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2228 Part XII: Hemostasis and Thrombosis Chapter 130: Hereditary Thrombophilia 2229

risk of bleeding. Whether such a strategy is beneficial for patients with the clinician should be cautious to not provide false reassurance in case
hereditary thrombophilia has never been tested, but is very unlikely of a negative test result. Observational studies show that patients who
given the very modest risk increases associated with hereditary throm- have had VTE and have thrombophilia are at most at a slightly increased
bophilia. Therefore, testing in this setting is not justified. risk for reoccurrence. Other determinants, including circumstances
during the first VTE, elevated D-dimer levels, and male sex, are better
70
THROMBOPHILIA TESTING IN WOMEN WITH predictors of recurrent VTE. Furthermore, no beneficial effect on the
risk of recurrent VTE was observed in patients who had been tested for
PREGNANCY COMPLICATIONS inherited thrombophilia. In the absence of trials that compared routine
Thrombophilia testing in women with pregnancy complications would and prolonged anticoagulant treatment in patients testing positive for
be indicated if a test result would alter management. However, to date, thrombophilia, testing for such defects to prolong anticoagulant therapy
testing for hereditary thrombophilia in this setting cannot be justi- cannot be justified. Finally, there is at present no reason to test patients
fied 10,102 for the following reasons. For women at moderate to high risk with arterial cardiovascular disease, or women with recurrent miscar-
of preeclampsia, ASA provides a modest benefit in reducing the risk of riage or late pregnancy complications for hereditary thrombophilia, in
preeclampsia, but this is regardless of the presence of hereditary throm- the absence of evidence-based guidelines for changes in management.
bophilia. 102,108 Whether anticoagulant treatment with heparin or LMWH
improves the chance of a successful pregnancy outcome in women with
pregnancy complications is presently unknown as results from random- REFERENCES
ized clinical trials are extremely inconsistent. 109–113 It is also uncertain 1. Nygaard KK, Brown GE: Essential thrombophilia: Report of five cases. Arch Intern Med
whether presence of hereditary thrombophilia is a prerequisite for an 59:82, 1937.
assumed beneficial effect, if any. Only three randomized controlled tri- 2. Jordan FLJ, Nandorff A: The familial tendency in thrombo-embolic disease. Acta Med
Scand 156:267, 1956.
als have been exclusively dedicated to women with hereditary throm- 3. Rosendaal FR: Venous thrombosis: A multicausal disease. Lancet 353:1167, 1999.
bophilia and recurrent miscarriage, a single fetal loss, or late pregnancy 4. Ye Z, Liu EH, Higgins JR, et al: Seven haemostatic gene polymorphisms in coronary
complications. The first trial found promising results in women with disease: Meta-analysis of 66,155 cases and 91,307 controls. Lancet 367:651, 2006.
heterozygous factor V Leiden mutation, prothrombin G20210A muta- 5. Boekholdt SM, Bijsterveld NR, Moons AH, et al: Genetic variation in coagulation and
fibrinolytic proteins and their relation with acute myocardial infarction: A systematic
tion, or protein S deficiency and a single previous pregnancy loss review. Circulation 104:3063, 2001.
114
after 10 weeks gestation. Women who were allocated to enoxaparin 6. Lin J, August P: Genetic thrombophilias and preeclampsia: A meta-analysis. Obstet
had a much higher chance of a livebirth than those allocated to ASA Gynecol 105:182, 2005.
(86 percent and 29 percent, respectively; OR 15.5; 95% CI 7 to 34), 7. Rey E, Kahn SR, David M, Shrier I: Thrombophilic disorders and fetal loss: A meta-anal-
ysis. Lancet 361:901, 2003.
but several methodologic issues were raised, and the results of this 8. Rodger MA, Walker MC, Smith GN, et al: Is thrombophilia associated with placenta-
single study have not been confirmed by other trials. 102,115 Second, in mediated pregnancy complications? A prospective cohort study. J Thromb Haemost
12:469, 2014.
the FRUIT trial, women with hereditary thrombophilia and a history 9. Coppens M, van Mourik JA, Eckmann CM, et al: Current practice of testing for hered-
of preeclampsia or intrauterine growth restriction requiring delivery itary thrombophilia in The Netherlands. J Thromb Haemost 5:1979, 2007.
before 34 weeks of gestation, were randomized between dalteparin with 10. Baglin T, Gray E, Greaves M, et al: Clinical guidelines for testing for heritable throm-
ASA and ASA alone. The primary outcome (recurrence of a hyper- bophilia. Br J Haematol 149:209, 2010.
116
tensive disorder, e.g., preeclampsia, HELLP, or eclampsia) did not differ 11. Middeldorp S, van Hylckama Vlieg A: Does thrombophilia testing help in the clinical
management of patients? Br J Haematol 143:321, 2008.
between the two groups, but none of the women in the LMWH/ASA 12. Bezemer ID, Bare LA, Doggen CJ, et al: Gene variants associated with deep vein throm-
group developed recurrent hypertensive disorders prior to 34 weeks ges- bosis. JAMA 299:1306, 2008.
tational age, whereas six women in the ASA-only group delivered before 13. Gohil R, Peck G, Sharma P: The genetics of venous thromboembolism. A meta-analysis
involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 102:360,
34 weeks because of recurrent hypertensive disorders (risk difference 2009.
8.7 percent; 95% CI 1.9 to 15.5 percent). Finally, the TIPPS study 14. Lotta LA, Wang M, Yu J, et al: Identification of genetic risk variants for deep vein
included thrombophilic women at high risk for pregnancy complications thrombosis by multiplexed next-generation sequencing of 186 hemostatic/pro-inflam-
matory genes. BMC Med Genomics 5:7, 2012.
or at increased risk of VTE and randomized them between dalteparin 15. Egeberg O: Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath
113
and no dalteparin. The primary composite outcome (severe or early Haemorrh 13:516, 1965.
onset preeclampsia, small-for-gestational-age infant, pregnancy loss, 16. Comp PC, Esmon CT: Recurrent venous thromboembolism in patients with a partial
deficiency of protein S. N Engl J Med 311:1525, 1984.
or VTE) did not differ between the groups. Hence, to date, there is no 17. Griffin JH, Evatt B, Zimmerman TS, et al: Deficiency of protein C in congenital throm-
evidence from sufficiently powered and adequately designed clinical botic disease. J Clin Invest 68:1370, 1981.
trials that justify use of heparin to improve pregnancy outcome in 18. Gandrille S, Borgel D, Sala N, et al: Protein S deficiency: A database of mutations—
Summary of the first update. Thromb Haemost 84:918, 2000.
women with hereditary thrombophilia, and heparin should only be 19. Lane DA, Bayston T, Olds RJ, et al: Antithrombin mutation database: 2nd (1997)
given in the context of a clinical trial. 117 update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and
Standardization Committee of the International Society on Thrombosis and Haemo-
stasis. Thromb Haemost 77:197, 1997.
CONCLUSIONS 20. Reitsma PH, Bernardi F, Doig RG, et al: Protein C deficiency: A database of mutations,
1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the
The knowledge about the hereditary contribution to the etiology of Scientific and Standardization Committee of the ISTH. Thromb Haemost 73:876, 1995.
VTE has increased tremendously over the past decades. Still, testing for 21. Dahlbäck B, Carlsson M, Svensson PJ: Familial thrombophilia due to a previously
unrecognized mechanism characterized by poor anticoagulant response to activated
thrombophilia serves only a limited purpose and should not be per- protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A
formed on a routine basis. Thrombophilia testing in asymptomatic rela- 90:1004, 1993.
tives may be useful in families with antithrombin, protein C, or protein 22. Bertina RM, Koeleman BP, Koster T, et al: Mutation in blood coagulation factor V asso-
ciated with resistance to activated protein C. Nature 369:64, 1994.
S deficiency, or for siblings of patients who are homozygous for factor 23. Greengard JS, Sun X, Xu X, et al: Activated protein C resistance caused by Arg506Gln
V Leiden, and is limited to women who intend to become pregnant mutation in factor Va. Lancet 343:1361, 1994.
or who would like to use oral contraceptives. Careful counseling with 24. Voorberg J, Roelse J, Koopman R, et al: Association of idiopathic venous thromboem-
bolism with single point-mutation at Arg506 of factor V. Lancet 343:1535, 1994.
knowledge of absolute risks helps patients make an informed decision 25. Zoller B, Dahlback B: Linkage between inherited resistance to activated protein C and
in which their own preferences can be taken into account, and in which factor V gene mutation in venous thrombosis. Lancet 343:1536, 1994.

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