Charles J. Lockwood, M.D.The Anita O’Keefe Young Professor and Chair

Department of Obstetrics, Gynecology and Reproductive SciencesYale University School of Medicine

What is the evidence for the relation of thrombophilia to adverse pregnancy outcome?

Inherited Thrombophilia

Factor VLeiden

ProthrombinG20210Amutation

667C-T MTHFR thermolabile mutant

antithrombin (aka ATIII) deficiency

protein C (PC) deficiency

protein S (PS) deficiency

Venous Thromboembolism (VTE) in Pregnancy

Pregnancy presents major challenges to a women’s hemostatic system including:

1) avoidance of hemorrhage during implantation, placentation and remodeling of spiral arteries; and

2) avoidance of catastrophic hemorrhage after separation of the placenta from the uterine wall following delivery.

Venous Thromboembolism (VTE) in Pregnancy

• To meet these hemostatic challenges pregnancy is accompanied by changes in both clotting and anti-clotting factors that maximize hemostasis.

• However, a high price is paid to prevent such hemorrhage as pregnancy and the puerperium are associated with a 10-fold increase in VTE, a leading cause of maternal mortality

Hemostatic Pathway

PlateletAggregation

X

IX

XIa /platelets IXa VIIIa

Xa

TF/ VII

X TFPI -

Va IIIIa

Fibrinogen

Fibrin

Anticoagulant Pathway

X

IX

XIa /platelets IXa VIIIa

Xa

TF/ VII

- (APC/S)

X TFPI -

Va II IIa

- (APC/S)

Anticoagulant Pathway (cont)

PlateletAggregation

X

IX

XIa /platelets IXa VIIIa

Xa

TF/ VII

X TFPI -

Va IIIIa

Fibrinogen

Fibrin +/- heparin

Antithrombin - 2 macroglobulin -

Hep.Cofactor II -

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

+/- heparin

heparin CoF II - 2 macroglobulin - Antithrombin -

PAI-1TAFIAntiplasmin

-

-

--

Pregnancy-Associated Changes in Hemostatic and Fibrinolytic Proteins

Increase in Clotting Factors:

20 to 200% increase in levels of fibrinogen

and factors II, VII, X, VIII and XII

Decrease in Anticoagulant and Fibrinolytic Activity:Protein S levels (free and total) decrease by 40%

PAI-1 levels increase two to three-fold in pregnancy

Risk of Maternal VTE in Patients with the Major

Thrombophilias

A) APCR/Factor VAPCR/Factor VLeidenLeiden mutation mutation

• 30% life-time risk of VTE • prevalence 5-15% in European population• accounts for 40% VTE in pregnancy• 10-fold increase risk of VTE in pregnancy• Risk of VTE in asympt. heterozygotes= 0.2%• Risk of VTE in homozygotes= 16 to 17%

Gerhardt A et al. N Engl J Med 2000; 342:374-380.Haematologica. 2001;86(12):1305-9. Br J Haematol. 2001;113(2):553-5.

B) ProthrombinG20210A mutation

• 30% life-time risk of VTE • prevalence 2-3% in European population• accounts for 17% VTE in pregnancy• 15-fold increase risk of VTE in pregnancy• Risk of VTE in heterozygotes = 0.5%• Risk of VTE in homozygotes = 15%• Risk with compound heterozygotes = 4-10%

Gerhardt A et al. N Engl J Med 2000; 342:374-380.Thromb Haemost. 2001;86(3):800-3.

C) Hyperhomocysteinemia

• 1.5 RR of VTE with hyperhomocysteinemia

• AD deficiencies in CBS (0.3-1.4% of population)

AR 667C-T MTHFR thermolabile mutant (11% of Europeans)

D) Antithrombin deficiency

• 70-90% life-time risk of VTE • prevalence 1/3000• accounts for 2-20% of VTE in pregnancy • > 50 fold increase risk of VTE in pregnancy• 50% risk of VTE per pregnant patient

Thromb Haemost 1990; 63:319-20

E) Protein C Deficiency:

• Life-time risk of VTE > 30%• Prevalence is 0.2-0.5% • Accounts for 10% of VTE in pregnancy• > 20-fold increased risk of VTE • Risk of VTE in pregnancy is 4%

Thromb Haemost 1990; 63:319-20

F) Protein S Deficiency

• Life-time risk of VTE > 30%• Prevalence of primary deficiency is 0.08%; of

acquired deficiency is 7%• Accounts for 10% of VTE in pregnancy• > 20-fold increase risk of VTE • Risk of VTE in pregnancy is 4%

Thromb Haemost 1990; 63:319-20

Risk of Maternal VTE in Patients with the Major Thrombophilias

Among 125 pregnant women with prior VTE:1) 0/44 recurrences among those with no thrombophilia and whose previous VTE was associated with a temporary risk 2) 3/51 recurrences (5.9%) (95% CI: 1.2- 16.2)if they had thrombophilia or unexplained previous VTE.

Brill-Edwards N Eng J Med 343; 1439-44.

Maternal Risks: Conclusions

• Patients with prior VTE associated with known risk factors without thrombophilia do not need antenatal heparin, but should receive postpartum therapy.

• Patients with prior VTE which is unexplained or who have a thrombophilia should be offered prophylactic heparin therapy during pregnancy.

Managment cont’d

• Patients with AT deficiency, or homozygotes for FVL or prothrombin mutations should receive full therapeutic heparin regardless of history throughout pregnancy and postpartum anticoagulation.

• Patients with a low thrombogenic thrombophilias but no history of VTE should only receive postpartum anticoagulation if they undergo C-sections or have other risk factors.

Management cont’d

• We have no evidence that patients with recurrent euploid fetal losses after 10 weeks, recurrent abruptions, severe, early onset preeclampsia or recurrent severe IUGR who are found to have an inherited low-thrombogenic thrombophilias will benefit from prophylactic heparin during pregnancy.

What is the Risk of Adverse Obstetrical Outcomes with Maternal Thrombophilias?

RFL and Other thrombophilias

• Prothrombin mutation associated with:

1) early recurrent (2.6, 1.0-0.3); and

2) late non-recurrent (2.3, 1.1-4.9) fetal loss;

• Protein S deficiency associated with:

1) recurrent fetal loss (14.7, 1.0-218); and

2) late non-recurrent fetal loss (7.4, 1.3-43).

Lancet. 2003;361(9361):901-8.

EPCOT Study: RFL and Other thrombophilias

• Of 1384 women enrolled in EPCOT risk of fetal loss was modestly increased in women with thrombophilia vs. controls: OR 1.35 (1.01-1.82).

• The odds ratio was higher for stillbirth than for miscarriage: 3.6(1.4-9.4) vs 1.27 (0.94-1.71).

Lancet. 1996;348(9032):913-6.

EPCOT Study: Cont.

OR for stillbirth was:

• 14.3 (2.4-86.0) with combined defects

• 5.2 (1.5-18.1) in AT

• 2.3 (0.6-8.3) in PC deficiency,

• 3.3 (1.0-11.3) in PS deficiency,

• 2.0 (0.5-7.7) for FVLLancet. 2003;361(9361):901-8.

EPCOT Study: Cont.

OR for SAB in these subgroups were • 0.8 (0.2-3.6) for combined defects

• 1.7 (1.0-2.8) for AT deficiency

• 1.4 (0.9-2.2) for PC deficiency

• 1.2 (0.7-1.9) for PS deficiency

• 0.9 (0.5-1.5) for FVL

Lancet. 2003;361(9361):901-8.

Thrombophilias and Latter Adverse Pregnancy OutcomesOutcome OR (95% CI)

Abruption 7.2 (2.6-20)

Severe PE 5.4 (2.3-12.4)

IUGR 4.8 (2.2-10.3)

N Engl J Med 1999;341:5

Management of Inherited Thrombophilias in Patients with Adverse Pregnancy Outcomes

Treat patients with:• history of recurrent (> 2) fetal loss > 10

weeks, recurrent severe IUGR, severe early-onset preeclampsia or massive abruptions with documented thrombophilias and characteristic placental pathology

Charles J. Lockwood, M.D.The Anita O’Keefe Young Professor and Chair

Department of Obstetrics, Gynecology and Reproductive SciencesYale University School of Medicine

What is the evidence for the relation of thrombophilia to adverse pregnancy outcome?