Monday, September 20, 2021

Thrombophilia Case File

Posted By: Medical Group - 9/20/2021 Post Author : Medical Group Post Date : Monday, September 20, 2021 Post Time : 9/20/2021
Thrombophilia Case File
Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 23
A 31-year-old nulligravida presents for preconceptional counseling secondary to a history of pulmonary embolism 7 years ago. She was anticoagulated for 3 months and has not required any further treatment or prophylaxis. As part of her evaluation at that time, she had thrombophilia testing and was found to have antithrombin (AT) deficiency (42%; normal 80%-140%). As a result, her two sisters sought testing and were also identified to have the same thrombophilia. There is no family history of thrombosis or other clotting disorders. She was told by her physician at the time of her pulmonary embolus that she should not conceive. However, she has recently married and is contemplating pregnancy. She is otherwise healthy and is using condoms for contraception.

➤ What is the next step in evaluating this patient?
➤ What are potential maternal complications of AT deficiency in pregnancy?
➤ What are potential fetal complications?
➤ How would you manage the pregnancy of a woman with AT deficiency?


Summary: A nulligravida with a personal history of pulmonary embolus and AT deficiency presents for preconceptional counseling. She has no family history of thrombosis.

Next step in evaluating this patient: Confirmation that the patient is truly AT deficient and does not have any other inherited or acquired thrombophilias.
Potential maternal complications of AT deficiency in pregnancy: Venous thromboembolism and although significantly rarer, arterial thromboses have been reported.
Potential fetal complication: Fetal growth restriction, stillbirth, and placental abruption.
Management plan for a pregnancy in a woman with AT deficiency: Therapeutic (adjusted-dose) anticoagulation with unfractionated (UH) or low-molecular-weight heparin (LMWH), serial growth ultrasounds.

  1. Recognize maternal and fetal complications of AT deficiency.
  2. Understand how to diagnose and treat AT deficiency.
  3. Understand whom to screen for inherited thrombophilias.
  4. Know which women with thrombophilias are candidates for treatment during pregnancy.

Antithrombin (AT; initially designated antithrombin III) is a plasma protease inhibitor that is able to neutralize all proteases of the intrinsic coagulation pathway, including thrombin, factors XIIa, XIa, Xa, and IXa. Of the heritable thrombophilias, AT deficiency is the most uncommon with a prevalence of 1 in 5000; however, it is also the most thrombogenic with a 70% to 90% lifetime risk of thromboembolism. It is usually inherited in an autosomal dominant fashion, and two major types of inherited AT deficiency exist. Type I AT deficiency, the most common type, is characterized by low levels of both antigen and activity. In type II AT deficiency, there is a specific defect within the AT protein itself, which leads to markedly decreased functional activity with essentially no effect on antigenic levels. Type II AT deficiency is further subclassified based on the actual site of the mutation, such as a defect at the heparin-binding site or a defect at the thrombin-binding site. This subclassification scheme further affects risk of thromboembolic events, with the type II heparin-binding site variant having the least clinical significance.

Because of the low prevalence of AT deficiency, it is only present in 1% of patients who present with a thrombotic event (Figure 23–1). This patient’s AT deficiency was detected after she suffered a pulmonary embolism. Similar to this patient, 42% of those with AT deficiency suffer an initial thrombotic event spontaneously, while the remaining cases occur in the presence of an


Figure 23–1. A patient with classic findings of left lower extremity DVT with
swelling, erythema, pain, and tenderness. (Reproduced, with permission, from Knoop
KJ, Stack LB, Storrow AB, et al. Atlas of Emergency Medicine. 3rd ed. New York, NY:
McGraw-Hill; 2010:336. Photo contributor: Kevin J. Knoop,MD, MS.).

additional risk factor such as pregnancy, oral contraceptive use, surgery, or trauma. Additional common sites of thrombosis are the deep veins of the leg, the iliofemoral veins, and the mesenteric veins. Arterial thrombosis has been reported, but does not seem to be characteristic of AT deficiency.

The first step in evaluating this patient is confirmation of her AT deficiency. Erroneous diagnoses of hereditary AT deficiency can occur. For instance, acute thrombosis, heparin therapy, sepsis, disseminated intravascular coagulation (DIC), oral contraceptives, and other acquired conditions such as liver disease can lead to decreased AT levels. There is also some controversy as to whether oral anticoagulation can falsely increase plasma AT concentrations into a normal range. Thus, optimally, repeat testing should be performed at least 2 weeks after completion of anticoagulation therapy for the acute thrombotic event, and an AT-factor Xa assay that measures AT activity will detect all types and subtypes of AT deficiency. Levels of AT are unchanged in pregnancy.

Once the diagnosis of AT deficiency is confirmed, preconceptional consultation should include a discussion regarding the additive effect of pregnancy on hypercoagulability The potential complications that may arise during pregnancy because of AT deficiency should also be reviewed. Although the data on thrombophilia and adverse pregnancy outcomes are heterogeneous, it appears that among the hereditary thrombophilias, AT deficiency appears to have the highest risk of stillbirth. Similarly, retrospective data also suggest that there is an increased risk for fetal growth restriction and placental abruption, and serial growth ultrasounds should be performed.

While the absolute risk of developing thromboembolism in pregnancy is low in the setting of AT deficiency, the relative risk is at least 250-fold greater when compared to that of controls without a known thrombophilia. Thus, in this patient with a “higher-risk” thrombophilia and a personal prior history of venous thromboembolism, therapeutic anticoagulation during pregnancy and the postpartum period is not unreasonable. Both unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) are appropriate choices. With UH, subcutaneous administration three times a day should be prescribed, with an activated partial thromboplastin time (aPTT) trough of 1.5 to 2 times the mean control aPTT. Enoxaparin, one of the more frequently prescribed LMWHs, can be given subcutaneously twice daily (1 mg/kg) in order to account for increased renal clearance and larger volume of distribution during pregnancy. With LMWH, peak anti-factor Xa levels should be drawn 4 hours after administration of a dose with a goal of approximately 0.5 to 1.0 IU/mL. Either aPTT or anti-factor Xa levels should also be checked serially depending on which anticoagulant is used to ensure that therapeutic anticoagulation is being maintained throughout pregnancy. A platelet count should be checked prior to initiating anticoagulation, and serial assessment of platelet counts should be performed for an additional 3 weeks thereafter to ensure that the patient is not developing heparininduced thrombocytopenia (HIT) which may occur in 2% of those treated. While the extent of therapeutic doses of UH or LMWH on bone mineral density is unclear, consideration should be given to an additional 500 mg of calcium supplementation daily.

In general, inherited thrombophilias in pregnancy increase the risk of thrombosis in either the maternal, fetal, or placental venous systems. AT deficiency, as well as protein C and protein S deficiencies, are less common causes of genetic thrombophilias with prevalence 0.2% to 0.5% and 0.08%, respectively and they are inherited in an autosomal dominant fashion. In contrast, mutations of the factor V Leiden (FVL) gene, the prothrombin G20210A mutation (PTGM), and hyperhomocysteinemia secondary to homozygosity for the MTHFR mutation (TT genotype) are more common genetic causes of thrombophilia, with hetero- or homozygous gene status affecting the degree of hypercoagulability. The prevalence is 5% to 9%, 2% to 3%, and 11% in white European population for FVL, PTGM, and MTHFR (TT genotype), respectively. Higher risk thrombophilias include AT deficiency, homozygotes for either FVL or PTGM, or compound heterozygotes with one copy of the FVL mutation and one copy of the PTGM. While protein C deficiency, protein S deficiency, and heterozygosity for FVL or PTGM are considered lower risk thrombophilias, personal and family history are important considerations in ascertaining thrombogenic risk.

Indications for Thrombophilia
Routine screening for inherited thrombophilias should not be performed. Testing should be performed in women with a personal history of thrombosis. There is controversy surrounding whether individuals with a strong family history of thromboembolism should be tested. Consideration to testing these patients should be given, especially if family members suffered from thrombosis earlier in life and in the absence of any associated risk factors (eg, oral contraceptives, trauma, etc.). There is even more uncertainty regarding testing in the setting of prior adverse pregnancy outcomes, but in the absence of substantial evidence in favor of testing for inherited thrombophilias, the American College of Obstetricians and Gynecologists (ACOG) recommends discussing the implications of testing and positive test results for an inherited thrombophilia on management. Of note, ACOG suggests that patients with a history of thrombosis, recurrent fetal loss, early/severe preeclampsia, or severe unexplained fetal growth restriction be tested for antiphospholipid antibodies.1

Thrombophilia and Pregnancy Outcome
From an obstetrical standpoint, inherited thrombophilias have been associated with an increased risk for various adverse pregnancy outcomes. However, findings are often conflicting. For instance, with regard to inherited thrombophilia and early pregnancy loss, a recent meta-analysis of 31 studies concluded that presence of the PTGM or FVL mutation increases the risk of early (< 13 weeks) recurrent (≥ 2 ) fetal loss approximately twofold, whereas there did not appear to be an association between protein C deficiency, protein S deficiency, AT deficiency, and MTHFR.2 In contrast, a subsequent cohort study performed by Roque and colleagues found that the presence of thrombophilia appeared protective of recurrent early pregnancy loss, decreasing the risk by approximately 50%3 (Level II-2). Early pregnancy is associated with a low oxygen environment and decreased flow through uteroplacental circulation.4,5 Thus, oxygen may actually be harmful to early pregnancy and maternal thrombophilias may paradoxically be helpful during this time in gestation.

The association between inherited thrombophilias and late fetal loss appears to be stronger, although the definition of late varies between studies. The same cohort study by Roque found that the presence of an inherited thrombophilia carries at least a threefold risk of late fetal loss, which the authors defined as loss after 14 weeks’ gestation. Similarly, a retrospective cohort analysis from data gathered by the European Prospective Cohort on Thrombophilia (EPCOT) demonstrated that the risk for stillbirth after 28 weeks’ gestation was significantly greater in women with a heritable thrombophilia such as AT and protein C and S deficiency. Moreover, these results were more pronounced in those with AT deficiency and combined defects6.6 (Level II-2).

Other potentially related obstetrical complications in the setting of inherited thrombophilia include abruption, intrauterine fetal growth restriction, and preeclampsia. For the most part, when the thrombophilias are examined individually, there are varying conclusions surrounding its association with these specific adverse pregnancy outcomes. However, when taken as a group, the presence of thrombophilia appears associated with placental abruption, and one study also found that this risk increased as the number of maternal thrombophilias increased.3,7 With regard to preeclampsia and fetal growth restriction, the relationship with thrombophilia is less clear, with certain studies demonstrating no link but others finding an association only in the setting of specific thrombophilias7,8 (Level II-2). Thus, without clear evidence of an association between thrombophilia and preeclampsia or fetal growth restriction, it is not unreasonable to consider intermittent growth ultrasounds, especially in the setting of a more thrombogenic thrombophilia.

Management Recommendations
Thrombogenic potential varies with the specific thrombophilia. Those with high-risk thrombophilias such as AT deficiency, homozygosity for either FVL or PTGM, or compound heterozygotes for FVL and PTGM require some degree of anticoagulation in pregnancy. ACOG recommends adjusted-dose anticoagulation in these patients.1 For patients who are incidentally found to be carriers of inherited thrombophilia such as heterozygotes for FVL or PTGM, treatment guidelines are based primarily on expert opinion. Many recommend low-dose prophylaxis in these patients who do not have a history of thrombosis but have a strong family history of idiopathic thrombosis or adverse pregnancy outcome. It is even less clear whether women who are incidental heterozygotes but lack personal, or family history of thrombosis or are without a history of adverse pregnancy outcome would benefit from anticoagulation. Consensus is also lacking regarding whether patients with a history of thrombosis who are afflicted with either protein C or protein S deficiency should receive low-dose or adjusted-dose anticoagulation in pregnancy.

Appropriate adjusted-dose anticoagulation regimens in pregnancy are described earlier. Low-dose prophylaxis can be achieved with UH in increasing doses each trimester (eg, 5000 U q12h in the first trimester, 7500 U q12h in the second trimester, and 10,000 U q12h in the third trimester). Similarly, LMWH is also appropriate, and as an example, enoxaparin 40 mg can be given q 12 hours. The recommendation to administer twice daily enoxaparin in pregnancy is based on pharmacologic data demonstrating that the pharmacokinetics of enoxaparin are significantly different during pregnancy than in the same cohort when nonpregnant, although outcome data are lacking at this point9 (Level II-3). A platelet count should be checked prior to initiating anticoagulation therapy and every week thereafter for an additional 3 weeks to observe for any evidence of HIT. While more common in patients receiving UH, LMWH may cross-react with the heparin/platelet factor IV antibodies and should not be used in women who have previously developed HIT. Consideration should also be given to additional calcium supplementation to women who are on either UH or LMWH during pregnancy.

Comprehension Questions

23.1 A 28-year-old G3P0030 presents at 7 weeks’ gestation. Her history is significant for a three prior miscarriages, ranging from 8 weeks’ to 11 weeks’ gestation. Which test is most indicated?
A. Lupus anticoagulant
B. Antithrombin-factor Xa assay
C. Protein S activity assay
D. Serum beta-hCG

23.2 A 30-year-old nulligravida recently suffered from a deep vein thrombosis and was diagnosed with homozygosity for the prothrombin gene G20210A mutation. What anticoagulation regimen would you recommend for her in pregnancy?
A. No anticoagulation
B. Warfarin
C. Low-dose LMWH
D. Adjusted-dose LMWH


23.1 A. Recurrent pregnancy loss is an indication for testing for antiphospholipid syndrome, an acquired thrombophilia.

23.2 D. Homozygosity for prothrombin gene G20210 mutation is considered to be in the high-risk category of inherited thrombophilias. With a personal history of thrombosis and a high-risk thrombophilia this patient should be treated with adjusted-dose LMWH.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1
➤ Women with a personal history (and possibly a strong family history) of thrombosis should be tested for inherited and acquired thrombophilias (Level II-3).
➤ Individuals with adverse pregnancy outcomes such as recurrent miscarriage, stillbirth, early/severe preeclampsia, and severe unexplained fetal growth restriction should be tested for acquired thrombophilias. Further discussion and consideration of implications is warranted regarding testing for heritable thrombophilias (Level III).
➤ Protein S free and total levels are normally decreased by 60% to 70% in normal pregnancy (Level II-2).
➤ Thrombophilias with more thrombogenic potential such as AT deficiency, homozygosity for FVL mutation or PTGM, or compound heterozygosity for FVL/PTGM require adjusted-dose anticoagulation (Level II-2).
➤ Platelet counts should be assessed prior to starting anticoagulation and serially for the next 3 weeks to ensure no evidence of HIT (Level III).

  • The extent of the association between inherited thrombophilias and early recurrent pregnancy loss, severe preeclampsia, and fetal growth restriction remains uncertain.
  • It is unknown whether low-dose or adjusted-dose anticoagulation should be administered to individuals with a history of thrombosis who are identified with protein C or protein S deficiency.
  • The effects of adjusted-dose anticoagulation on bone mineral density and its potential response to calcium supplementation are unknown.


1. Thromboembolism in Pregnancy. ACOG Practice Bulletin No. 19; 2000. 

2. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901. Meta-analysis of 31 prospective and retrospective observational studies, which found that FVL and PTGM were associated with a two-to threefold increase in both early recurrent pregnancy loss and late, nonrecurrent fetal loss. 

3. Roque H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost. 2004;91:290. This retrospective cohort study found that the presence of one or more thrombophilias decreased the risk of recurrent early pregnancy loss (< 10 wk) by approximately one-half. The authors comment on the biologic plausibility of this finding as low oxygen tension is normally present in early pregnancy. 

4. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992 Aug;80(2):283-285. 

5. Watson AL, Skepper JN, Jauniaux E, Burton GJ. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab. 1998 May;83(5):1697-1705. 

6. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348:913. These authors analyzed the frequencies of miscarriage, which they defined as loss at or before 28 weeks gestation, and stillbirth, which was loss after 28 weeks gestation. They found that the risk of fetal loss overall was about one-third greater in women with an inherited thrombophilia, although when subcategorized, the association was stronger between stillbirth and thrombophilia. 

7. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340:9. The authors performed a case-control analysis of 110 women who had an adverse pregnancy outcome such as severe preeclampsia, placental abruption, fetal growth restriction, and stillbirth and tested them for inherited thrombophilias in comparison to a control population. 

8. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med. 2002;347:19. This case-control study demonstrated that the risk of fetal growth restriction was not increased among women with a thrombophilia. 

9. Casele H, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol. 1999;181:1113. Subjects requiring prophylactic doses of enoxaparin sodium were tested in early pregnancy, in late pregnancy, and in the nonpregnant state for anti-factor Xa activity. These authors found that the area under the plasma activity versus time curve was significantly lower in pregnancy than in the postpartum state, suggesting that the pharmacokinetics of enoxaparin in pregnancy may reach more steady-states with twice-daily dosing.


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