1. THROMBOPHILIA & PREGNANCY
Selçuk ÖZDEN MD, Prof

2. THROMBOEMBOLIC DISORDERS
The risk of venous thrombosis and pulmonary embolism in otherwise healthy women is considered highest during pregnancy and the puerperium.
The incidence of all thromboembolic events averages approximately 1 per 1000 pregnancies, and about an equal number are identified antepartum and in the puerperium.

3. THROMBOEMBOLIC DISORDERS
The incidence of all thromboembolic events averages approximately 1 per 1000 pregnancies
The risks of venous thromboembolism:
During the third trimester six times higher,
During the first 6 weeks postpartum 22 times higher than for nonpregnant women.
The incidence of all thromboembolic events averages approximately 1 per 1000 pregnancies, and about an equal number are identified antepartum and in the puerperium.

4. THROMBOEMBOLIC DISORDERS
Venous thromboembolism frequency during the puerperium has decreased remarkably as early ambulation has become more widely practiced...
Pulmonary embolism still remains a leading cause of maternal death in the United States

5. PATHOPHISIOLOGY Triad of Virchow (1856) Stasis,
Local trauma to the vessel wall, and
Hypercoagulability predisposed to venous thrombosis development.
The risk for each of these increases during normal pregnancy.

6. THROMBOPHILIAS
Several important regulatory proteins act as inhibitors in the coagulation cascade.
Inherited or acquired deficiencies of these inhibitory proteins are collectively referred to as thrombophilias.
These can lead to hypercoagulability and recurrent venous thromboembolism.

7. THROMBOPHILIAS
These disorders are responsible for approximately 50 percent of all thromboembolic events during pregnancy.

8. THROMBOPHILIAS Inherited thrombophilias Factor V Leiden Mutation
Prothrombin Gene Mutation
Hyperhomocysteinemia
Antithrombin Deficiency
Protein C Deficiency
Protein S Deficiency
Acquired Thrombophilias:
Antiphospholipid Antibody Syndrome (APAS)

9. INHERITED THROMBOPHILIAS
Patients with inherited thrombophilic disorders often have a family history of thrombosis.
Inherited thrombophilias are also found in up to half of all patients who present with venous thromboembolism before the age of 45 years
Thromboembolism occur in the absence of risk factors such as surgery or immobilization.

10. INHERITED THROMBOPHILIAS
Of greatest significance is a family history of sudden death due to pulmonary embolism or a history of multiple family members requiring long-term anticoagulation therapy because of recurrent thrombosis.

11. INHERITED THROMBOPHILIAS

13. ANTITHROMBIN DEFICIENCY
Antithrombin is synthesized in the liver and one of the most important inhibitors of thrombin in clot formation.
Antithrombin deficiency is the most thrombogenic of the heritable coagulopathies.
Antithrombin functions as a natural anticoagulant by binding and inactivating thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

14. ANTITHROMBIN DEFICIENCY
It may result from hundreds of different mutations that are almost always autosomal dominant.
Homozygous antithrombin deficiency is lethal.
Antithrombin deficiency affects approximately 1 in 2000 to individuals,
Thrombosis risk during pregnancy:
without a personal or family history: 3 to 7 percent,
with such a history : 11 to 40 percent

15. ANTITHROMBIN DEFICIENCY
Type I deficiency is the result of reduced synthesis of biologically normal antithrombin, and
Type II deficiency is characterized by normal levels of antithrombin with reduced functional activity.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

16. ANTITHROMBIN DEFICIENCY
Affected women are treated during pregnancy with heparin regardless of whether they have had a prior thrombosis.
When anticoagulation is necessarily withheld, such as during surgery or delivery, treatment with recombinant human antithrombin protected against venous thromboembolism.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

17. PROTEIN C DEFICIENCY Protein C is a natural anticoagulant
In the presence of protein S, controls thrombin generation, in part, by inactivating factors Va and VIIIa.
Activated protein C also inhibits the synthesis of plasminogen activator inhibitor 1
When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized.

18. PROTEIN C DEFICIENCY
More than 100 different autosomal dominant mutations for the protein C gene have been described.
The prevalence of protein C deficiency is 2 to 3 per 1000,
With functional activity threshold values of 50 to 60 percent, a six- to 12-fold increased risk for venous thromboembolism.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

19. PROTEIN S DEFICIENCY
This circulating anticoagulant is activated by protein C, which enhances its capacity to inactiviate factors Va and VIIIa.
Protein S deficiency may be caused by more than 100 different mutations,
Prevalence: ~ 2 per 1000.
With a positive family history, the venous thromboembolism risk in pregnancy has been reported to be 6 to 7 percent .
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

20. PROTEIN S DEFICIENCY
Protein S deficiency may be measured by antigenically determined free, functional, and total S levels.
All three decline substantively during normal gestation, thus the diagnosis in pregnant women—as well as in those taking certain oral contraceptives—is difficult
If screening during pregnancy is necessary, threshold values for free protein S antigen levels in the second and third trimesters have been identified at less than 30 percent and less than 24 percent, respectively.

21. FACTOR V LEIDEN MUTATION
It is the most prevalent of the known thrombophilia syndromes,
Because of this mutation, factor V gains resistance to degradation by activated protein C
The unimpeded abnormal factor V protein retains its procoagulant activity and predisposes to thrombosis.
A number of mutations have been described, but the most common is the factor V Leiden mutation.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.
his condition is characterized by resistance of plasma to the anticoagulant effects of activated protein C.

22. FACTOR V LEIDEN MUTATION
Heterozygous inheritance for factor V Leiden is the most common heritable thrombophilia
Women who are heterozygous for factor V Leiden account for approximately 40 percent of venous thromboembolism cases during pregnancy.
It is found in 3 to 15 percent of select European populations and 3 percent of African Americans, but it is virtually absent in African blacks and Asians.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

23. FACTOR V LEIDEN MUTATION
Without personal or family history of thrombosis, risk of VTE among pregnant women who are heterozygous is 5 to 12 per 1000.
With a personal or family history, this risk increases to at least 10 percent among women.
Of note, the rate of antithrombin interaction with its target proteases is accelerated by heparin.

24. FACTOR V LEIDEN MUTATION
Pregnant women who are homozygous without a personal or family history have a 1- to 4-percent risk for venous thromboembolism, whereas those with such a history have an approximately 17-percent risk.
Diagnosis during pregnancy is performed by DNA analysis for the mutant factor V gene.
This is because bioassay is confounded by the fact that resistance is normally increased after early pregnancy because of alterations in other coagulation proteins.
Of note, activated protein C resistance can also be caused by antiphospholipid syndrome.

25. PROTHROMBIN G20210 MUTATION
Mutation in the prothrombin gene leads to excessive accumulation of prothrombin, which then may be converted to thrombin.

26. PROTHROMBIN G20210 MUTATION
For a heterozygous carrier with a family history, risk of venous thromboembolism during pregnancy exceeds 10 percent.
Without such a history, risk of venous thromboembolism during pregnancy is less than a 1-percent
Homozygous patients or those who coinherit a G20210A mutation with a factor V Leiden mutation have an even greater thromboembolism risk.

27. HYPERHOMOCYSTEINEMIA
The most common cause of elevated homocysteine is the C667T mutation of the enzyme methylenetetrahydrofolate reductase (MTHFR).
Inheritance is autosomal recessive.

28. HYPERHOMOCYSTEINEMIA
Elevated homocysteine levels may also result from:
Deficiency of one of several enzymes involved in methionine metabolism and,
From correctible nutritional deficiencies of folic acid, vitamin B6, or vitamin B12.

29. HYPERHOMOCYSTEINEMIA
During normal pregnancy, mean homocysteine plasma concentrations are decreased.
To make a diagnosis of hyperhomocysteinemia during pregnancy: a fasting threshold is > 12 μmol/L .
Elevated homocysteine level is a weak risk factor for venous thromboembolism. (OR: )

30. HYPERHOMOCYSTEINEMIA
There is insufficient evidence to support assessment of MTHFR polymorphisms or measurement of fasting homocysteine levels in the evaluation for venous thromboembolism. (ACOG-2013)

31. ACQUIRED THROMBOPHILIAS
Antiphospholipid syndrome (APS) ,
Antiphospholipid antibodies are a heterogeneous group of autoantibodies recognizing epitopes expressed by negatively charged phospholipids, proteins, or a phospholipid-protein complex.

32. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
A diagnosis of APS requires at least one clinical criterion and one laboratory criterion to be met.
Positive results may be transient, especially in the setting of infection.
Testing should be repeated in 6 to 12 weeks to confirm the finding

33. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Clinical Criteria:
Vascular thrombosis: One or more clinical episodes of arterial, venous, or small-vessel thrombosis
Pregnancy morbidity
at least one unexplained fetal death at or beyond 10 weeks
at least one preterm birth before 34 weeks because of eclampsia, severe preeclampsia, or placental insufficiency or
at least three unexplained consecutive spontaneous abortions before 10 weeks.

34. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Laboratory Criteria:The three best standardized assays are:
Lupus anticoagulant (LA): The assay for LA is interpreted as being present or absent.
Anticardiolipin antibodies (ACAs) Levels ≥ 40 GPL unite,
Anti-β2-glycoprotein-1 antibodies: levels ≥40 SGU are most strongly associated with antiphospholipid antibody syndrome (APS).
Lupus anticoagulant (LA) is a misnomer for an antibody found in patients who need not have lupus and are not anticoagulated.
It is necessary to do confirmatory testing because thereare reasons other than LA for prolonged clotting times, such as a clotting factor deficiency or specific inhibitor.
It was initially recognized in patients with lupus, accounting for the poor nomenclature.
The name was derived from the fact that the antibody interferes with phospholipid-dependent clotting assays, prolonging the assay clotting time and making it appear that the individual is anticoagulated.
It can be detected by any of several phospholipid-dependent clotting tests, including the activated partial thromboplastin time, the dilute Russell viper venom time, the kaolin clotting time, and the plasma clotting time.

35. ANTİPHOSPHOLIPID ANTIBODIES
Up to 25 percent of thrombotic events in women with antiphospholipid syndrome occur during pregnancy or in the puerperium.
Women with antiphospholipid syndrome have a 5- to 12- percent risk of thrombosis during pregnancy or the puerperium.
Thromboembolism—either venous or arterial— most commonly involves the lower extremities.
Women with moderate-to-high levels of these antibodies may have antiphospholipid syndrome, which, as summarized by the American College of Obstetricians and Gynecologists (2012), is defined by a number of clinical features.

36. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Venous thromboses
Two thirds of the events are venous
Up to 50% of venous thromboses are pulmonary emboli
Thromboses in unusual locations also are common (such as the portal, mesenteric, splenic, subclavian, axillary, and cerebral veins.)
Lupus anticoagulant (LA) is a misnomer for an antibody found in patients who need not have lupus and are not anticoagulated.
It is necessary to do confirmatory testing because thereare reasons other than LA for prolonged clotting times, such as a clotting factor deficiency or specific inhibitor.
It was initially recognized in patients with lupus, accounting for the poor nomenclature.
The name was derived from the fact that the antibody interferes with phospholipid-dependent clotting assays, prolonging the assay clotting time and making it appear that the individual is anticoagulated.
It can be detected by any of several phospholipid-dependent clotting tests, including the activated partial thromboplastin time, the dilute Russell viper venom time, the kaolin clotting time, and the plasma clotting time.

37. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Arterial thromboses:
Cerebrovascular accident (most common).
Coronary occlusions and
Arterial thromboses in atypical sites also may occur (such as the retinal, subclavian, brachial, or digital arteries.)
Lupus anticoagulant (LA) is a misnomer for an antibody found in patients who need not have lupus and are not anticoagulated.
It is necessary to do confirmatory testing because thereare reasons other than LA for prolonged clotting times, such as a clotting factor deficiency or specific inhibitor.
It was initially recognized in patients with lupus, accounting for the poor nomenclature.
The name was derived from the fact that the antibody interferes with phospholipid-dependent clotting assays, prolonging the assay clotting time and making it appear that the individual is anticoagulated.
It can be detected by any of several phospholipid-dependent clotting tests, including the activated partial thromboplastin time, the dilute Russell viper venom time, the kaolin clotting time, and the plasma clotting time.

38. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Autoimmune thrombocytopenia is a frequent medical complication of APS, occurring in almost one half of cases.
The condition is hard to distinguish from idiopathic thrombocytopenic purpura and is treated in a similar fashion.

39. ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Other medical disorders associated with APS include: autoimmune hemolytic anemia,
Livedo reticularis,
Chorea gravidarum,
Transverse myelitis,
Pyoderma-like leg ulcers, and
Cardiac valve disease.

40. THROMBOPHILIAS AND PREGNANCY COMPLICATIONS
The American College of Obstetricians and Gynecologists (2013) has concluded that a definitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

41. THROMBOPHILIAS AND PREGNANCY COMPLICATIONS
Women with moderate-to-high levels of these antibodies may have antiphospholipid syndrome, which, as summarized by the American College of Obstetricians and Gynecologists (2012), is defined by a number of clinical features.

42. THROMBOPHILIA SCREENING
American College of Chest Physicians recently concluded that it was unclear whether screening for inherited thrombophilias is prudent in women with pregnancy complications.
In contrast, and as the association between antiphospholipid syndrome and adverse pregnancy outcomes—including fetal loss, recurrent pregnancy loss, and preeclampsia—is much stronger.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

43. SCREENING TESTS

44. THROMBOPHILIA SCREENING
Given the high incidence of thrombophilia in the population and the low incidence of venous thromboembolism, universal screening during pregnancy is not cost effective.
Thus, a selective screening strategy is required.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

45. THROMBOPHILIA SCREENING
Screening is considered in the following clinical circumstances:
a personal history of venous thromboembolism that was associated with a nonrecurrent risk factor such as fractures, surgery, and/or prolonged immobilization,
a first-degree relative (parent or sibling) with a history of high-risk thrombophilia or venous thromboembolism before age 50 years in the absence of other risk factors.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

46. THROMBOPHILIA SCREENING
Testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because there is insufficient clinical evidence that antepartum heparin prophylaxis prevents recurrence.
Similarly, testing is not recommended for women with a history of fetal-growth restriction or preeclampsia.
Screening for antiphospholipid antibodies may be appropriate in women who have experienced a fetal loss.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

47. SCREENING TESTS
Whenever possible, laboratory testing should be performed:
at least 6 weeks after the thrombotic event,
while the patient is not pregnant, and
when she is not receiving anticoagulation or hormonal therapy.
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

48. SCREENING TESTS
Because of the lack of association between methylenetetrahydrofolate reductase (MTHFR) gene mutations (the most common cause of hyperhomocysteinemia) and adverse pregnancy outcomes, screening with fasting homocysteine levels or MTHFR mutation analyses is not recommended (ACOG 2013).
Because of uncertainties associated with the magnitude of risk as well as any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interest of these women.

49. REFERENCES
Williams Obstetrics 24.th edition-Cunningham et al. The McGraw-Hill Companies-2014
Creasy And Resnik’s Maternal-fetal Medicine, Seventh Edition, Elsevier Saunders, 2014