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Abstract

The utility of thrombophilia testing in clinical practice is still a matter of debate because studies have not shown a benefit in the reduction of recurrent venous thromboembolism (VTE) risk in patients with thrombosis, despite the clearly higher VTE risk for first thrombosis. Screening for thrombophilia is indicated in selected patients. Particularly in selected young patients, especially women of childbearing age, the knowledge of the genetic thrombophilic defect may help in specific situations to decrease the risk of VTE events. Avoidance of modifiable risk factors and/or prophylactic thromboembolic procedures may be evaluated in selected patients. A comprehensive workup including personal and familial history, clinical examination, and laboratory test results including hereditary thrombophilia remains helpful in assessing the cumulative risk and the management of this group of selected patients.

Keywords

genetic thrombophilia thrombophilia screening venous thromboembolism

Introduction

Thrombophilia is an imbalance in hemostasis with an increased tendency to form intravascular pathologic venous or arterial thrombus. Predisposing factors for venous thrombosis are inherited or acquired, and venous thromboembolism (VTE) is considered a multifactorial disease.¹ The so-called Virchow triad describes the factors contributing to VTE, including endothelial injury or activation, reduced blood flow, and hypercoagulability of the blood. The latter is often present on the basis of an inherited genetic predisposition. On the other hand, a genetic predisposition is not like illness. Not all patients with such mutations of coagulation factors will develop VTE throughout life. Therefore, diagnosing a prothrombotic state in clinical practice is difficult and it is usually done only after a VTE. In addition, screening for inherited thrombophilic conditions in clinical practice is still a matter of debate because studies have not shown a benefit in the reduction of recurrent VTE risk in patients with thrombosis, despite the clearly higher VTE risk for first thrombosis.

Although evidence suggests in specific situations against screening tests, patients may be anxious and unwilling to skip the thrombophilia screening. In the situation where the patient is willing to know the risk for—or the cause of—VTE, the physician may have difficulty to reconcile 2 different opinions. We believe that guidelines for thrombophilia screening are helpful for clinical decisions and may help to reduce tests that are not indicated. In this review, we discuss indications for screening in selected patients with VTE based on consensus guidelines and personal experience.

Inherited Thrombophilia

Inherited thrombophilia is a genetic predisposing condition to VTE. The clinical manifestations of inherited thrombophilia are heterogeneous concerning severity and type of events. Manifestations consist of superficial thrombophlebitis, VTE on classical (deep venous thrombosis of the legs, pulmonary embolism) or atypical localizations (splanchnic, hepatic, upper limbs, cerebral venous thrombosis), and complications of pregnancy or puerperium.

In the past 50 years, our knowledge on the etiology of VTE has improved, starting in 1965 with the first description of inherited thrombophilia caused by antithrombin deficiency.² The deficiency of this naturally occurring anticoagulant protein was for many years the only identified cause of inherited thrombophilia. Over time the description of protein C deficiency,³ protein S deficiency,⁴ activated protein C resistance associated with a point mutation in the factor V gene,⁵ and prothrombin gene mutation⁶ improved our knowledge of the pathogenesis of VTE. Following the discovery of these proteins, the possibility to identify an inherited cause in patients with VTE increased (Table 1).⁷ For example, it was reported recently that missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance-related thrombophilia.⁸ Other genetic risk factors for VTE are dysfibrinogenemia (FGG, fibrinogen γ′),¹¹ F11 gene,⁹ and non-O blood group.^12
–14 The initial observation that an elevated factor VIII level is a risk factor for venous thrombosis¹⁵ is now supported by robust evidence. Over the past years, research to identify genetic variants associated with VTE focused on hundreds of single-nucleotide polymorphisms.¹⁶ Recently, a genome-wide association study approach led to the identification of 2 VTE-associated loci, TSPAN15 and SLC44A2. The odds ratio for VTE are 1.31 for TSPAN15 and 1.21 for SLC44A2.¹⁰

Table 1.

Causes of Inherited Thrombophilia.^7–10

Frequent or well established

Antithrombin deficiency

Antithrombin resistance

Protein C deficiency

Protein S deficiency

Factor V Leiden heterozygous/homozygous

Factor II G20210A heterozygous/homozygous

Elevated factor VIII level

Dysfibrinogenemia

Non-O blood group

Hyperhomocysteinemia

Other susceptibility loci for VTE: TSPAN15, SLC44A2

Abbreviation: VTE, venous thromboembolism.

Inherited thrombophilia affects the risk of a first thrombosis lifelong. However, the first episode of VTE occurs frequently at a young age (before 40 years) without apparent causes. Gradually, clinical studies elucidated the role of inherited thrombophilia in first and recurrent VTE. Over time it became evident that these inherited risk factors impact differently the relative risk for the first^{17

–24} and recurrent VTE (Table 2).^{25

–35}

Table 2.

Main Thrombophilic Defects: Relative Risk of First and Recurrent VTE.

Thrombophilia	General Population	First VTE	Recurrent VTE
Thrombophilia	Prevalence (%)	Relative Risk	Relative Risk
Antithrombin deficiency	0.02-0.2	5-8	0.5
Protein C deficiency	0.2-0.4	5-8	2.5
Protein S deficiency	<0.5	1.7-8	2.5
Factor V Leiden heterozygous	3-7	4.9-9.7	1.3
Factor V Leiden homozygous	0.02	40-80	–
Prothrombin G20210A	1-3	1.9-3.8	1.4
Factor V Leiden + prothrombin G20210A	0.01	20-50	2.5

Abbreviation: VTE, venous thromboembolism.

Note: Relative Risk first VTE, References: Antithrombin deficiency^17,22, Protein C deficiency^17,18,22, Protein S deficiency^17,22, Factor V Leiden heterozygous^21,36, Factor V Leiden homozygous¹⁹, Prothrombin G20201A²¹, Factor V Leiden + Prothrombin G20210A²¹. Relative Risk recurrent VTE, References: Antithrombin deficiency^26,34, Protein C deficiency³⁴, Protein S deficiency³⁴, Factor V Leiden heterozygous^25,28, Prothrombin G20201A²⁷, Factor V Leiden + Prothrombin G20210A^31,33.

Acquired Thrombophilia

Clinical evidence supported the hypothesis that VTE is due to interactions of inherited and/or acquired thrombophilic traits (Table 3).^1,37
–39 The thrombotic event is the final clinical sign of interactions of single or multiple genetic and/or acquired predisposing factors such as age, elevated body mass index (BMI), immobility, trauma, use of oral contraceptives or hormone replacement therapy, and pregnancy–puerperium. Evidence concerning the role of other risk factors or diseases in VTE is growing (Table 3). Contribution of these modifiable factors on VTE is variable during different age segments and depends on acquired risk factors, which can overcome a threshold resulting in VTE.

Table 3.

Causes of Acquired Thrombophilia.

Age >65 years	Inflammatory states
BMI >30 kg/m²	Malignancy
Immobilization—flight >6 hours	Extended varicosis
Trauma	Post thrombotic syndrome
Surgery	Myeloproliferative neoplasm
Pregnancy–puerperium	Essential thrombocythemia
Medication	Polycythemia vera
Synthetic estrogens	Nephrotic syndrome
Chemotherapy	PNH
Antiphospholipid antibodies	Depression
Lupus anticoagulant	Smoking
Severe infection

Abbreviations: BMI, body mass index; PNH, Paroxysmal nocturnal hemoglobinuria.

Note: References: Age, BMI, Immobilization, Medication, Antiphospholipid antibodies, Lupus anticoagulant, severe infection, smoking¹; Trauma, surgery, pregnancy-puerperium^37,39; Inflammatory states, malignancy³⁷; Extended varicosis, post thrombotic syndrome, myeloproliferative neoplasm, nephrotic syndrome, PNH³⁹; Depression³⁸.

Universal or Selected Thrombophilia Screening?

Idiopathic VTE is a diagnosis of exclusion by ruling out known causes. In young patients, diagnosis of idiopathic VTE should be done or ruled out because it has important consequences concerning the duration of therapy. Therefore, we suggest thrombophilia screening in selected patients with VTE, selective family member, and against an universal screening. To argue against thrombophilia screening in any case is contrary to medical knowledge and to helpfulness to the patients. Thrombophilia screening should be a comprehensive evaluation of patient’s prothrombotic state. A merely laboratory analysis without careful consideration of personal and familial anamnesis, past clinical history, acquired risk factors for VTE, associated diseases, prognosis, and therapy’s adverse effects does not reflect the screening sense. Accordingly, testing all women at random before prescribing estrogen medications (oral contraceptives or hormone substitution) is not indicated.⁴⁰

Patients With First Symptomatic Venous Thrombosis

Because the prevalence of thrombophilic defects in the general population is low (Table 2), testing for heritable thrombophilia in unselected patients with a first episode of VTE is normally not indicated.^41,42 In line with the model of multifactorial nature of VTE, according to which the thrombotic event is the sum of multiple gene–gene and gene–environment interactions, inherited thrombophilia interacts with other established acquired predisposing factors for VTE (Table 3).^43,44 Recognition of gene–gene and/or gene–environmental interactions may be important in selected patients for therapeutic decisions and for prevention of VTE in patients and family member. The most common inherited thrombophilic defects (deficiency of antithrombin, protein C, protein S, activated protein C (APC) resistance due to factor V Leiden mutation, and prothrombin G20210A mutation) and hyperhomocysteinemia are diagnosed in about 50% of patients with VTE. Non-O blood group is the commonest mild genetic risk factor for VTE and is associated with an approximately 2-fold increase in VTE risk.^12
–14 Not all patients with an inherited thrombophilia develop a VTE, but the risk becomes particularly high in the presence of additional acquired risk factors. In this setting, the risk of VTE may increase in a multiplicative way.

Pregnancy- and Puerperium-Associated VTE

The physiological changes in hemostasis and the physical changes in women during pregnancy are responsible for a prothrombotic state and an increase in blood stasis. These result in an increased risk of VTE during pregnancy. The antenatal VTE risk in pregnant women is at least 4-fold higher (5-10 fold) compared to age-matched nonpregnant women. The antenatal VTE risk is further increased in cases of BMI ≥30 kg/m², age >35 years, multiple births, and varicose veins. The postpartum VTE risk is 2- to 5-fold higher compared to antenatal and up to 20-fold (15-35 fold) compared to age-matched nonpregnant women. The risk is high for 6 weeks postpartum and returns to baseline at 12 to 18 weeks postpartum. The postpartum VTE risk is further increased in cases of BMI ≥25 kg/m², cesarean delivery, obstetrical hemorrhage, and preterm delivery (<36 gestational weeks).^45

–49 The rate of VTE complicating pregnancy and puerperium among women with antithrombin, protein C, and protein S deficiency is 37.8%, 14.7%, and 17.1%, respectively.⁵⁰ The risk of VTE during pregnancy and puerperium increases 8-fold in women with a deficiency of natural coagulation inhibitors. The risk is particularly high in cases with positive family history (Table 4).

Table 4.

Relative Risk of First and Recurrent VTE in Pregnancy on the Background of Genetic Thrombophilia.

Thrombophilia	VTE Risk Per Pregnancy, No History of VTE (%)^45,46	VTE Risk Per Pregnancy, With Previous VTE (%)^47,49,51,52
Antithrombin deficiency	3-7	40
Protein C deficiency	0.1-0.8	4-17
Protein S deficiency	0.1	0-22
Factor V Leiden heterozygous	0.5-1.2	10
Factor V Leiden homozygous	4	17
Prothrombin G20210A heterozygous	<0.5	>10
Prothrombin G20210A homozygous	2-4	>17
Factor V Leiden + prothrombin G20210A	4-5	>20

Abbreviation: VTE, venous thromboembolism.

Inherited Thrombophilia and Risk of Obstetric Complications

Complications other than thrombosis in the presence of inherited thrombophilia are pregnancy-induced hypertension, preeclampsia (increased risk of 11-fold in protein S–deficient women), fetal loss (overall risk of stillbirth and miscarriage increased 3.6- and 1.3-fold, respectively), fetal growth retardation (risk increased 5- to 6-fold in prothrombin G20210A mutation and 7-fold in factor V Leiden mutation), and abruptio placentae.^{51

–58} Recent prospective cohort studies showed that carriers of factor V Leiden or prothrombin gene mutations are not at significantly increased risk of placenta-mediated pregnancy complications (ie, pregnancy loss, preeclampsia, and/or placental abruption).^59,60 Then the risk of obstetric complications in women with inherited thrombophilia is further influenced by personal characteristics, personal and familial history, circumstantial risk factors, and type of genetic defect. A comprehensive assessment is indicated to estimate the risk of first or recurrent VTE or other complications in pregnancy. With this prerequisite, it appears important to know the thrombophilic defect in women with a previous VTE or a positive familial history.

Thrombophilia Testing in Selected Patients

Thrombophilia screening should be avoided in the acute phase after the thromboembolic event. It should be performed 1 month after the end of the anticoagulation therapy or otherwise 3 months after the VTE, under consideration of the current therapy and the possible interference with the laboratory test results.

Testing selected patients may help to predict the risk of recurrence following completion of anticoagulation therapy, for example, in young patients (<50 years), in member of thrombosis-prone families, and pregnant women. Although no controlled clinical trials have assessed the benefits of testing for thrombophilia on the risk of recurrent VTE,⁶¹ in pregnant women the risk is particularly high (Table 4) and information about the thrombophilic factors may be of clinical utility. Thrombophilia screening for women with pregnancy complication is controversial and The American College of Obstetricians and Gynecologists Women’s health-care physicians recommend against routine thrombophilia testing for such women.⁶² Because a causal link between inherited thrombophilia and adverse pregnancy outcome has not been established,^59,60 thrombophilia screening should not be routinely performed for such women; otherwise thrombophilia screening can help women with multiple inexplicable pregnancy losses. For example, in case of 3 or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, we would recommend to perform a thrombophilia screening, among others for exclusion of the antiphospholipid syndrome. Patients with a recognized and transient clinical risk factor such as surgery (Table 3) with a first VTE have a low risk of recurrence.

A comprehensive workup including personal and family history and clinical examination is indicated in all patients with VTE. Laboratory test results including hereditary thrombophilia remain helpful in the management of selected patients (Table 5). Because testing for thrombophilia is advantageous if it influences the management of affected patients, we suggest screening in primary young women with VTE during pregnancy, puerperium, oral contraceptives use, hormone replacement therapy, or women with multiple unexplained pregnancy losses. Other indications for thrombophilia screening are thrombosis before 50 years without apparent cause, venous thrombosis in unusual sites, first VTE and a strong family history of VTE.^50,63,64 Identification of asymptomatic family members with hereditary thrombophilia is useful in order to prevent VTE or other complications, especially in young women of childbearing age. These patients may benefit from avoidance of modifiable acquired risk factors (ie, oral contraceptives) and from specific VTE prophylaxis in high-risk situations (ie, pregnancy, puerperium, immobility, trauma, surgery).⁶⁵ Testing asymptomatic women randomly before prescribing estrogen medications (oral contraceptives or hormone substitution) is not indicated.⁴⁰ Women with a previous VTE and/or positive familial history, though, should be tested. Another indication for venous thrombophilic screening is an arterial ischemia in young patients with right-to-left shunt, such as atrial or ventricular septal defect or arteriovenous malformation (paradoxical embolism).

Table 5.

Proposed Indications for Venous Thrombophilia Screening.

Age <50 years

Women with VTE during pregnancy or puerperium

Women with VTE during use of oral contraceptive or hormonal replacement

Women with VTE before prescribing hormonal replacement

Women with multiple inexplicable pregnancy losses

Young women with a positive family history, before prescribing oral contraceptive

VTE in unusual sites

First VTE and a positive family history for VTE

Young patients with arterial ischemia and right-to-left shunt (paradoxical embolism)

Abbreviation: VTE, venous thromboembolism.

Although diagnosis of genetic thrombophilia is not a criterion anymore to choose the mode and intensity or the length of anticoagulation after a thromboembolic event, knowing whether thrombophilia is present might be useful in assessing the cumulative risk for thrombosis in selected patients. The recent American College of Chest Physicians consensus guidelines 2016 for the treatment of thrombosis stress even more the issue of the personalized risk assessment to determine the length of anticoagulation.⁶⁶ There is still no conclusive evidence that thrombophilia testing can prevent thrombotic events in previously unaffected persons. In a cohort study on the prevalence of thrombosis in family members of patients with VTE, only provoked thrombotic events showed a trend for lower prevalence after testing and knowing that thrombophilia is present. In this study, unprovoked thrombosis could not be prevented in the intervention arm.⁶⁷ In parallel, various predictive scores for the thrombotic risk have been published, which can be used to assess the clinical risk. These scores do not use genetic thrombophilia as a risk element, but they also have not been prospectively validated in the clinical setting yet.^68,69

Conclusion

In conclusion, our knowledge of VTE etiology has improved over time. Thrombophilia screening is indicated in selected young patients, especially women of childbearing age. The knowledge of the genetic thrombophilic background may help in specific situations to avoid modifiable risk factors and/or introduce prophylactic thromboembolic procedures to decrease the cumulative risk of VTE events. A comprehensive workup including personal and familial history, clinical examination, and laboratory test results including hereditary thrombophilia remains helpful in the management of selected patients. Various national guidelines have discussed indications for thrombophilia testing^70,71; a practical one representing the above-mentioned present views is given by the French consensus guideline with Swiss participation.⁷²

Footnotes

Authors’ Note

All authors have substantially contributed to the conception and design of the article, interpretation of data, drafting of the article, and approved the final version to be published.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Rosendaal

. Venous thrombosis: a multicausal disease. Lancet (London, England). 1999;353(9159):1167–1173.

Egeberg

. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516–530.

Griffin

Evatt

Zimmerman

Kleiss

Wideman

. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981;68(5):1370–1373.

Comp

Esmon

. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med. 1984;311(24):1525–1528.

Bertina

Koeleman

Koster

. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–67.

Poort

Rosendaal

Reitsma

Bertina

. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88(10):3698–3703.

Rosendaal

Reitsma

. Genetics of venous thrombosis. J Thromb Haemost. 2009;7(suppl 1):301–304.

Takagi

Murata

Kozuka

. Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance. Thromb Haemost. 2016;116(6):1022–1031.

Morange

Tregouet

. Current knowledge on the genetics of incident venous thrombosis. J Thromb Haemost. 2013;11(suppl 1):111–121.

10.

Germain

Chasman

de Haan

. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet. 2015;96(4):532–542.

11.

Uitte de Willige

de Visser

MCH

Houwing-Duistermaat

Rosendaal

Vos

Bertina

. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels. Blood. 2005;106(13):4176–4183.

12.

Tirado

Mateo

Soria

. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost. 2005;93(3):468–474.

13.

Dentali

Sironi

Ageno

. Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature. Semin Thromb Hemost. 2012;38(5):535–548.

14.

Procare-GEHT Group. ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the factor V Leiden mutation. Br J Haematol. 2006;135(5):697–702.

15.

Jenkins

Rawley

Smith

O’Donnell

. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157(6):653–663.

16.

Margaglione

Grandone

. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost. 2011;105(2):221–231.

17.

Pabinger

Schneider

. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thrombose-und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol. 1996;16(6):742–748.

18.

Koster

Rosendaal

Briet

. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995;85(10):2756–2761.

19.

Rosendaal

Koster

Vandenbroucke

Reitsma

. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508.

20.

Heit

Sobell

Sommer

. The incidence of venous thromboembolism among factor V Leiden carriers: a community-based cohort study. J Thromb Haemost. 2005;3(2):305–311.

21.

Martinelli

Bucciarelli

Margaglione

De Stefano

Castaman

Mannucci

. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol. 2000;111(4):1223–1229.

22.

Vossen

Conard

Fontcuberta

. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost. 2005;3(3):459–464.

23.

Middeldorp

Henkens

Koopman

. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med. 1998;128(1):15–20.

24.

Simioni

Sanson

Prandoni

. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999;81(2):198–202.

25.

Rintelen

Pabinger

Knobl

Lechner

Mannhalter

. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost. 1996;75(2):229–232.

26.

van den Belt

Sanson

Simioni

. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997;157(19):2227–2232.

27.

De Stefano

Martinelli

Mannucci

. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. Br J Haematol. 2001;113(3):630–635.

28.

Eichinger

Weltermann

Mannhalter

. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med. 2002;162(20):2357–2360.

29.

Procare Group. Is recurrent venous thromboembolism more frequent in homozygous patients for the factor V Leiden mutation than in heterozygous patients? Blood Coagul Fibrinolysis. 2003;14(6):523–529.

30.

Baglin

Luddington

Brown

Baglin

. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet (London, England). 2003;362(9383):523–526.

31.

Kyrle

Minar

Bialonczyk

Hirschl

Weltermann

Eichinger

. The risk of recurrent venous thromboembolism in men and women. N Engl J Med. 2004;350(25):2558–2563.

32.

Baglin

Luddington

Brown

Baglin

. High risk of recurrent venous thromboembolism in men. J Thromb Haemost. 2004;2(12):2152–2155.

33.

Mansilha

Araujo

Severo

Sampaio

Toledo

Albuquerque

. Genetic polymorphisms and risk of recurrent deep venous thrombosis in young people: prospective cohort study. Eur J Vasc Endovasc Surg. 2005;30(5):545–549.

34.

De Stefano

Simioni

Rossi

. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006;91(5):695–698.

35.

Sanson

Simioni

Tormene

. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study. Blood. 1999;94(11):3702–3706.

36.

Bertina

Koeleman

Koster

. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. Blood. 1995;85(6):1504–1508.

37.

Martinelli

Bucciarelli

Mannucci

. Thrombotic risk factors: basic pathophysiology. Crit Care Med. 2010;38(2 suppl):S3–S9.

38.

von Kanel

Margani

Stauber

. Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation. PLoS One. 2015;10(5):e0125858.

39.

Martinelli

De Stefano

Mannucci

. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol. 2014;11(3):140–156.

40.

Creinin

Lisman

Strickler

. Screening for factor V Leiden mutation before prescribing combination oral contraceptives. Fertil Steril. 1999;72(4):646–651.

41.

Robertson

Twaddle

; Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol. 2005;131(1):80–90.

42.

Robertson

Twaddle

. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Health Technol Assess. 2006;10(11):1–110.

43.

Varga

Kujovich

. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012;81(1):7–17.

44.

Christiansen

Cannegieter

Koster

Vandenbroucke

Rosendaal

. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293(19):2352–2361.

45.

Greer

. Thrombosis in pregnancy: maternal and fetal issues. Lancet (London, England). 1999;353(9160):1258–1265.

46.

Marik

Plante

. Venous thromboembolic disease and pregnancy. N Engl J Med. 2008;359(19):2025–2033.

47.

Pomp

Lenselink

Rosendaal

Doggen

CJM

. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6(4):632–637.

48.

Sultan

Tata

West

. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood. 2013;121(19):3953–3961.

49.

De Stefano

Martinelli

Rossi

. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol. 2006;135(3):386–391.

50.

De Stefano

Rossi

Paciaroni

Leone

. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica. 2002;87(10):1095–1108.

51.

Rey

Kahn

David

Shrier

. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet (London, England). 2003;361(9361):901–908.

52.

Heit

Kobbervig

James

Petterson

Bailey

Melton

III . Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143(10):697–706.

53.

Opatrny

David

Kahn

Shrier

Rey

. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33(11):2214–2221.

54.

Boekholdt

Kramer

MHH

. Arterial thrombosis and the role of thrombophilia. Semin Thromb Hemost. 2007;33(6):588–596.

55.

Robertson

Langhorne

. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132(2):171–196.

56.

Middeldorp

. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost. 2007;5(suppl 1):276–282.

57.

Middeldorp

. Pregnancy failure and heritable thrombophilia. Semin Hematol. 2007;44(2):93–97.

58.

Rodger

Paidas

McLintock

. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112(2 pt 1):320–324.

59.

Rodger

Walker

Smith

. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost. 2014;12(4):469–478.

60.

Rodger

Betancourt

Clark

. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010;7(6):e1000292.

61.

Cohn

Vansenne

de Borgie

Middeldorp

. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane database Syst Rev. 2012;12:CD007069.

62.

American College of Obstetricians and Gynecologists Women’s Health Care Physicians. ACOG practice bulletin no. 138: inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122(3):706–717.

63.

Lindhoff-Last

Luxembourg

. Evidence-based indications for thrombophilia screening. Vasa. 2008;37(1):19–30.

64.

Lijfering

Brouwer

JLP

Veeger

NJGM

. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009;113(21):5314–5322.

65.

Guimicheva

Czuprynska

Arya

. The prevention of pregnancy-related venous thromboembolism. Br J Haematol. 2015;168(2):163–174.

66.

Kearon

Akl

Ornelas

. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315–352.

67.

Mahmoodi

Brouwer

JLP

Ten Kate

. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost. 2010;8(6):1193–1200.

68.

Prandoni

Barbar

Milan

Vedovetto

Pesavento

. The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities. Eur J Intern Med. 2014;25(1):25–30.

69.

Prandoni

Barbar

Milan

. Optimal duration of anticoagulation. Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests. Thromb Haemost. 2015;113(6):1210–1215.

70.

De Stefano

Rossi

. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost. 2013;110(4):697–705.

71.

Foy

Moll

. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. 2009;11(2):114–28.

72.

Pernod

Biron-Andreani

Morange

; French group on haemostasis and thrombosis; French Society of vascular medicine. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline [in English, French]. J Mal Vasc. 2009;34(3):156–203.

Thrombophilia Screening: Universal,Selected,or Neither?

Abstract

Keywords

Introduction

Inherited Thrombophilia

Acquired Thrombophilia

Universal or Selected Thrombophilia Screening?

Patients With First Symptomatic Venous Thrombosis

Pregnancy- and Puerperium-Associated VTE

Inherited Thrombophilia and Risk of Obstetric Complications

Thrombophilia Testing in Selected Patients

Conclusion

Footnotes

Authors’ Note

Declaration of Conflicting Interests

Funding

References