ2GPI) must be verified for positivity within a 12-week interval. If negative, with clinical suspicion due to obstetric complication, repeat the determination.
Types of Thrombophilia
GENETIC inherited thrombophilia
Factor V Leiden mutation.
Factor II G20210A mutation.
PLASMA INHERITED thrombophilia
Antithrombin:
- Inherited Physiological anticoagulant deficiency.
- AD Legacy.
Antithrombin deficiency due to other causes:
- Drugs: heparin, chemotherapy, contraception.
- Acute episode of thrombosis, CID.
- Hepatopathy, Nephrotic syndrome, Sepsis.
Protein C:
- Inherited Physiological anticoagulant deficiency
- AD Legacy.
Protein C deficiency due to other causes:
- Drugs: SIntrom® Warfarin®
- Hepatopathy.
- Acute episode of thrombosis, CID, Sepsis.
Protein S:
- Physiological anticoagulant deficiency.
- AD Legacy.
Protein S deficiency due to other causes:
- Physiological during gestation (30-24% in 2nd-3rd trimester).
- Hepatopathy.
- Nephrotic syndrome, HIV, chemotherapy and
contraceptives.
APCR:
RResistance to PC inhibition due to mutation Factor V Leiden (FVL), FV not Leiden (HR2) and other unidentified ones.
P C resistance activated due to other causes:
- Increase in Factor VIII.
- Lupus anticoagulant .
- Oral anticoagulants, Pregnancy, Contraceptives.
ACQUIRED thrombophilia
Antiphospholipid antibodies or APA:
- Lupus anticoagulant (DRVVT).
- Anti-cardiolipin and anti-B2GP1 antibodies.
Cause ACQUIRED by:
- Lupus, Behcet syndrome, infections and drugs and sometimes with no justifying cause.
- Antiphospholipid Syndrome or APS: When APA is associated with thrombosis or GVC.
Favaloro EJ, McDonald D, Lippi G.Semin Thromb Hemos vol 35, nº7, 2009. p 695-710
Prevalence and Thrombotic risk in different thrombophilias

Prevalence in general population (%)

VTE risk in pregnancy with no history of thrombosis (%)

VTE risk in pregnancy with history of thrombosis (%)

Percentage of all VTE (%)

Heterozygote Factor V Leiden

1 - 15 %

< 0,3

10

40

Homozygote Factor V Leiden

< 1

1,5

17

2

Heterozygote mutation A20210G of the Prothrombin gene

2 - 5

< 0,5

> 10

17

Homozygote mutation A20210G of the Prothrombin gene

< 1

2,8

> 17

0,5

Factor V Leiden + double heterozygote mutation A20210G

0,01

4,7

> 20

1 - 3

Antithrombin activity III (<60 %)

0,02

3 - 7

40

1

Protein C activity (<50 %)

0,2 - 0,4

0,1 - 0,8

4 - 17

14

Protein S free antigen (<55 %)*

0,03 - 0,13

0,1

0 - 22

3

VTE: Venous thromboembolic disease.
*Modification: Loockwood C, Wendel G; Committee on Practice Bulletins Obstetrics. Practice bulletins no. 124: inherited thrombophilias in pregnancy. Obstet Gynecol; 2011 Sept: 118(3): 730-40.