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안현경

Inherited Thrombophilia and Pregnancy

선천성혈전성향증과임신

Inherited Thrombophilia

• A heterogeneous group of conditions that

predispose individuals to (venous) thromboembolism

Thrombophilia:

Disorder associated with an increased tendency to thrombosis

: Acquired or

Congenital tendency:

Inherited defect in the coagulation system

Coagulation pathway

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

Major Mechanisms Involved in the Normal Control of Coagulation and Inherited Thrombophilias

In inherited thrombophilias, thrombosis is most often

caused by impaired neutralization of thrombin or failure to

control the generation of thrombin

Seligsohn U and Lubetsky A. N Engl J Me

d 2001;344:1222-1231

• Factor IX

• Factor VIII

• Factor X

• Factor V

• Factor II

• Factor XIII

• Factor VII

• Protein C

• Protein S

• Antithrombin III

• Fibrinolysis

• PAI-1

Components of Hemostasis

Procoagulant Anticoagulant

Inherited thrombophilia

• Qualitative or quantitative defects of endogenous inhibitors of the coagulation pathway

– antithrombin, protein C, protein S, heparin cofactor II, tissue factor pathway

inhibitor, and thrombomodulin deficiencies

• Increased levels or function of coagulation factors

• Factor V Leiden [FVL], prothrombin gene mutation G20210A, dysfibrinogenemia and

hyperfibrinogenemia, and increased levels of factors VII, VIII, IX, and XI

• Inherited hyperhomocysteinemia, mainly due to C677T homozygosis of the

methylentetrahydrofolate reductase (MTHFR) gene

• Defects of the fibrinolytic system, involving plasminogen, the tissue plasminogen

activator (tPA), the plasminogen activator inhibitor (PAI), the thrombinactivatable

fibrinolysis inhibitor (TAFI), factor XIII, and lipoprotein “a.”

• Altered platelet function (platelet glycoproteins GPIb-IX, GPIa-IIa, and GPIIb-IIIa).

Inherited Thrombophilias

Inherited hypercoaguable states A genetic tendency for venous thromboembolism

Should be suspected in anyone who:◦ Presents with an unprovoked venous or arterial thromboemboli

c disease at <45 yrs◦ 2 or more thrombotic episodes in the absence of a risk factor f

or thrombosis◦ History of objectively confirmed idiopathic thrombosis in first-

degree relative◦ Thrombosis in an unusual site

Mesenteric veins, dural sinus

◦ Neonatal thromobosis or stroke◦ History of recurrent fetal loss

• Common obstetric problems

– Early and Late Fetal Loss

– Severe IUGR

– Severe Preeclampsia

– Placental Abruption

Why we care

Pathogenetic Models of the Clinical Manifestations associated with

Inherited Thrombophilia

Venous thromboembolic disease (VTE)

Unicausal model

Gene Defect

Triggering event

Multicausal Model

Gene defect

Gene defect

Venous Thromboembolic disease (VTE) and

Obstetric complications (OC)

age

Dietary habit

Triggering event

VTE

VTE

OC

Thrombophilia and pregnancy

Pregnancy related hemostatic alteration

Hemostatic changes in pregnancy that tend to create a pro-thrombotic milieu have been will documented.

– Increasing coagulation factor:

• Factor fibrinogen

• Factors VII

• Factors VIII

• Factor X

• von Willebrand factor

– Decrease in the natural anticoagulant system

• Lower level of protein S

• Increased resistance to activated protein C

– Impairment of the fibrynolytic process

• Increased levels of plasminogen activator inhibitor-1 and 2

• Increased levels of thrombin activatable fibrinolysis inhibitor

Pre-eclampsia

• Incidence: 2.6% of births

• 10.7-fold increase in risk in PS-deficient women

• women with a history of pre-eclampsia or HELLP syndrome

– a total of 1,458 patients

– factor V Leiden was diagnosed in from 4% up to 26% of the cases

Fetal Loss

• AT, PC, and PS deficiency or factor V Leiden

– stillbirth (late fetal loss after the 28th week of gestation)

• 3.6-fold

– Miscarriage (fetal loss before the 28th week of gestation):

• 1.3-fold increased.

• AT, PC, and PS deficiency and factor V Leiden

– 2.0-fold increase in the risk of fetal loss

• Prothrombin G20210A and fetal loss

– 3.3-fold increased risk of late fetal loss

Pregnancy loss

• Nonrecurrent early pregnancy losses

– FVL

– Prothrombin G20210A mutation

– Protein S deficiency

– no association: Homozygous MTHFR mutation

• Recurrent fetal loss

– 2.01 for FVL

– 2.32 for prothrombin mutation

– Hyperhomocysteinaemia

– No significant association:

• Homozygous MTHFR mutation

• protein C deficiency

• protein S deficiency

Fetal growth retardation

• Carriership of the prothrombin 20210A allele

– 4.6 to 5.9-fold increase in risk of unexplained fetal growth retardation

• Factor V Leiden

– 6.9-fold increase in the risk of FGR

• Carriership of factor V Leiden or prothrombin G20210A

– 1.7-fold increase in the risk of having a baby under the 10th growth centile

• Multiple or homozygous defects

– 4-fold increase in the risk of FGR among babie

Placental abruption

• Heterozygous FVL

– OR 4.70, 95%CI 1.13–19.59

• Heterozygous prothrombin G20210A

– OR 7.71, 95%CI 3.01–19.76

• No association was detected with antithrombin, protein C, or protein S

deficiencies, aCL, and hyperhomocysteinaemia

Inherited thrombophilia and adverse pregnancy outcome

• Adverse pregnancy outcome

– FVL

– PGM

– PS

– Antithrombin

– PC

• Insufficient evidence

– PAI-1 levels

– PAI-1 4G/5G mutation

– MTHFR

– Homocysteine

Screening patients for thrombophilia

• Laboratory evaluation for the inherited thrombophilias

– Factor V Leiden

– Prothrombin gene mutation G20210A

– MTHFR C677T

– Antithrombin activity

– Protein C activity

– Protein S activity, or free protein S antigen

– Protein Z antigen

– Homocysteine

– 4G/4G plasminogen Activator Inhibitor I mutation

– Plasminogen Activator Inhibitor I activity

• The following conditions should warrant a thrombophilia evaluation:

– Personal history of thrombosis (idiopathic, pregnancy, oral contraceptives,

trauma, obesity, cancer, underlying medical conditions)

– History of unexplained loss > 20weeks

– History of severe preeclampsia/HELLP

– History of severe IUGR (< 5percentile)

– History of abruption

– Family history of thrombosis

– Fetal loss > 10weeks

– two or more episodes of early fetal loss

Screening patients for thrombophilia

Asymptomatic women with a family history of venous thromboembolism are potential

candidates for screening before use of oral contraceptives, hormone replacement therapy,

or pregnancy

임상계획

• High risk pregnancy

assessment clinic

– 임신중독증

– 저체중아및

– 조기진통및조산

연구계획

• Cytokines in amniotic

fluid of women who had

adverse pregnancy

outcome

• Cord blood