Inherited thrombophilia refers to inherited defects in the coagulation system that increase the tendency to develop blood clots. During pregnancy, inherited thrombophilia can lead to complications such as early or late fetal loss, severe preeclampsia, severe fetal growth restriction, and placental abruption. The most common inherited thrombophilias are Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in antithrombin, protein C, and protein S. Screening for inherited thrombophilia is recommended for women with a personal or family history of blood clots or pregnancy complications.

1. 해외 연수 보고
산부인과 주산기분과
안현경

2. Inherited Thrombophilia and Pregnancy
선천성 혈전성향증과 임신

3. 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

4. Coagulation pathway

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

6. 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

7. • 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

8. 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).

9. 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

10. • Common obstetric problems
– Early and Late Fetal Loss
– Severe IUGR
– Severe Preeclampsia
– Placental Abruption
Why we care

11. 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

12. Thrombophilia and pregnancy

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. • 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

22. 임상계획
• High risk pregnancy
assessment clinic
– 임신 중독증
– 저 체중아 및
– 조기진통 및 조산
연구계획
• Cytokines in amniotic
fluid of women who had
adverse pregnancy
outcome
• Cord blood