Bob Silver, MD University of Utah Health Sciences Thrombophilias in Obstetrics Modified from a presentation to the Society of Maternal Fetal Medicine by by

A heterogeneous group of conditions that predispose individuals to (venous) thromboembolism Thrombophilias

Thromboembolism Thromboembolism #1 killer in pregnancy #1 killer in pregnancy Common obstetric problems Common obstetric problems Stillbirth Stillbirth Severe IUGR Severe IUGR Severe preeclampsia Severe preeclampsia Abruption Abruption Why we care

Initiation of Hemostasis

Limitation of Hemostasis

Procoagulant Anticoagulant

Procoagulant Anticoagulant

Factor IX Factor IX Factor VIII Factor VIII Factor X Factor X Factor V Factor V Factor II Factor II Factor XIII Factor XIII Factor VII Factor VII Protein C Protein C Protein S Protein S Antithrombin III Antithrombin III Fibrinolysis Fibrinolysis PAI-1 PAI-1 Components of Hemostasis

Increase % Increase % Factor II Factor II Factor VII Factor VII Factor VIII Factor VIII Factor X Factor X Factor XII Factor XII Decrease in Protein S Decrease in Protein S Increase in PAI-1 300% Increase in PAI-1 300% Resistance to APC Resistance to APC Impaired fibrinolysis Impaired fibrinolysis Pregnancy enhances clotting

Protein C pathway Protein C pathway Factor V Leiden Factor V Leiden Protein C deficiency Protein C deficiency Protein S deficiency Protein S deficiency Prothrombin G20210A mutation Prothrombin G20210A mutation Antithrombin III deficiency Antithrombin III deficiency Hyperhomocystinemia Hyperhomocystinemia C677T MTHFR mutation C677T MTHFR mutation Hereditary Thrombophilias

Mutation in Factor V Mutation in Factor V Protein C/S complex Protein C/S complex Impaired anticoagulation Impaired anticoagulation 5-11% of white Europeans 5-11% of white Europeans Heterozygous Heterozygous Autosomal dominant Autosomal dominant Homozygous rare Homozygous rare Factor V Leiden Mutation

Mutation in promotor Mutation in promotor %  in prothrombin levels %  in prothrombin levels 2-3% of Europeans 2-3% of Europeans Heterozygous Heterozygous autosomal dominant autosomal dominant Homozygous similar to Factor V Homozygous similar to Factor V Prothrombin G20210A mutation

Protein C deficiency Protein C deficiency Type I –  number and activity Type I –  number and activity Type II –  activity Type II –  activity Protein S deficiency Protein S deficiency Type I –  total and free forms Type I –  total and free forms Type II –  cofactor activity Type II –  cofactor activity Type III -  free only Type III -  free only Autosomal dominant Autosomal dominant , 0.8 prevalence , 0.8 prevalence Protein C / Protein S Deficiencies

Multiple mutations Multiple mutations Most thrombogenic disorder Most thrombogenic disorder Type I Type I Levels and activity Levels and activity Type II Type II Activity Activity AT III Deficiency

Atherosclerosis, NTD, thromboembolism Atherosclerosis, NTD, thromboembolism Severe – homozygous Severe – homozygous 1 in 200, ,000 1 in 200, ,000 Cystathionine  -synthase Cystathionine  -synthase Mild to moderate – Mild to moderate – Heterozygotes for C  S mutation Heterozygotes for C  S mutation Homozygous for 667C-T MTHFR (11%) Homozygous for 667C-T MTHFR (11%) Hyperhomocysteinemia

Gen Pop * Prevalence lower in African, Latin, and Asian Americans Thrombosis Factor V Leiden 5-9%20-40%* Prothrombin G20210A 3% 3%6-15% Protein C deficiency 0.3% 0.3%1-2% AT III deficiency 0.07% 0.07%<1% Protein S deficiency 0.2% 0.2%1-2% Hyperhomocystinemia 5% 5%5-10% Prevalence in Populations

Factor V Leiden 5-10 PT G PC deficiency 5-50 PS deficiency 5-50 ATIII deficiency MTHFR +/+ C677T MTHFR +/ %RR Lifetime Prevalence of Thromboembolism

0.70 – 1.0 per 1,000 pregnancies 0.70 – 1.0 per 1,000 pregnancies Presence of Thrombophilias Presence of Thrombophilias 8 fold increase in risk (overall) 8 fold increase in risk (overall) Dramatic increase in risk if > 1 thrombophilia Dramatic increase in risk if > 1 thrombophilia Thromboembolism in Pregnancy

Case-control study Case-control study 119 with prior VTE in pregnancy 119 with prior VTE in pregnancy 233 age-matched controls 233 age-matched controls Tested Tested inherited thrombophilias inherited thrombophilias APS APS Gerhardt et al, N Engl J Med Gerhardt et al, N Engl J Med 2000; 342:374 Thrombophilias and VTE in Pregnancy

Thrombophilia Cases(119)Controls(233) Prothrombin G20210A 17%3% Factor V Leiden 44%8% C677T MTHFR +/+ 10%9% Antithrombin III deficiency 7%1.5% Protein C deficiency 14%4% Protein S deficiency 12%5% Gerhardt, NEJM 2000; 342:374 Prothrombin and Factor V Mutations in Women with VTE in Pregnancy

1 660 RR Factor V 6.9 PT G PC def. 2.2 AT III def Risk of VTE Associated with Hereditary Thrombophilias

Gerhardt, NEJM 2000; 342:374 PT G20210A 0.5% Factor V Leiden 0.25% AT III deficiency 0.4% PC deficiency 0.1% PT G20210A & Factor V 4.6% No thrombophilia 0.03% Estimated Probability of Thromboembolism

Preeclampsia Preeclampsia Pregnancy loss Pregnancy loss Fetal growth restriction Fetal growth restriction Placental abruption Placental abruption Thrombophilias and Pregnancy Complications

Thrombosis in uteroplacental circulation causes infarction Thrombosis in uteroplacental circulation causes infarction Abnormal placentation Abnormal placentation Insufficiency Insufficiency Abruption Abruption Pregnancy loss Pregnancy loss preeclampsia preeclampsia Pathophysiology of Thrombophilia in Pregnancy

Villous Infarction Normal Villi

Percent < 10% Infarction > 10% Infarction N = 372 N = 24 Factor V Leiden Mutation Dizon-Townson, AJOG 1997;177:402

Case control study Case control study 110 women with severe preeclampsia, IUGR, stillbirth, or abruption 110 women with severe preeclampsia, IUGR, stillbirth, or abruption Inherited thrombophilias and APS Inherited thrombophilias and APS 65% cases positive (18% controls) 65% cases positive (18% controls) 52% mutation 52% mutation 13% acquired/inherited 13% acquired/inherited OR for thrombophilia= 8.2, OR for thrombophilia= 8.2, Thrombophilias and Pregnancy Complications Kupferminc, NEJM 1999;340:9

Factor V 5 (2-16) 5 (1-7) 2 (0.6-6) 5 (1-22) PTG (0.4-14) 9 (2-44) 5 (1-20) 0 MTHFR (+/+) 3 (1-85) 2 (0.5-8) 4 (2-11) 2 (0.4-12) Preeclampsia Abruption IUGR Stillbirth Thrombophilias and Pregnancy Complications

Case control study Case control study 67 women 67 women 1st fetal death  20 wks 1st fetal death  20 wks no prior thrombosis no prior thrombosis 232 fertile controls 232 fertile controls Postpartum tests for 3 mutations Postpartum tests for 3 mutations Martinelli, NEJM 2000;343:1015 Thrombophilias and Pregnancy Loss

FetalDeath(N=67)FertileControls(N=20) OR(95%CI) Factor V 5 (7%) 6 (3%) 3.2 (1.1-11) C677T MTHFR 9 (13%) 46 (20%) 0.8 (.5-1) PT G20210A 6 (9%) 7 (3%) 3.3 (1.2-10) Martinelli, N Engl J Med 2000;343:1015 Either FV or PT 11 (16%) 13 (6%) 3.3 (1.1-7) Thrombophilias and Pregnancy Loss

Case-Control study Case-Control study 50 women with 3 or more 1 st trimester SAB 50 women with 3 or more 1 st trimester SAB 50 healthy women 50 healthy women Tested for three mutations plus IgG anticardiolipin Tested for three mutations plus IgG anticardiolipin Kutteh, Fertil Steril 2000;71: Thrombophilias and Recurrent Miscarriage

1 0 RR 2530 Factor V 0.5 PT G MTHFR +/+ 2.1 APS6 Kutteh, Fertil Steril 2000;71: Thrombophilias and Recurrent Miscarriage

Rey et al., Lancet 2003;361:901 Medline 1975 – 2002 Medline 1975 – studies 31 studies Mostly retrospective Mostly retrospective Moderate-high quality Moderate-high quality Thrombophilias and Pregnancy Loss: Meta-analysis

Rey et al., Lancet 2003;361:901 Factor V Leiden: Factor V Leiden: Early recurrent loss: 2.0 (1.1 – 3.6) Early recurrent loss: 2.0 (1.1 – 3.6) Late recurrent loss: 7.8 (2.8 – 21.7) Late recurrent loss: 7.8 (2.8 – 21.7) Late sporadic loss: 3.3 (1.8 – 5.8) Late sporadic loss: 3.3 (1.8 – 5.8) Increased effect if other pathologies excluded Increased effect if other pathologies excluded Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI)

Rey et al., Lancet 2003;361:901 Prothrombin gene mutation: Prothrombin gene mutation: Early recurrent loss: 2.6 (1.0 – 6.3) Early recurrent loss: 2.6 (1.0 – 6.3) Late sporadic loss: 2.3 (1.1 – 4.9) Late sporadic loss: 2.3 (1.1 – 4.9) Protein S deficiency: Protein S deficiency: Recurrent loss: 14.7 (1.0 – 218.0) Recurrent loss: 14.7 (1.0 – 218.0) Late sporadic loss: 7.4 (1.3 – 42.6) Late sporadic loss: 7.4 (1.3 – 42.6) Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI)

Rey et al., Lancet 2003;361:901 Protein C deficiency Protein C deficiency ATIII deficiency ATIII deficiency MTHFR homozygosity MTHFR homozygosity No association with fetal loss No association with fetal loss Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI)

Case-control study Case-control study 493 IUGR pregnancies (<10%) 493 IUGR pregnancies (<10%) 472 normal pregnancies 472 normal pregnancies Tested newborns and mothers Tested newborns and mothers Three mutations Three mutations Infante-Rivard, NEJM 2002;347:57-9 Thrombophilias and IUGR

1 0 RR 23 Factor V 1.2 PT G MTHFR +/ MTHFR +/+ 1.6 Infante-Rivard, NEJM 2002;347:57-9 Thrombophilias and IUGR

1 0 RR 23 Preeclampsia1.2 HELLP1.7 Livingston, AJOG 2001;185: IUGR2.4 Thrombophilias and Preeclampsia

Fetal death Fetal death Consistent (not uniform) association (Not MTHFR) Consistent (not uniform) association (Not MTHFR) Spontaneous abortion Spontaneous abortion Some association with APS Some association with APS Others? Mostly No Others? Mostly No Other complications: Mixed results Other complications: Mixed results Preeclampsia? Preeclampsia? IUGR? IUGR? Abruption? Abruption? Thrombophilias and Adverse Pregnancy Outcomes

Prospective cohort Prospective cohort 2,480 women in early pregnancy 2,480 women in early pregnancy Factor V Leiden – 270 (11%) Factor V Leiden – 270 (11%) 8 fold increase in VTE 8 fold increase in VTE Less intrapartum blood loss Less intrapartum blood loss Lindqvist, Thromb Haemost 1999;81:532-7 Factor V Leiden Prospective Obstetric Outcome

Percent PIHIUGR Abruptio Controls Factor V Leiden Lindqvist, Thromb Haemost 1999;81:532-7 SabFD Obstetric Outcome

Prospective cohort - MFMU Prospective cohort - MFMU 5,188 women in early pregnancy 5,188 women in early pregnancy Factor V Leiden – 134 (2.7%) Factor V Leiden – 134 (2.7%) No increase in VTE! No increase in VTE! 4 VTE – all testing negative 4 VTE – all testing negative Dizon-Townson, AJOG 2002;187:S159 (SFMFM) Factor V Leiden Prospective Obstetric Outcome

Dizon-Townson, AJOG 2002;187:S159 (SMFM) CarriersControls RR (95% CI) Pregnancy Loss 5.97%5.49% 1.1( ) Preeclampsia3.73%2.99% 1.3 ( ) Abruption00.65% 0.9 (0.4 – 2.1) SGA (< 10%) 9.7%10.8% 0.9 (0.5 – 1.6) Factor V Leiden Prospective Obstetric Outcome

Apparently conflicting results Apparently conflicting results Retrospective vs. prospective Retrospective vs. prospective Most women with thrombophilias: Most women with thrombophilias: Normal pregnancy outcome Normal pregnancy outcome “Two-hit” hypothesis “Two-hit” hypothesis Thrombophilia and fetal death (or thrombosis) is different than thrombophilia alone Thrombophilia and fetal death (or thrombosis) is different than thrombophilia alone Thrombophilias and Adverse Pregnancy Outcomes

Thrombophilias: Who Should we Test?

Venous thrombosis or embolism Consider other (PC def, PS def, AT-III def) Antiphospholipid Antibodies (LA and aCL) Factor V Leiden + Prothrombin G20210A

Family History of Venous thrombosis or thrombophilia ??????

What About Obstetric Complications?

Case control Case control 102 women with complications 102 women with complications 44 healthy women 44 healthy women 10 weeks postpartum 10 weeks postpartum Tested for all thrombophilias Tested for all thrombophilias 53% of cases positive 53% of cases positive 39% of controls positive 39% of controls positive Alfirevic, OBGYN 2001;97753 Postnatal Screening for Thrombophilias

Factor V PTG20210 MTHFR (+/+).2 (.02-2).7 ( ) 3 (.4-13) 0 1 (.08-11) 0.6 ( ) 2 (.2-14) 4 (.7-23) 01(.1-15)1(.1-15)Preeclampsia Abruption IUGR Stillbirth Alfirevic, OBGYN 2001;97753 Postnatal Screening for Thrombophilias

Statistically significant: Statistically significant: ? Clinically significant ? Clinically significant Most women with thrombophilias: Most women with thrombophilias: Normal pregnancy outcome Normal pregnancy outcome Ability to predict which subset of women with thrombophilia will have adverse outcomes: Ability to predict which subset of women with thrombophilia will have adverse outcomes: Poor – history better than labs Poor – history better than labs Thrombophilias and Adverse Pregnancy Outcomes

Thromboembolism: YES Thromboembolism: YES Family history of VTE: YES Family history of VTE: YES AT III, protein C, protein S AT III, protein C, protein S Obstetric complications: Obstetric complications: Unexplained fetal death: Maybe Unexplained fetal death: Maybe Recurrent 1 st trimester losses: NO Recurrent 1 st trimester losses: NO Severe preeclampsia: ? Severe preeclampsia: ? Severe IUGR, abruption: ? Severe IUGR, abruption: ? Recurrent cases: yes Recurrent cases: yes Who Should we Test?

Which Tests Should We Use?

Factor V Leiden Factor V Leiden Prothrombin G20210A Prothrombin G20210A Antithrombin III deficiency Antithrombin III deficiency Protein C deficiency Protein C deficiency Protein S deficiency Protein S deficiency Antiphospholipid antibodies Antiphospholipid antibodies Anticardiolipin and lupus anticoagulant Anticardiolipin and lupus anticoagulant Standard Thrombophilias

Experimental (at best) Experimental (at best) MTHFR MTHFR “Other” antiphospholipid antibodies “Other” antiphospholipid antibodies Some tests affected by Some tests affected by Anticoagulation Anticoagulation Acute thrombosis Acute thrombosis Pregnancy! Pregnancy! Caution

DNA tests (Factor V Leiden & Prothrombin G20210A) - anytime DNA tests (Factor V Leiden & Prothrombin G20210A) - anytime Antithrombin functional assay altered by Antithrombin functional assay altered by Acute thrombosis Acute thrombosis Heparin Heparin Protein C functional assay altered by Protein C functional assay altered by Pregnancy and OCPs Pregnancy and OCPs Warfarin – wait 2 wks Warfarin – wait 2 wks Acute thrombosis Acute thrombosis Thrombophilias: Laboratory Issues

Free Protein S functional assay altered by Free Protein S functional assay altered by Pregnancy and OCPs Pregnancy and OCPs Warfarin – wait 2 wks Warfarin – wait 2 wks Acute thrombosis Acute thrombosis Inflammatory states – always repeat! Inflammatory states – always repeat! Thrombophilias Laboratory Aspects

What to do with a Positive result?

Lack of data from RCTs Lack of data from RCTs Retrospective studies Retrospective studies Selection bias Selection bias Increased relative risk Increased relative risk Low absolute risk Low absolute risk Theoretical risk versus risk / cost of interventions Theoretical risk versus risk / cost of interventions Thrombophilias Treatment (Problems)

Thrombophilias: Treatment Recommendations

Personal history Personal history Thrombosis Thrombosis Obstetric complications Obstetric complications Family history Family history Thrombophilia Thrombophilia Thrombophilias: Treatment Recommendations

Full anticoagulation for pregnant women with: Full anticoagulation for pregnant women with: AT III deficiency AT III deficiency Homozygous for factor V Leiden or prothrombin G20210A or double heterozygotes Homozygous for factor V Leiden or prothrombin G20210A or double heterozygotes APS and previous thrombosis APS and previous thrombosis ACOG Recommendations: Thrombophilias

Full anticoagulation OR thromboprophylaxis for pregnant women with prior thrombosis and: Full anticoagulation OR thromboprophylaxis for pregnant women with prior thrombosis and: PC or PS deficiency PC or PS deficiency Heterozygous for factor V Leiden or prothrombin G20210A mutations Heterozygous for factor V Leiden or prothrombin G20210A mutations MTHFR and hyperhomocysteinemia ? MTHFR and hyperhomocysteinemia ? ACOG Recommendations: Thrombophilias

Thromboprophylaxis OR no treatment for pregnant women with NO personal history of thrombosis, but: Thromboprophylaxis OR no treatment for pregnant women with NO personal history of thrombosis, but: An inherited thrombophilia and a strong family history of thrombosis An inherited thrombophilia and a strong family history of thrombosis Consider postpartum anticoagulation Consider postpartum anticoagulation (I do NOT treat these women) (I do NOT treat these women) ACOG Recommendations: Thrombophilias

Don’t know what to do with women with NO personal or family history of VTE and: Don’t know what to do with women with NO personal or family history of VTE and: Heterozygous for factor V Leiden or prothrombin G20210A mutations Heterozygous for factor V Leiden or prothrombin G20210A mutations PC or PS deficiency PC or PS deficiency MTHFR and hyperhomocysteinemia MTHFR and hyperhomocysteinemia ACOG Recommendations: Thrombophilias

All women at risk for thrombosis should receive postpartum anticoagulation for 6 weeks All women at risk for thrombosis should receive postpartum anticoagulation for 6 weeks (No data) (No data) Consider prophylaxis for cesarean delivery in high risk cases Consider prophylaxis for cesarean delivery in high risk cases ACOG Recommendations: Thrombophilias

What about asymptomatic women with a prior Ob complication(s) and a thrombophilia? What about asymptomatic women with a prior Ob complication(s) and a thrombophilia? There are few good data upon which to base management, and expert opinion varies! Treatment is experimental Consider recurrent cases ACOG Recommendations: Thrombophilias

Multicenter RCT Multicenter RCT One prior loss > 10 weeks One prior loss > 10 weeks Thrombophilia Thrombophilia Factor V Leiden Factor V Leiden Prothrombin Prothrombin Protein S deficiency Protein S deficiency Gris et al., Blood 2004;103:3695 Thrombophilias and Pregnancy Loss Thromboprophylaxis

5 mg folic acid preconception 5 mg folic acid preconception Randomization Randomization Low dose aspirin (100 mg QD) Low dose aspirin (100 mg QD) N = 80N = 80 Enoxiparin (40 mg QD at 8 weeks) Enoxiparin (40 mg QD at 8 weeks) N = 80N = 80 Gris et al., Blood 2004;103:3695 Thrombophilias and Pregnancy Loss Thromboprophylaxis

Gris et al., Blood 2004;103:3695 LDA LMWH PregnancyLossSGA < 10% Percent Thrombophilias and Pregnancy Loss Thromboprophylaxis

LMWH - OR for live birth: LMWH - OR for live birth: 15.5 (7 – 34) 15.5 (7 – 34) Similar results for each thrombophilia Similar results for each thrombophilia Protein Z deficiency associated with worse outcomes Protein Z deficiency associated with worse outcomes Lower birth weight in LDA group Lower birth weight in LDA group Gris et al., Blood 2004;103:3695 Thrombophilias and Pregnancy Loss Thromboprophylaxis

Similar data from uncontrolled trials Similar data from uncontrolled trials Caution: Caution: One study – not confirmed One study – not confirmed Many Obstetricians in USA are not aware of the results Many Obstetricians in USA are not aware of the results Studies needed Studies needed “window of opportunity” “window of opportunity” Thrombophilias and Pregnancy Loss Thromboprophylaxis

Not yet! Not yet! Available data supports: Available data supports: Heparin for thrombophilia and Heparin for thrombophilia and Unexplained fetal deathUnexplained fetal death Adverse effects / cost of treatment Adverse effects / cost of treatment Prevalence in normal people Prevalence in normal people Consider other causes – especially RSAB Consider other causes – especially RSAB Be on the lookout for new data Be on the lookout for new data Thrombophilias and Obstetric Complications Will everyone end up on heparin?