Thrombophilia Testing in Women and Adolescent Girls—Position Paper from the Standing Committee on Women’s Health Issues of the Society for Thrombosis and Haemostasis Research (GTH)

Abstract

Hereditary and acquired thrombophilia increase the risk of first-time and recurrent venous thromboembolism (VTE). In unselected VTE cohorts, thrombophilic disorders are detected in approximately 40–50% of cases. The probability of a positive test result is higher in patients with a positive family history and VTE manifestation at a young age. The diagnosis of thrombophilia does not necessarily have consequences for further treatment. On the other hand, there are several aspects specific to women where knowledge of thrombophilia influences treatment decisions. The aim of this paper is to describe the various situations specific to women, to present current evidence, and to make recommendations regarding the usefulness and scope of thrombophilia screening. To this end, a panel of 18 experts was assembled within the Standing Committee on Women’s Health Issues of the Society for Thrombosis and Haemostasis Research (GTH), which developed recommendations as part of a Delphi process.

Keywords

Antiphospholipid syndrome - Hereditary thrombophilia - Hormonal contraception - Pregnancy - Venous thromboembolism

Introduction

Selecting patients for evaluation for hypercoagulable disorders has been the subject of controversial debate for years. Testing for thrombophilia after a venous thromboembolic (VTE) event can have various objectives, such as clarifying potential causes that contributed to the occurrence of VTE, determining the acute treatment strategy, estimating the risk of recurrent VTE events, and, based on this, determining the optimal strategy for preventing further VTE events.

Although hereditary and acquired thrombophilia increase the risk of first-time and recurrent VTE,[1] [2] the detection of thrombophilia does not necessarily result in consequences for the further management in individual cases. The majority of healthy individuals with thrombophilia do not develop deep vein thrombosis (DVT) or pulmonary embolism (PE) during their lifetime, and in those who suffer a VTE, thrombophilia is often not the only factor explaining the occurrence of VTE. In the majority of cases, multifactorial thrombogenesis must be assumed, in which predisposing genetic and comorbidity-related risk factors and situational trigger factors coincide. In these cases, it is difficult to determine the extent to which a single risk factor influences the manifestation of VTE in the individual case and how this risk factor must be taken into account when assessing the risk of VTE recurrence.

In unselected VTE cohorts, thrombophilic disorders are detected in approximately 40–50% of cases. The probability of detecting thrombophilia is higher after an unprovoked VTE than after a VTE associated with a strong triggering factor.[3] [4] The probability is highest in cases with a positive family history and VTE manifestation at a young age and decreases with increasing age. However, in over 70-year-olds, thrombophilia can still be detected in approximately 20% of patients with VTE.[5]

Several aspects of thromboembolic disease and VTE risk assessment specifically affect women. The use of combined hormonal contraceptives (CHCs) and pregnancy increase the risk of DVT and PE in women of childbearing age, whereas menopausal hormone therapy (MHT) is associated with an increased risk of VTE later in life.[6] [7] [8] [9] Ovarian stimulation as part of fertility treatment also increases the risk of VTE. In general, the risk of VTE per in vitro fertilization cycle is low (≈0.1 to 0.4%) but increases substantially in women who develop severe ovarian hyperstimulation syndrome (≈2 to 4%).[10] [11] [12] [13] An inherited or acquired thrombophilia, advanced age, obesity, and smoking are common additional VTE risk factors in this context. In addition, physicians are often consulted by women seeking advice on VTE risk assessment and VTE prevention measures when hormone treatment is being considered or pregnancy is being planned, especially if there is a personal or family history of VTE.

The aim of this work by the Standing Committee on Women’s Health Issues of the Society for Thrombosis and Haemostasis Research (GTH) is to summarize the scientific evidence for the various risk situations specific to women and, based on the data available, to make recommendations as to whether and to what extent thrombophilia screening is useful. Since data from randomized controlled trials (RCTs) on the various risk situations are scarce, the following recommendations are based on an expert consensus reached through a Delphi process within our Standing Committee. Our position paper focuses on women with a history of VTE and those without VTE who are at increased risk due to thrombophilia or a positive family history. We refer to a positive family history if at least one first-degree relative (i.e., parents, siblings, or children) is affected by thrombophilia or VTE. Some thrombophilias are also associated with the occurrence of arterial thrombosis (e.g., ischemic stroke), but this is not the subject of this article.

Methods

A Delphi process was initiated to gather expert opinions through a structured survey and to reach a consensus on previously formulated questions. Within the GTH Standing Committee on Women’s Health Issues, an expert panel was composed and comprised 18 experts from various disciplines (i.e., hemostaseology, angiology, hematology, oncology, internal medicine, pediatrics, and transfusion medicine). Based on a comprehensive literature review, the authors identified 13 key issues specific to women that arise in everyday clinical practice in the context with thrombophilia. A proposal for recommendations and a summary of current evidence were provided to the members of the expert panel. An online questionnaire was made available via the SurveyMonkey® platform, a tool that can be used to create and conduct online surveys and reliably evaluate the results. The experts were asked to agree with, reject, or abstain from each recommendation. They were also given the opportunity to provide feedback, suggest rewording, and contribute additional study data and references. It was determined in advance that a statement would be accepted if it received >75% approval and that a consensus of >95% would be considered strong approval.

Already in the first Delphi round, approval ratings of ≥88% were achieved for all key issues. Suggestions for rewording concerned only sentence restructuring for better comprehensibility, without resulting in any significant changes to content, so that a second Delphi round was not necessary. Personal discussions were held on certain points to efficiently clarify any differences of opinion or ambiguities. Some panel members made suggestions for additions or modifications to the text or provided references, which were incorporated into the background text by the authors. Ultimately, the final version was endorsed by the GTH Executive Board.

Definition of Thrombophilia

Established Thrombophilic Markers

The term thrombophilia refers to defined congenital or acquired disorders of blood clotting that are associated with an increased risk of developing thromboembolic events.[14] Well-established markers of hereditary thrombophilia include the factor V Leiden (FVL) and the prothrombin G20210A gene variants (PT) as well as hereditary deficiencies of the natural coagulation inhibitors antithrombin (AT), protein C (PC), and protein S (PS) ([Table 1]).[15] The presence of hereditary thrombophilia is usually considered in cases of VTE manifestations in childhood, adolescence, or young adulthood and if VTE events have occurred in first-degree relatives at a young age and/or without strong triggering factors.[16] However, a family history with several affected second-degree relatives can also be indicative of hereditary thrombophilia.

Table 1 Thrombophilic markers according to current evidence.[15] [153] [154]

Classic thrombophilia (included in thrombophilia screening profiles according to guideline recommendations)	Additional thrombophilic markers (may be useful in extended thrombophilia screening profiles, but not generally recommended in current guidelines)	Uncertain thrombophilic markers (not recommended in routine thrombophilia screening profiles due to insufficient evidence for an association with VTE)
Hereditary thrombophilia − Factor V Leiden variant − Prothrombin-G20210A variant − Antithrombin deficiency − Protein C deficiency − Protein S deficiency	− Non-O blood group − Elevated factor VIII levels − Elevated factor IX levels − Elevated factor XI levels − Dysfibrinogenemia − Elevated von Willebrand factor − Hyperhomocysteinemia	− ADAMTS13 − Alpha-2-antiplasmin − Angiotensin-converting enzyme − Endothelial protein C receptor − Factors V, VII, X − Factor XIII Val34Leu variant − Heparin cofactor II − Lipoprotein (a) − MTHFR A1298C variant − MTHFR C677T variant − Plasminogen deficiency − Plasminogen activator inhibitor-1 4G variant − Protein Z − Protein Z-dependent protease inhibitor − Thrombin activatable fibrinolysis inhibitor − Thrombomodulin − Tissue factor pathway inhibitor
Acquired thrombophilia − Antiphospholipid syndrome − Lupus anticoagulants − Anti-cardiolipin IgG-/IgM isotype − Anti-beta-2-glycoprotein-I IgG-/IgM isotype

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; MTHFR, methylenetetrahydrofolate reductase.

It is worth noting that ethnic origin influences the likelihood of thrombophilia. For example, there is a much lower prevalence of the FVL and PT variants among East Asians, whereas the prevalence of AT, PC, and PS deficiencies is higher in this population.[17] [18] Chinese people have generally lower levels of PC and PS than Caucasians and other Asians.[19] Sex-specific differences in the reference ranges of AT, PC, or PS have also been described.[20] Depending on the respective coagulation parameter, reference values adjusted for gender, ethnic origin, and clinical situation (e.g., pregnancy) would be helpful but are often not established.[21] [22] [23]

The most important acquired thrombophilia is the antiphospholipid syndrome (APS), which is—according to the 2006 revised Sapporo criteria—characterized by the presence of lupus anticoagulants, anti-cardiolipin (aCL), and/or anti-β-2-glycoprotein-I antibodies (ab2GPI) of the IgG or IgM type persisting for at least 3 months close to the onset of thrombotic events or pregnancy complications ([Table 2]).[24] [25] [26] [27] The presence of APS should be considered in young patients (<50 years) with unprovoked VTE, in atypical localization of venous thrombosis (e.g., splanchnic vein thrombosis, cerebral vein or sinus thrombosis), and in VTE progression despite adequate anticoagulation and suspected treatment adherence. In addition, thromboses of the arterial or capillary system, pregnancy complications (e.g., miscarriage, preeclampsia, placental insufficiency), autoimmune diseases (e.g., systemic lupus erythematosus), or otherwise unexplained laboratory abnormalities (e.g., thrombocytopenia, aPTT prolongation) may indicate the presence of APS.

Table 2 Antiphospholipid syndrome—clinical and laboratory diagnostic criteria.[24] [25]

Clinical criteria:

Thrombotic antiphospholipid syndrome (TAPS) − At least one clinical episode of arterial, venous, or small vessel thrombosis, in any tissue or organ Obstetric antiphospholipid syndrome (OAPS) − At least three consecutive unexplained spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded − At least one unexplained fetal death at or beyond the 10th week of gestation with a morphologically normal fetus documented by ultrasound or by direct examination of the fetus − At least one premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia, severe preeclampsia, or features of placental insufficiency

Laboratory criteria:

Persistence of antiphospholipid antibodies in repeated testing over a period of at least 3 months − Anti-cardiolipin of the IgG or IgM isotype with titers above the 99th percentile − Anti-ß2-glycoprotein-I of the IgG or IgM isotype with titers above the 99th percentile − Lupus anticoagulant confirmed in phospholipid-dependent coagulation-based assays (e.g., Diluted Russell’s Viper Venom Time (DRVVT), lupus-sensitive aPTT)

Additional clinical criteria and laboratory findings have been described in APS patients but have not yet been included in the definition because they are considered nonspecific. These so-called nondiagnostic clinical criteria include thrombocytopenia, autoimmune hemolytic anemia, valvular heart disease, renal microangiopathy, cognitive disorders, and livedo racemosa. Antiphospholipid (APL) antibodies, which do not contribute to the diagnosis but are often present in addition, include, for example, IgA antibodies against cardiolipin or b2GPI, antibodies against the domain 1 of b2GPI (aD1), or antibodies against phosphatidylserine and prothrombin (aPS/PT). Whether testing for these antibody entities, in addition to classic APL diagnostics, provides any additional clinical benefit has not been sufficiently investigated.[25]

Additional Thrombophilia Markers

The non-O blood group characteristics have been identified as an independent risk factor for VTE.[28] [29] Further thrombophilia markers include persistently elevated activities of coagulation factor VIII, IX, or XI, von Willebrand antigen, fibrinogen, D-dimers, and prothrombin fragments.[28] [30] [31] In recent studies in older people, higher levels of factors VIII, IX, and XI, von Willebrand factor, and homocysteine have been positively associated with the occurrence of VTE or recurrent VTE.[32] [33] The genetic basis of these changes has been less well studied, and increased levels of various parameters are non-specific and can be found, for example, in inflammatory systemic diseases. Due to the low to moderate relative risk increase for the occurrence of VTE and recurrent VTE, these parameters are to be categorized as mild thrombophilia. They are not a routine part of thrombophilia screening but may be determined in individual cases.

Inherited or acquired blood cell disorders such as myeloproliferative disease, sickle cell disease or paroxysmal nocturnal hemoglobinuria also predispose to thrombosis and vascular occlusion.[34] [35] However, these clinical pictures are rare among Central Europeans and are not the subject of this publication.

Absolute and Relative Risk of VTE

The frequencies of the most commonly tested thrombophilias and the relative increase in risk for a first and recurrent thromboembolic event are summarized in [Table 3]. It is important to note that the relative risk should never be considered in isolation but always in conjunction with the absolute risk. The absolute risk of VTE for persons without a history of VTE is significantly lower than the risk of VTE recurrence in patients with a history of VTE. In this respect, mild thrombophilia—alone or in combination—can also lead to a clinically relevant risk increase if the baseline absolute risk is high ([Fig. 1]). Additional risk factors for VTE or VTE recurrence should be considered in this regard.

Table 3 Prevalence of thrombophilia and relative risk of a first VTE or VTE recurrence.[47]

	Prevalence (%)		Relative risk increase
	General population	Unselected VTE cohort	First VTE	Recurrent VTE (after termination of anticoagulant therapy)
Severe or high-risk thrombophilia
Antiphospholipid syndrome	1–5	2–7%	5–33	1.8–4.5
Antithrombin deficiency	0.02–0.2	1	4–50	2.5 (?)
Protein C deficiency	0.2–0.4	3	15	2.5 (?)
Protein S deficiency	0.03–0.1	2	5–10	2.5 (?)
Factor V Leiden variant, homozygous	0.02	1.5	40–80	(?)
Prothrombin G20210A variant, homozygous	0.02	<1	20–30	(?)
Factor V Leiden and prothrombin G20210A variant, compound heterozygous	0.1	<1	15–20	(?)
Mild or low-risk thrombophilia
Factor V Leiden variant, heterozygous	5	20	5–7	1.5
Prothrombin G20210A variant, heterozygous	2	6	3–4	1.5
Persistently elevated factor VIII	(?)	(?)	5	1.5 (?)
Blood group A/B/AB (non-O)	55–57	75	2	2

Abbreviation: VTE, venous thromboembolism.

Fig. 1 Absolute and relative risk of VTE or recurrent VTE using the example of the factor V Leiden (FVL) mutation.

Consequences of Thrombophilia Testing

Current national and international guidelines agree that thrombophilia screening should only be performed when the knowledge of the test results will benefit the patient in terms of preventing further VTE.[14] [36] [37] The expected benefits of recognizing thrombophilia and implementing prophylactic measures must always be weighed against the disadvantages of testing, including the possible lack of primary or secondary prevention measures, the exclusion from certain professions and insurance policies, and the fear of VTE manifestation in patients and their (asymptomatic) relatives. The determination of genetic variants with unclear or no clinical significance (e.g., methylenetetrahydrofolate reductase [MTHFR] C677T, plasminogen activator inhibitor-1 [PAI-1 4G]) is not useful and also not compatible with the German Genetic Diagnostics Act (GenDG).

Since the GenDG came into force on February 1, 2010, medical information and written consent from the person being tested are required for diagnostic genetic tests. One of the basic principles of the law is the right of the individual to informational self-determination. This includes both the right to know one’s own genetic findings and the right not to know. Therefore, it is essential that patients are able to understand the benefits, risks, and potential consequences of genetic testing. In principle, a distinction is made between diagnostic tests for symptomatic patients with VTE and predictive tests of asymptomatic individuals (e.g., due to a positive family history of VTE or thrombophilia). It should be noted that predictive diagnostics and counseling may only be performed by qualified physicians who meet the requirements for specialized genetic counseling.[38] [39]

Content and Timing of Thrombophilia Testing

Standard panels for hereditary thrombophilia include genetic testing for the FVL and PT variant, as well as tests for a deficiency of AT, PC, or PS by means of activity measurement or—in the case of PS—the determination of free protein S ([Table 1]).[14] [36] [37] Antithrombin activity is measured using a chromogenic amidolytic assay based on thrombin or factor Xa. Some mutations influence the activity measurement differently so that both test variants should be used to rule out a relevant AT deficiency.[40] [41] If the presence of APL is suspected APS-defining antibodies (i.e., LA, aCL IgG and IgM, ab2GPI IgG and IgM) should be determined using tests that meet the recently updated recommendations of the Scientific and Standardization Committee (SSC) on Lupus Anticoagulants/Antiphospholipid Antibodies of the International Society on Thrombosis and Haemostasis (ISTH).[25] For the detection of LA, coagulation-based methods are used, and parallel testing using the Diluted Russell's Viper Venom Time (DRVVT) and a lupus-sensitive aPTT is recommended as the tests of first choice. Solid-phase ELISA-based assays were the standard for the detection of aCL and anti-β2GPI of the IgG/IgM isotypes in plasma or serum for many years. Nowadays, many laboratories use chemiluminescence immunoassays (CLIAs), which are characterized by higher sensitivity, can be performed fully automatically, and are less labor-intensive.[42]

In general, thrombophilia screening is not useful in the acute phase of VTE, as plasma levels and/or functional activity of coagulation factors and inhibitors can be altered by extensive thrombosis or by the influence of anticoagulants, and the tests would therefore needlessly have to be repeated. If testing is performed during anticoagulant therapy, the intake of a direct oral anticoagulant (DOAC) should be paused for at least 48 hours and the administration of a low-molecular-weight heparin (LMWH) for at least 24 hours. Alternatively, the residual DOAC effects in the plasma sample can be eliminated by adding charcoal reagents (e.g., DOAC-Stop®, DOAC-Remove®).[25] [43] [44] When treating with a vitamin K antagonist (VKA), phenprocoumon should be discontinued for at least 4 weeks and warfarin for at least 2 weeks to ensure a valid interpretation of the test results.

CHC, MHT, and pregnancy can affect the results of coagulation tests, particularly those of free PS and factor VIII activity. If medically justifiable, estrogen therapy should be paused for at least 4 to 6 weeks before testing for these parameters,[45] [46] and thrombophilia testing should be performed preferably outside of pregnancy, as physiological changes in the coagulation system complicate the interpretation of test results during pregnancy and in the early postpartum period.[47] If testing under hormonal influence is considered unavoidable, the results must be handled with care and testing should be repeated at a later date without hormonal influence. Direct genetic analysis may be considered in individual cases if this has immediate therapeutic consequences (e.g., in the case of severe PS deficiency in an ongoing pregnancy and a known familial PROS gene variant).

Thrombophilia Testing in Women with a History of VTE

1. Should thrombophilia testing be performed in women with unprovoked VTE?

Women with unprovoked VTE should be offered thrombophilia screening with the aim of deciding on the type, duration, and intensity of anticoagulation. This applies in particular to women of childbearing age and women with a positive family history.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

A recent analysis of the multinational multicenter RIETE registry found that patients who were tested for classical hereditary thrombophilia—20.4% of the total cohort—had lower risks of VTE recurrence, major bleeding, and mortality than patients who were not tested.[1] However, this may be due to a higher prevalence of cancer or other underlying disorders in the nontested population. The duration of anticoagulant treatment was longer in those who were tested for thrombophilia and those who were tested positive. After cessation of anticoagulation, the risk of VTE recurrence was particularly high in patients with an unprovoked first VTE and hereditary thrombophilia (9.9 per 100 patient-years [95% CI 8.03–11.07]). The increased risk of VTE recurrence after unprovoked proximal DVT and/or PE therefore justifies indefinite anticoagulation in many cases.

Since the decision for or against continuing anticoagulation may depend on the additional presence of a thrombophilic disorder, the expert panel recommends an assessment for thrombophilia, particularly in the case of a positive family history of VTE and in women of childbearing age. Even if the decision to continue anticoagulation has been made, the question remains as to whether low-dose rivaroxaban or apixaban is sufficient to prevent future VTE events in severe or combined thrombophilia. To date, the therapeutic maintenance dose for secondary prophylaxis is predominantly recommended for patients with severe hereditary thrombophilia.[15] [48] In cases of a confirmed APS with high-risk APL (i.e., triple positivity or presence of lupus anticoagulants) or arterial thrombotic events, continued therapeutic anticoagulation with a VKA is preferable to a DOAC-based anticoagulation regimen.

Regardless of whether anticoagulation is continued or discontinued after the first VTE, women of childbearing age should be counseled regarding the secondary prevention of VTE in subsequent pregnancies.[47] [48] [49] [50] [51] Pregnancies increase the risk of VTE recurrence after a first unprovoked VTE. A pooled proportion of 6.4% (95% CI, 3.9–10.4%) was calculated for recurrent VTE during subsequent pregnancy without anticoagulant prophylaxis.[49] Therefore, pharmacological prophylaxis is generally recommended during pregnancy and postpartum after a previous unprovoked VTE. Some thrombophilias give rise to additional considerations for the treatment strategy in pregnant women. Thus, anti-Xa level monitoring and adjustment of LMWH dosing is recommended for women with AT deficiency, while LMWH and aspirin comedication is recommended for women with confirmed (thrombotic) APS to prevent APL-related pregnancy complications.[52] [53]

2. Should thrombophilia testing be performed in women who have suffered a VTE in association with the use of CHCs?

Women with a VTE that has occurred while taking a CHC should be offered thrombophilia screening. This applies in particular to women with a positive family history of VTE or thrombophilia.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

The use of CHC is a contributing factor to the occurrence of VTE.[54] [55] [56] The risk varies depending on the dose of estrogen, the progestin component, and the form of application. It increases with higher estrogen doses and is highest in combined pills with newer progestins (formerly known as 3rd generation).[57] [58] The risk of VTE is particularly increased in the first year of use but remains elevated even with long-term use. By contrast, progestogen-only oral contraceptives or levonorgestrel-releasing intrauterine devices do not increase the risk of VTE.

CHC is considered a minor risk factor for VTE.[59] A meta-analysis showed a significantly lower risk of VTE recurrence compared with unprovoked VTE when CHC was discontinued prior to the termination of anticoagulation (RR 0.37; 95% CI 0.26–0.54).[60] However, the risk of VTE recurrence after discontinuation of anticoagulant therapy is increased if use of CHC is continued or resumed later.[61] [62] A second meta-analysis, which analyzed data from 14 studies involving 3112 women with estrogen-related VTE, calculated a low absolute risk of recurrence (i.e., 1.54 per 100 patient-years) after discontinuation of estrogen therapy.[63] The low risk of recurrence generally favors short-term anticoagulation for at least 3 to 6 months after CHC-related VTE.[14]

Despite the low risk of recurrent VTE, as young women are affected, the lifetime risk of recurrence should be considered. In addition, the risk of VTE in pregnancy is substantially increased after a CHC-associated initial event and is estimated at 6–10%.[64] [65] [66] The risk seems to be even higher in the presence of thrombophilia. Although pharmacological prophylaxis is generally recommended after a previous VTE related to the use of CHC during a subsequent pregnancy and the postpartum period, knowledge of a specific thrombophilia may modify the secondary preventive strategy in individual cases. The same applies to the lifetime risk of recurrent VTE.

The use of CHC can unmask severe thrombophilia in young women by causing VTE at a younger age. It has been shown that the coincidence of thrombophilia and CHC use increases the risk of VTE significantly more than the use of CHCs alone.[67] [68] [69] Therefore, our expert panel recommends that women should be offered thrombophilia screening after CHC-associated VTE, with specialized counseling on secondary preventive measures to avoid VTE recurrence later in life.

3. Should thrombophilia testing be performed in women who have suffered a VTE during pregnancy or postpartum?

Women with a VTE that has occurred during pregnancy or in the postpartum period should be offered thrombophilia screening. This applies in particular to women with a positive family history of VTE or thrombophilia.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

In the context of pregnancy, the risk of VTE is increased due to physiological changes of the coagulation system, progestin-related vasodilation, venous stasis, and mechanical compression of the inferior vena cava and pelvic veins by the gravid uterus. In addition, endothelial injury occurs in preeclampsia and may result from delivery-related trauma. The latter is considered to be one of the causes of the increased risk of thrombosis in the postpartum period.

The risk of pregnancy-related VTE is up to 5 times higher than in the general population, with an absolute incidence of 1.2 per 1000 deliveries (95% CI 0.6–1.8).[70] The risk of recurrence appears to be even higher if the index event was a PE.[71] The incidence is roughly the same during pregnancy and postpartum, although this means a higher risk of VTE in the much shorter postpartum phase.[72] [73]

According to current understanding, pregnancy is considered a transient and minor provoking risk factor. However, the long-term risk of recurrent VTE is not well studied. A subgroup analysis of the multinational prospective RIETE registry, which included 607 women with pregnancy-related VTE, found an incidence of 2.28 recurrent VTE events per 100 patient-years and a cumulative incidence of 1.8% at 6 months, 2.7% at 1 year, and 3.3% at 2 years.[72] A recent monocentric observational study of 587 patients found an annual incidence of recurrent VTE of 2.4% and a cumulative incidence of 6, 13, 17, and 30% after 2, 5, 10, and 30 years, respectively.[71] Compared with women with unprovoked VTE, women with pregnancy-related VTE have a significantly lower long-term risk of recurrent VTE but a higher risk of recurrent VTE during a subsequent pregnancy.[64] [74]

An analysis of 1119 women from the RIETE registry showed a higher prevalence of classic thrombophilia in women with VTE during pregnancy or after childbirth compared with nonpregnant women with VTE (55, 50, and 46%, respectively).[73] Moreover, those with VTE related to pregnancy or postpartum were less likely to have an additional VTE risk factor (e.g., immobility, recent travel, or active cancer) or comorbidities (e.g., smoking, renal insufficiency).

Based on current evidence and in line with the recommendations for CHC-associated VTE, our expert panel recommends that all women with pregnancy-associated VTE should be offered thrombophilia screening with the aim of optimized risk-adapted secondary prevention in future risk situations (e.g., subsequent pregnancies) and with regard to lifetime risk of VTE in cases with confirmed thrombophilia.

4. Should thrombophilia testing be performed in women who have suffered a VTE event during MHT?

Women with a VTE that has occurred during MHT may be offered thrombophilia screening if the results are expected to influence the strategy of secondary prophylaxis.

Women with a VTE that has occurred during MHT should be offered thrombophilia screening if there is a positive family history of VTE.

(Strong consensus; approval: 16/16 = 100%; abstention: 2)

Menopausal hormone therapy (MHT; also known as hormone replacement therapy or HRT) is extremely effective in controlling menopausal symptoms such as vasomotor symptoms like hot flashes, sleep disturbances, depressive moods, urologic complaints, and other complaints that can significantly affect the quality of life and productivity of some women. The aim of MHT is not to restore previous hormone concentrations but to specifically eliminate the symptoms and illnesses associated with menopause, which are mainly caused by a lack of estrogen. The lowest effective dose of MHT is therefore applied. The duration of treatment is individualized and depends on the clinical symptoms; after 3 to 5 years, a tapering off can be considered. Ideally, MHT should begin at the onset of the menopause, but no later than the age of 60 or within 10 years of the onset of the menopause. As estrogen monotherapy is associated with an increased risk of endometrial cancer, estrogens are usually applied in combination with a progestin.

The different estrogen types used for MHT — mainly conjugated equine estrogens and/or estradiol (E2) — are less potent than ethinyl estradiol used in CHCs. Oral MHT preparations, in monotherapy as well as in combination with a progestin, increase the risk of VTE 2- to 4-fold.[9] [75] [76] For women with previous VTE, an up to 4-fold risk increase has been described.[77] [78] Similar to CHCs, the risk of VTE increases with the estrogen dose and depends on the progestin component in combined preparations. An increased risk of VTE has been described in particular when norpregnane derivatives (e.g., nomogestrol acetate, promegestone) were used in combination with estrogens.[79] [80] [81]

The risk of VTE is highest in the first year of application and remains elevated for the duration of therapy. A further risk increase is observed with the presence of additional VTE risk factors, such as older age, a higher body mass index, or the presence of thrombophilia. As MHT patients are generally older, MHT populations have a higher absolute baseline risk than CHC populations.[6] [82]

In a multicenter case–control study of VTE in postmenopausal women, the combination of the FVL or PT variant and oral estrogen resulted in a 25-fold increased risk of VTE compared with women not taking estrogens and not carrying the gene variant (95% CI, 6.9 to 95.0).[83] However, the risk for women with a prothrombotic variant using transdermal estrogen was similar to that of women with a mutation who were not using estrogen.

The transdermal application of estrogen in combination with micronized progesterone is considered safe with regard to the risk of VTE and is therefore also an option for women who have an increased risk of (recurrent) VTE due to thrombophilia or previous VTE.[79] [84] [85] Given the current evidence and the increased risk of VTE and recurrent VTE with advancing age, women with MHT-associated VTE may be offered thrombophilia screening. Our expert panel recommends that women with a positive family history of VTE events should be screened for thrombophilia. Testing for antiphospholipid antibodies is also advisable, as the incidence of autoimmune diseases increases, particularly in middle-aged and older women. Additional etiologic factors for VTE should always be taken into consideration. In this context, it is recommended to update the age- and gender-specific cancer-screening examinations.

5. Should thrombophilia testing be performed in transgender people who have suffered a VTE during gender-affirming hormone therapy (GAHT)?

Transgender people with a VTE that has occurred during GAHT may be offered thrombophilia screening if the results are expected to influence the strategy of secondary prophylaxis.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

Transgender women require GAHT. To achieve estradiol levels in the physiological range of cisgender women, estradiol is administered in a daily oral dose of 2–6 mg or transdermally at 500–200 μg/24 hours.[86] Antiandrogens (e.g., spironolactone or cyproterone acetate) or gonadotrophin-releasing hormone agonists are often used in addition to suppress the endogenous testosterone effect. As part of GAHT, estrogen substitution results in changes of hemostaseological parameters, as does the use of CHC or HRT.

In a study of 98 transgender women who started estradiol therapy, increased activities of factor IX and factor XI and decreased PC activity were found.[87] In addition, an increased thrombopoiesis, resulting in a higher platelet count, was observed. The result is a prothrombogenic state associated with an increased risk of VTE. Data on VTE risk in transgender women with GAHT are limited. A recent meta-analysis involving 5 studies and 10,651 transgender women treated with estrogen found a 2.2-fold increased (95% CI 1.1–4.5) risk of VTE when compared with 60,003 cisgender men.[88] In most cases, however, the estrogen preparation, the estrogen dose, and the serum estradiol levels achieved were unknown.

For transgender individuals seeking masculinization, testosterone is administered intramuscularly, subcutaneously, or transdermally to both suppress estrogen production and produce the physical changes associated with the desired male gender.[86] The aim is to achieve hormone levels in the physiological range of cisgender men. However, an increase in serum hemoglobin and hematocrit and an increased risk of VTE have been associated with the exogenous intake of testosterone.[87] [89] In addition, transgender men are often found to have higher estrogen levels than cisgender men, possibly as a result of the metabolization of exogenously supplied testosterone into estrogen.[90]

In a large case–control study, which included 2115 transgender men, the comparison with cisgender men and cisgender women only showed a trend toward an increased risk of VTE (HR 1.6; 95% CI 0.9 to 2.9 and 1.1, respectively, 95% CI 0.6 to 2.1).[91] However, studies on cisgender men receiving testosterone replacement therapy for hypogonadism or other reasons revealed a 1.6- to 3.1-fold increased risk of VTE.[92] [93] [94]

GAHT will generally be continued after a VTE has occurred. As GAHT is a persistent risk factor for VTE recurrence, continuation of anticoagulation is usually indicated to prevent further VTE events. Therefore, thrombophilia screening will rarely influence further treatment strategies. Our expert panel recommends that thrombophilia testing may be considered in situations where the results can be expected to influence secondary prophylaxis for VTE.

6. Should thrombophilia testing be performed in women who have suffered a VTE provoked by a strong nonhormonal trigger (e.g., surgery, major trauma, prolonged immobility)?

Thrombophilia testing in women with a VTE provoked by a strong nonhormonal trigger is not recommended.

(Consensus; approval: 16/17 = 94%; abstention: 1)

After a VTE that occurred in connection with a temporary strong nonhormonal trigger, the risk of recurrence is low if the corresponding trigger is no longer present after the therapy phase (i.e., after 3–6 months of anticoagulation).[14] [59] In these cases, anticoagulation is usually discontinued unless there are additional persistent risk factors that require pharmacological VTE secondary prophylaxis. Previous studies have not yet convincingly demonstrated that knowledge of thrombophilia is beneficial for affected patients in terms of secondary preventive measures and VTE recurrences.[1] [61] [95] [96]

However, testing may be considered if the results are likely to influence VTE secondary prophylaxis measures. This may be the case, for example, for women of childbearing age, a positive family history of VTE or thrombophilia, or if VTE has occurred during adolescence or young adulthood or despite appropriate pharmacological thromboprophylaxis.

7. Should thrombophilia testing be performed before starting treatment with tamoxifen in breast cancer patients who have suffered a VTE?

Breast cancer patients with a history of VTE may be offered thrombophilia testing if the results are expected to have an impact on the strategy of secondary prophylaxis.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

Women with breast cancer have a 3–4 times higher risk of VTE than women of the same age without cancer.[97] Additional risk factors further increase the risk of VTE, including treatment with selective estrogen receptor modulator tamoxifen, which is used as standard in the adjuvant therapy of estrogen receptor-positive women (ER+) to improve long-term prognosis.[98] Although tamoxifen is better tolerated than aromatase inhibitors, it is associated with a higher risk of VTE.[99] [100] A 5-fold increase in the risk of VTE was observed during the first 3 months of tamoxifen therapy.[101] Even after several years of therapy, the risk of VTE remains 2–3 times higher with the continued intake of tamoxifen.[102] [103]

During tamoxifen therapy, procoagulant factors such as factor VIII, factor IX, and von Willebrand factor have been shown to be elevated, while the activities of the physiological coagulation inhibitors AT, PC, and PS are reduced, thus resulting in a hemostatic imbalance and an increased thrombin generation.[104] [105] The coincidence with thrombophilia additionally increases the risk of VTE.[106]

If tamoxifen therapy cannot be switched to an aromatase inhibitor, which is an option for postmenopausal women, then a persistently increased risk of VTE recurrence is to be assumed as long as tamoxifen therapy is continued. If a VTE has occurred in the context of breast cancer, anticoagulation is often continued until tamoxifen therapy is stopped. If the VTE occurred before breast cancer manifestation and anticoagulant therapy has already been stopped, the question arises as to whether anticoagulation should be resumed for secondary VTE prophylaxis. There are no reliable study data on this topic, so it is ultimately a case-by-case decision that should also take into account other VTE risk factors and the circumstances of the first thrombosis. Thrombophilia testing cannot be recommended generally in these cases but can be offered if the results are expected to have an impact on the strategy of secondary prophylaxis.

Thrombophilia Testing in Women with Pregnancy Complications

8. Should thrombophilia testing be performed in women without previous VTE who suffered pregnancy complications (e.g., recurrent early miscarriages, unexplained fetal death, premature birth related to eclampsia, preeclampsia, or placental insufficiency)?

Testing for antiphospholipid antibodies is recommended for all women who meet the clinical criteria for an obstetric APS, regardless of whether thromboembolic events have occurred previously.

Testing for hereditary thrombophilia in women who suffered pregnancy complications without a history of VTE cannot generally be recommended.

(Consensus; approval: 14/16 = 88%; abstention: 2)

APS is a major risk factor for pregnancy complications. The clinical criteria for obstetric APS include recurrent unexplained early miscarriages before the 10th week of gestation, unexplained fetal death after the 10th week of gestation, and premature birth (<34th week of gestation) due to severe preeclampsia, eclampsia, or placental insufficiency.[24] It is estimated that 0.5–1.4 per 100,000 women who develop APS and APL are related in up to 10% of pregnancy complications including fetal growth restriction (FGR).[107] In women with confirmed APS, rates for recurrent early miscarriages, late fetal loss, and preeclampsia of 54, 36 to 74, and 10 to 48%, respectively, have been reported.[108] The risk is highest when lupus anticoagulants are present.[109] However, with early treatment with heparin and low-dose aspirin during pregnancy, a live birth rate of 70% can be achieved.[110] [111] [112] Women with obstetric APS should therefore receive preconception counseling regarding antithrombotic therapy during a subsequent pregnancy.

Screening for hereditary thrombophilia in women with obstetric morbidity remains controversial. It has been suggested that hereditary thrombophilia may promote the occurrence of thrombosis in maternal placental vessels, resulting in ischemia and infarction. Furthermore, it has been speculated that the association of thrombophilia with late miscarriages may be stronger than with early miscarriages.[113] Despite numerous studies and several meta-analyses, the existence and strength of a link among recurrent early miscarriages, late pregnancy complications, and hereditary thrombophilia remain unclear. A weak-to-moderate association of late miscarriages or recurrent early miscarriages was found for certain thrombophilias and was also confirmed in meta-analyses[109] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] ([Table 4]). However, clear conclusions are difficult to draw due to the considerable heterogeneity of study designs, absent or differing definitions of early and late miscarriages, and the lack of studies linking hereditary thrombophilia to thrombotic complications of the maternal placental vessels. Moreover, RCTs have not shown any benefit of heparin treatment during pregnancy with regard to live birth rate, meaning that knowledge of hereditary thrombophilia in general has no significant therapeutic implications for the course of pregnancy.[126]

Table 4 Thrombophilia and risk of pregnancy complications according to systematic reviews, meta-analyses, and a large Scandinavian nested case–control study.[114] [115] [116] [117] [118] [119] [120] [121]

	Recurrent (≥3) early miscarriages RR (95% CI)	At least one late miscarriage RR (95% CI)	Preeclampsia RR (95% CI)	Fetal growth restriction RR (95% CI)
Lupus anticoagulant	7.79 (2.30–26.45)[123]	2.38 (0.81–6.98)[116] 5.02 (2.14–7.89)[109] 10.6 (1.87–59.9)[114]	1.45 (0.70–4.61)[116] 2.10 (1.14–3.85)[124] 2.34 (1.18–4.64)[114]	0.82 (0.54–1.10)[122] 4.65 (1.29–16.7)[114]
Anti-cardiolipin antibodies	3.56 (1.48–8.59)[123] 5.05 (1.92–14.01)[116]	3.30 (1.62–6.70)[116] 3.47 (0.68–6.26)[109] 4.29 (1.34–13.68)[114]	1.52 (1.05–2.20)[114] 2.86 (1.37–5.98)[125]	2.25 (1.55–2.94)[122] 6.91 (2.70–17.7)[116]
Anti-beta-2-glycoprotein-I antibodies	2.12 (0.69–6.53)[123]	3.13 (0.75–5.50)[109] 23.5 (1.21–455.0)[114]	19.1 (6.34–57.8)[114]	1.31 (1.12–1.49)[122] 20.0 (4.59–87.4)[114]
Antithrombin deficiency	NA	7.63 (0.30–196.4)[116]	3.89 (0.16–97.2)[116]	NA
Protein C deficiency	NA	3.05 (0.24–38.5)[116]	5.15 (0.26–102.2)[116]	NA
Protein S deficiency	NA	7.39 (1.28–42.8)[115] 20.1 (3.7–109.2)[116]	2.83 (0.76–10.6)[116]	NA
Factor V Leiden variant	1.91 (1.01–3.61)[116] 2.01 (1.13–3.58)[115]	2.06 (1.1–3.86)[116] 3.26 (1.82–5.83)[115]	1.23 (0.89–1.70)[117] 1.81 (1.14–2.87)[118] 1.94 (1.27–2.96)[121] 2.19 (1.46–3.27)[116]	1.00 (0.80–1.25)[117] 1.51 (1.15–1.98)[121] 2.68 (0.59–12.1)[116] 2.72 (1.35–5.49)[119]
Prothrombin G20210A variant	1.81 (1.26–2.60)[120] 2.32 (1.12–4.79)[115] 2.70 (1.37–5.34)[116]	2.3 (1.09–4.87)[115] 2.66 (1.28–5.53)[116]	0.81 (0.29–2.30)[121] 1.25 (0.79–1.99)[117] 1.37 (0.72–2.57)[118] 2.54 (1.52–4.23)[116]	0.82 (0.46–1.43)[121] 1.25 (0.92–1.70)[117] 2.51 (1.26–4.98)[119] 2.92 (0.62–13.7)[116]

Current guidelines for the management of women with recurrent miscarriage therefore do not recommend testing for hereditary thrombophilia for the sole purpose of improving pregnancy outcomes.[127] [128] [129] However, the 2019 German guideline recommends screening for hereditary thrombophilia (FVL, PT, AT, PC, PS) for women with additional thromboembolic risk factors.[127] The corresponding British guideline recommends that women with a miscarriage in the second trimester may be offered testing for the FVL and PT variant and PS deficiency, ideally as part of a research study.[129] The Dutch guideline goes even further and clearly recommends no testing for hereditary thrombophilia outside of studies due to unclear therapeutic consequences.[128]

It should be noted that numerous factors and concomitant diseases have been identified that can impair the course of pregnancy and have clear therapeutic implications. For further diagnosis and treatment in this regard, we refer you to the relevant gynecological guidelines.[125] [128] [129]

9. Should thrombophilia testing be performed in women with implantation failure after medically assisted reproduction (MAR)?

Testing for antiphospholipid antibodies is recommended in women with implantation failure after MAR who meet the clinical criteria for obstetric antiphospholipid syndrome (OAPS) or with a history of thromboembolic events.

Testing for hereditary thrombophilia in women without previous VTE who suffered implantation failure after MAR is not recommended.

(Consensus; approval: 14/15 = 93%; abstention: 3)

Implantation failure after MAR is not a typical manifestation of OAPS. Women with aspects of an obstetric APS who do not fully meet the clinical and laboratory criteria are often classified as “non-criteria OAPS” or “APL-related obstetric morbidity” (OMAPS). This group includes, for example, women with one or two miscarriages before the 10th week of pregnancy, three nonconsecutive miscarriages, late onset of preeclampsia, placental insufficiency or FGR (after the 34th week of pregnancy), or repeated implantation failure (RIF) after MAR.[130] [131] [132] There is currently no standard definition for this entity. In particular, data on a possible link between APL and recurrent implantation failure are contradictory. Although two meta-analyses showed a higher prevalence of APL in women with recurrent implantation failure,[131] [133] [134] this could not be confirmed in another meta-analysis.[134]

Whether and to what extent hereditary thrombophilia triggers implantation failure after MAR is also a matter of controversy. While older case–control and retrospective cohort studies found a higher prevalence of hereditary thrombophilia in women with implantation failure, other studies were unable to confirm an association between thrombophilia and MAR treatment failure.[135] [136] [137] [138] [139] [140] [141] In the largest prospective cohort study to date, involving 1717 women and a total of 4169 IVF cycles, no difference was detected with regard to the study endpoints of positive pregnancy test, successful implantation, occurrence of clinical pregnancy or live birth, and miscarriage rates.[142] In another study, no higher prevalence of thrombophilic diatheses was found in women with ovarian hyperstimulation syndrome (OHSS).[143]

Consequently, routine testing for hereditary or acquired thrombophilia as part of fertility treatment cannot be recommended.[144]

Predictive Thrombophilia Testing in Women Without a History of VTE

10. Should thrombophilia testing be performed before starting combined hormonal contraception in women without a previous VTE who have a positive family history of VTE or thrombophilia?

Thrombophilia testing is not generally recommended for women without a history of VTE who have a positive family history of VTE or thrombophilia and are starting combined hormonal contraception.

The primary approach should be to use estrogen-free contraception. However, if estrogens are essential, then testing for the known thrombophilia in the family may be performed to assess the risk of VTE before starting estrogen treatment.

(Consensus; approval: 16/17 = 94%; abstention: 1)

Depending on the estrogen concentration and type of progestogen, the intake of CHC is associated with a 2- to 6-fold increased risk of VTE. Although the presence of thrombophilia further increases the relative risk of thrombosis, the absolute risk remains very low in young women without additional VTE risk factors. In any case, a careful medical history and assessment of potential VTE risk factors are essential for the individual VTE risk assessment before prescribing a new contraceptive. In this context, laboratory screening for thrombophilia is only of limited use.

Routine thrombophilia testing prior to prescribing contraceptives is not advisable, especially since the most common forms of hereditary thrombophilia are harmless, quality requirements for preanalytical sample handling in outpatient settings are often not adequately met, and findings of questionable clinical relevance tend to cause uncertainty, anxiety, and high demand for advice in women rather than minimizing the risk of VTE.[46] Studies that focused on thrombophilia screening in the general female population have suggested little utility and lack of cost-effectiveness. For example, the number needed to test to prevent VTE would be 666 for the FVL variant and is expected to be even higher for the rare thrombophilias.[145] Testing only women with a family history of VTE will most likely improve cost-effectiveness. However, studies have shown that women with a family history of VTE in one or more first-degree relatives have an increased risk of estrogen-associated VTE, regardless of the presence of thrombophilia.[146] [147]

If hereditary thrombophilia is known to be present in first-degree relatives, testing for the specific defect may be performed. It should be noted that if mild thrombophilia (e.g., heterozygosity for the FVL variant) is present in family members and is ruled out in the index patient, this may lead to a false sense of security, as this may not be the only causative thrombophilia in the family. In this respect, it is advantageous to avoid estrogens and to choose a contraceptive preparation with the lowest possible VTE risk (e.g., progestin-only pill). Only if estrogen-containing contraception cannot be avoided, screening for classic thrombophilia may be performed, whereby the woman must be informed and advised by a physician qualified to provide specialist genetic counseling in accordance with the requirements of the German Genetic Diagnosis Act (GenDG).[38] [39]

11. Should thrombophilia testing be performed before pregnancy in women without previous VTE who have a positive family history of VTE or thrombophilia?

Thrombophilia testing is generally not recommended for women with no history of VTE who have a positive family history of VTE or thrombophilia and are planning to become pregnant.

Thrombophilia testing may be offered to women without a history of VTE who have a positive family history of VTE or thrombophilia if the results are expected to have an impact on the strategy of primary VTE prophylaxis during pregnancy or postpartum.

(Strong consensus; approval: 15/15 = 100%; abstention: 3)

As mentioned before, pregnancy is considered a risk factor for VTE. The risk of VTE increases during the course of pregnancy and is highest around the time of birth and in the early postpartum period. Even though thrombophilia leads to a further increase in risk, the absolute risk of VTE in young women with the frequent mild thrombophilias remains low, so that pharmacologic VTE prophylaxis is not generally recommended unless additional VTE risk factors are present. If hereditary thrombophilia is known to be present in first-degree relatives, testing for the specific defect may be performed. In cases with a positive family history of VTE, the index patient should preferably be tested and the otherwise healthy woman should ideally only be tested for the specific defect of the first-degree relative. If the medical findings of the relative affected by VTE are not available, the woman may be offered thrombophilia screening if the results are likely to influence the decision on primary VTE prevention during pregnancy or postpartum. This requires prior consultation with a physician who is qualified to provide specialized genetic counseling in accordance with the provisions of the GenDG.[38] [39]

12. Should thrombophilia testing be performed before MHT in the perimenopause in women without previous VTE who have a positive family history of VTE or thrombophilia?

Thrombophilia testing is not generally recommended for women without a history of VTE but with a positive family history of VTE or thrombophilia who are considering MHT. A nonoral form of application (e.g., transdermal, vaginal) should primarily be chosen for estrogen therapy. However, if an oral application is essential, a test of the known thrombophilia in the family may be performed before starting treatment to assess the risk of VTE.

(Strong consensus; approval: 17/17 = 100%; abstention: 1)

As mentioned before, estrogen-containing MHT as well as advancing age are established risk factors for VTE.[9] [75] [148] The risk of VTE increases further with the presence of thrombophilia.[79] As already stated for the use of CHC, routine thrombophilia testing prior to prescribing MHT is not advisable. If there is a family history of VTE or thrombophilia, oral estrogens should be avoided, whereas transdermal or vaginal forms of administration have no effect on the risk of VTE and can be used safely. Progestins can be used in any form of application without increasing the risk of VTE. Only if oral estrogen therapy is unavoidable, women may be offered testing for the thrombophilia defect known in their family or, if the family medical findings are not available, screening for the classic thrombophilias.

13. Should thrombophilia testing be offered to minors?

Thrombophilia testing is recommended for young and adolescent girls with a history of VTE.

(Consensus; approval: 17/18 = 94%; abstention: 0)

Severe thrombophilia (e.g., congenital deficiencies of AT, PC, or PS) often manifests early in life with DVT and/or PE. In rare cases of homozygous or compound heterozygous severe PC or PS deficiencies, life-threatening purpura fulminans may develop within hours to days after birth, leading to rapidly progressive, extensive thrombosis resulting in tissue necrosis and organ failure. Homozygous AT deficiency is generally incompatible with life.

As in adults, VTE is often associated with multiple factors, and risk factors are also clinically relevant in minors. It has been shown that up to 80% of VTE events in children occur in association with central venous catheters.[149] In adolescent girls, hormonal factors (e.g., use of estrogen-containing contraceptives) are becoming increasingly important and are found in 30–40% of patients with VTE aged 12–18 years.[150] Therefore, adolescent girls should undergo thrombophilia testing for the same reasons as adult women.

In addition, thrombophilia testing should generally be considered for young and adolescent girls after a previous VTE, as thrombophilia is associated with VTE more commonly in children and adolescents than in adults. This applies in particular to those with an additional positive family history of VTE or thrombophilia. In a cohort study of unselected patients with VTE, hereditary thrombophilia was detected in 50% of patients when VTE manifested before the age of 20.[5]

Current pediatric guidelines recommend to avoid thrombophilia testing in cases with CVC-associated thrombosis or VTE in the context of active tumor disease and no positive family history.[149] [151] However, a meta-analysis from 2016, which included 16 cohort studies with 1279 children, 277 of whom had CVC-related DVT, calculated a prevalence of at least one thrombophilic trait of approximately 20% (95% CI 14–26%).[152] This exceeds the expected prevalence of thrombophilia in the healthy normal population. It should also be noted that 9 of the 16 studies were conducted on patients with malignant tumors. Remarkably, in this meta-analysis, the presence of at least one thrombophilic trait was related to a 3-fold increased risk of CVC-related VTE (pooled OR 3.2; 95% CI 1.56–6.54). The association with thrombophilia was even higher for patients with symptomatic VTE (pooled OR 6.71; 95% CI 1.93–23.37) than for asymptomatic VTE (pooled OR 2.14; 95% CI 1.10–4.18).

Young and adolescent girls without previous VTE but with one or more first-degree relatives with severe thrombophilia should be tested for the defect known in their family. As the absolute risk of VTE is very low in early childhood, testing should be performed once the girl reaches adolescence, and in particular when hormonal contraception is being considered.

The prerequisite for genetic thrombophilia testing is the provision of information, consent, and extensive genetic counseling to the patient themselves—as far as possible—and their parents according to the GenDG.[37] [38] During the consultation, in addition to medical advantages for the further course of treatment, any disadvantages should also be addressed, such as the psychological burden of knowing about an increased risk of VTE or an unfavorable risk assessment when decisions on certain career choices or private insurance policies are pending.

Final Remarks

Using the Delphi method, our expert panel within the Standing Committee of Women’s Health Issues of the Society of Thrombosis and Haemostasis Research has developed recommendations for women-specific issues regarding testing for thrombophilia. The agreed statements and voting results are summarized in [Table 5].

Table 5 Consensus statements and results of the Delphi voting process.

No.	Statement	Agree (n)	Disagree (n)	Consensus (%)	Neutral (n)
1	Women with unprovoked VTE should be offered thrombophilia screening with the aim of deciding on the type, duration, and intensity of anticoagulation. This applies in particular to women of childbearing age and women with a positive family history	17	0	100%	1
2	Women with a VTE that has occurred while taking a CHC should be offered thrombophilia screening. This applies in particular to women with a positive family history of VTE or thrombophilia	17	0	100%	1
3	Women with a VTE that has occurred during pregnancy or in the postpartum period should be offered thrombophilia screening. This applies in particular to women with a positive family history of VTE or thrombophilia	17	0	100%	1
4	Women with a VTE that has occurred during menopausal hormone therapy (MHT) may be offered thrombophilia screening if the results are expected to influence the strategy of secondary prophylaxis Women with a VTE that has occurred during MHT should be offered thrombophilia screening if there is a positive family history of VTE	16	0	100%	2
5	Transgender people with a VTE that has occurred during gender-affirming hormone therapy may be offered thrombophilia screening if the results are expected to influence the strategy of secondary prophylaxis	17	0	100%	1
6	Thrombophilia testing in women with a VTE provoked by a strong nonhormonal trigger is not recommended	16	1	94%	1
7	Breast cancer patients with a history of VTE may be offered thrombophilia testing if the results are expected to have an impact on the strategy of secondary prophylaxis	17	0	100%	1
8	Testing for antiphospholipid antibodies is recommended for all women who meet the clinical criteria for an obstetric APS, regardless of whether thromboembolic events have occurred previously Testing for hereditary thrombophilia in women who suffered pregnancy complications without a history of VTE cannot generally be recommended	14	2	88%	2
9	Testing for antiphospholipid antibodies is recommended in women with implantation failure after medically assisted reproduction who meet the clinical criteria for OAPS or with a history of thromboembolic events Testing for hereditary thrombophilia in women without previous VTE who suffered implantation failure after medical assisted reproduction is not recommended	14	1	93%	3
10	Thrombophilia testing is not generally recommended for women with no history of VTE who have a positive family history of VTE or thrombophilia and are starting combined hormonal contraception The primary approach should be to use estrogen-free contraception. However, if estrogens are essential, then testing for the known thrombophilia in the family may be carried out to assess the risk of VTE before starting estrogen treatment	16	1	94%	1
11	Thrombophilia testing is not generally recommended for women with no history of VTE who have a positive family history of VTE or thrombophilia and are planning to become pregnant Thrombophilia testing may be offered to women with no history of VTE who have a positive family history of VTE or thrombophilia if the results are expected to have an impact on the strategy of primary VTE prophylaxis during pregnancy or postpartum	15	0	100%	3
12	Thrombophilia testing is not generally recommended for women without a history of VTE but with a positive family history of VTE or thrombophilia who are considering menopausal hormone therapy. A nonoral form of application (e.g., transdermal, vaginal) should primarily be chosen for estrogen therapy. However, if an oral application is essential, a test of the known thrombophilia in the family may be carried out before starting treatment in order to assess the risk of VTE	17	0	100%	1
13	Thrombophilia testing is recommended for minors with a history of VTE	17	1	94%	0

Abbreviations: APS, antiphospholipid syndrome; CHC, combined hormonal contraceptive; OAPS, obstetric antiphospholipid syndrome; VTE, venous thromboembolism.

Contributorsʼ Statement

B.L.: conceptualization, data curation, formal analysis, methodology, project administration, supervision, visualization, writing—original draft, writing—review and editing; R.B.: conceptualization, data curation, formal analysis, methodology, writing—review and editing; F.B.: conceptualization, data curation, formal analysis, methodology, writing—review and editing; C.H.: conceptualization, data curation, formal analysis, methodology, writing—review and editing; E.L.-L.: conceptualization, data curation, formal analysis, methodology, writing—review and editing; H.R.: conceptualization, data curation, formal analysis, methodology, writing—review and editing; C.P.: conceptualization, data curation, formal analysis, methodology, software, supervision, validation, writing—review and editing.

Acknowledgement

We would like to thank the following experts who participated in the Delphi expert panel, provided advice, supplied additional literature, and thus contributed to the content of this manuscript: Charis von Auer, Hämostaseologie und Hemophilia-Comprehensive Care Center (HCCC), Universitätsmedizin Mainz; Jan Beyer-Westendorf, Bereich Hämatologie und Hämostaseologie, Universitätsklinikum Carl Gustav Carus Dresden; Alessandra Bosch-Spiteri, Spezielle Pädiatrische Onkologie-Hämatologie (FMH), Universitäts-Kinderspital Zürich; Kai Gutensohn, Werlhof-Institut MVZ GmbH, Hannover; Konstantin Kirchmayr, punktmed Medizinisches Versorgungszentrum GmbH, Amberg; Manuela Krause, Hämostaseologie, DKD Helios Klinik Wiesbaden; Michael Krause, Zentrum für Blutgerinnungsstörungen Leipzig; Sandra Marten, Bereich Hämatologie und Hämostaseologie, Universitätsklinikum Carl Gustav Carus Dresden; Jürgen Ringwald, MVZ Labor Volkmann Karlsruhe; Ute Scholz, Zentrum für Blutgerinnungsstörungen Leipzig; Swee Wenning, Hämophilie-Zentrum und Gerinnungsambulanz, Kurpfalzkrankenhaus Heidelberg.

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Publication History

Received: 23 September 2025

Accepted after revision: 30 December 2025

Article published online:
12 February 2026