Hereditary Thrombophilias

Literature and regulatory information updated: 6 October 2026.

Factor V Leiden, prothrombin G20210A variant and hereditary deficiencies of antithrombin, protein C and protein S — risks, testing, contraception, pregnancy, anticoagulation and severe neonatal forms

0. Initial Reference Table

1. Introduction

Hereditary thrombophilias are genetic abnormalities of haemostasis that shift the balance between the procoagulant and natural anticoagulant systems towards thrombus formation. Their predominant clinical expression is venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of venous thrombosis in the general population is approximately one case per 1000 person-years and, in the United States, VTE causes approximately 50,000 deaths annually. VTE is a multifactorial disease with gene–gene and gene–environment interactions: genetic causes are identified in approximately 25% of unselected cases of venous thrombosis and up to 63% of familial cases [1]. The central concept this article seeks to convey is the gap between relative and absolute risk: common variants (FVL and prothrombin G20210A) multiply risk, but most carriers will never have thrombosis, whereas deficiencies of the natural anticoagulants (AT, PC and PS), which are much rarer, confer absolute risks that may change clinical decisions [2, 3].

The history of these entities parallels the discovery of the natural anticoagulants themselves. In 1965, Olav Egeberg described a Norwegian family with recurrent venous thromboses and antithrombin levels reduced to approximately half, introducing the concept of hereditary thrombophilia [4]. In 1981, Griffin and colleagues identified protein C deficiency in a family with congenital thrombotic disease [5], and in 1983–1984 the first newborns with homozygous protein C deficiency and purpura fulminans or massive neonatal venous thrombosis were described [6, 7]. In 1984, Comp and Esmon associated partial protein S deficiency with recurrent VTE [8], and in 1990 homozygous protein S deficiency was described in an infant with purpura fulminans [9]. In 1993, Dahlbäck and colleagues described a familial thrombophilia characterised by a poor anticoagulant response to activated protein C [10], whose molecular basis — the Arg506Gln substitution (historical numbering, = NM_000130.5:c.1601G>A p.(Arg534Gln)) in factor V, named factor V Leiden after the city where it was identified — was published by Bertina and colleagues in 1994 [11]. In 1996, Poort and colleagues identified the 20210G>A variant in the 3' untranslated region of the prothrombin gene, associated with elevated plasma prothrombin levels and a higher risk of venous thrombosis [12].

The clinical utility of thrombophilia testing has progressively been redefined. The 2001 American College of Medical Genetics (ACMG) consensus on FVL testing [13], the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) group in 2011 [14], the 2022 British Society for Haematology (BSH) guideline [15] and the 2023 American Society of Hematology (ASH) guidelines on thrombophilia testing [2] converge on one principle: test only when the result changes management. The geneticist's role in this field is therefore both to identify families in which testing has value (particularly those with AT, PC and PS deficiencies) and to avoid tests that do not affect management and overinterpretation of low-impact results [1].

2. Molecular Genetics and Pathophysiology

2.1. The natural anticoagulant system

Thrombin generated by the coagulation cascade is simultaneously the principal procoagulant effector and the activator of its own brake: when bound to endothelial thrombomodulin, it activates protein C. Activated protein C (APC), with protein S as a cofactor, proteolytically inactivates factors Va and VIIIa. Antithrombin, a serpin (serine protease inhibitor), inhibits thrombin and factors Xa, IXa and XIa, and its activity is accelerated by heparin. The hereditary defects described in this article act at three distinct points: they make factor Va resistant to APC (FVL), increase the substrate for thrombin generation (prothrombin G20210A) or reduce the amount or function of natural inhibitors (AT, PC and PS) [1, 16, 17].

2.2. Factor V Leiden (F5)

The F5 gene encodes factor V, a plasma and platelet glycoprotein that, when activated by thrombin, acts as an essential cofactor for factor Xa in the prothrombinase complex. The NM_000130.5:c.1601G>A p.(Arg534Gln) variant (Arg506Gln in the former numbering, which omits the 28 amino acids of the signal peptide) abolishes the Arg534 cleavage site for APC. Factor Va Leiden is inactivated approximately ten times more slowly, persists longer in circulation and increases thrombin generation, creating a mild hypercoagulable state documented by elevated D-dimers, prothrombin fragment 1+2 and other activation markers. Other variants at APC cleavage sites, such as NM_000130.5:c.1001G>C p.(Arg334Thr) (F5 Cambridge; historical numbering Arg306Thr) and NM_000130.5:c.1000A>G p.(Arg334Gly) (historical numbering Arg306Gly), are not major risk factors but may contribute when combined with other genetic or acquired factors [16]. The high population frequency led to the hypothesis of a selective advantage of the heterozygous state [16].

The same gene causes the opposite disease: congenital factor V deficiency (parahaemophilia, Owren disease), which is autosomal recessive and haemorrhagic, with an incidence of the severe form of approximately one per million live births [18]. Coexistence of the two allelic classes gives rise to so-called pseudo-homozygotes — compound heterozygotes for FVL and a factor V deficiency variant — who show a homozygous pattern on an APC resistance assay despite having a single Leiden allele [16].

2.3. Prothrombin G20210A (F2)

The F2 gene encodes prothrombin (factor II), the vitamin K-dependent zymogen precursor of thrombin. The NM_000506.5:c.*97G>A (20210G>A) variant lies in the 3' untranslated region, 97 nucleotides downstream of the termination codon, and increases the efficiency and accuracy of processing of the messenger RNA 3' end, with mRNA accumulation and increased prothrombin synthesis; the mechanism is gain of function [12, 17]. Heterozygotes have, on average, plasma prothrombin approximately 30% above controls, but values overlap the normal range, so prothrombin measurement is not diagnostic. Haplotype analysis indicates a single mutational event occurring 20,000 to 30,000 years ago, after populations of European ancestry separated from Asian and African populations (a later analysis places it 21,000–24,000 years ago, at the end of the last glaciation) [17]. Other F2 variants are of uncertain significance: NM_000506.5:c.1787G>T p.(Arg596Leu) (prothrombin Yukuhashi), which confers antithrombin resistance and was described in a Japanese family with very early thrombosis, other substitutions at Arg596 (prothrombins Belgrade, Amrita and Padua 2), NM_000506.5:c.1621C>T p.(Arg541Trp) and 20209C>T (historical numbering, = NM_000506.5:c.*96C>T), described mainly in individuals of African ancestry; routine testing for these is not recommended [17]. Conversely, biallelic loss-of-function variants in F2 cause congenital prothrombin deficiency (hypoprothrombinaemia and dysprothrombinaemia, OMIM 613679), a bleeding disorder [17].

2.4. Antithrombin deficiency (SERPINC1)

Antithrombin is the most important physiological inhibitor of coagulation. Hereditary deficiency is classified into type I, quantitative, with antigen and activity reduced to approximately 50%, and type II, qualitative, with normal antigen and deficient function; type II is subdivided into IIa (reactive site, the most thrombogenic), IIb (heparin-binding site, more frequent but less thrombogenic in heterozygosity) and IIc (pleiotropic) [19]. Because heparin acts through antithrombin, deficiency also manifests as relative heparin resistance, namely inability to achieve the anticoagulation target with usual doses of unfractionated or low-molecular-weight heparin [19, 20]. In the largest paediatric cohort, type I accounted for 76.7% of cases [21].

2.5. Protein C deficiency (PROC)

Protein C is a vitamin K-dependent zymogen, activated by the thrombin–thrombomodulin complex, that inactivates factors Va and VIIIa and contributes to endothelial barrier function. Type I deficiency has concordantly low activity and antigen; type II has low activity with normal antigen. In the severe biallelic form (homozygosity or compound heterozygosity), activity is typically undetectable or very low, and thrombin generation is unopposed from birth [22, 23]. The short half-life of protein C explains coumarin-induced skin necrosis: on initiation of a vitamin K antagonist, protein C falls faster than factors II and X, creating a transient window of hypercoagulability [22, 24].

2.6. Protein S deficiency (PROS1)

Protein S is the non-enzymatic cofactor of APC. Approximately 60% circulates bound to C4b-binding protein (C4BP) and is inactive as a cofactor; the functionally relevant fraction is free protein S. Type I (low total and free PS, low activity), type III (low free PS and activity with normal total PS) and the rare type II (normal antigen, low cofactor activity) are described; approximately 95% of patients have type I or III [25]. In population studies using exome sequencing and plasma proteomics (UK Biobank, n = 426,436; All of Us, n = 204,006), heterozygosity for maximum-impact PROS1 variants (nonsense, frameshift and essential splice-site variants) had an adjusted prevalence of 0.0091% in the United Kingdom and 0.0178% in the United States and was associated with an OR of 14.01 (95% CI 6.98–27.14) for VTE, with total protein S at 48% of normal in carriers; less damaging missense variants were more frequent (0.20–0.22%) and conferred only a marginal risk [26]. The same study showed that coding PROS1 variants explain low plasma levels poorly, as these depend mainly on acquired factors or genetic factors in trans [26].

2.7. Gene–gene and gene–environment interaction

Individual risk results from the sum of factors: number of risk alleles, coexistence of another hereditary or acquired thrombophilia (antiphospholipid syndrome, paroxysmal nocturnal haemoglobinuria, myeloproliferative neoplasms, elevated coagulation factor levels) and circumstantial factors (pregnancy, puerperium, oestrogens, malignancy, central venous catheters, travel, immobilisation, obesity, lower-limb trauma and age) [16]. Pregnancy increases baseline risk through increased factor VIII, and the effect of oestrogens combines supra-additively with FVL and prothrombin G20210A [1, 16]. Approximately 8–14% of G20210A heterozygotes have another hereditary thrombophilia, and 20–40% of symptomatic G20210A heterozygotes also carry FVL [17].

3. Clinical Spectrum and Manifestations by System

3.1. Venous thromboembolism: magnitude of risk by defect

The principal manifestation of all hereditary thrombophilias is VTE, particularly lower-limb DVT and PE. The following table brings together the relative and absolute risk estimates from the principal sources.

The divergence between the high relative risks in family studies and the intermediate ORs in the 2024 meta-analysis for AT, PC and PS deficiencies reflects the heterogeneous thrombogenicity of the underlying variants and selection bias towards families with thrombosis [27]. In the Italian family study, mean age at onset was between 30 and 40 years for all defects, with an earlier peak in women (21–40 years), and lifetime risk was 4.4 times higher in AT deficiency than in APC resistance [28].

3.2. Atypical sites

FVL heterozygotes have an approximately sixfold higher risk of primary upper-limb thrombosis and superficial venous thrombosis unrelated to varicose veins, malignancy or autoimmune disease; the meta-analysis of cerebral venous thrombosis (1822 cases and 7795 controls) showed an OR of 2.70 (95% CI 2.16–3.38), that of retinal vein occlusion an OR of 1.66 (1.19–2.32), and the prevalence of FVL in Budd-Chiari syndrome ranged from 4% to 26% [16]. Prothrombin G20210A is associated with a three- to sixfold higher risk of upper-limb thrombosis (nine- to 14-fold in oral contraceptive users), a six- to tenfold higher risk of cerebral venous thrombosis (80- to 150-fold with oral contraception), a fourfold higher risk of portal vein thrombosis and an almost fourfold higher risk of superficial venous thrombosis, without a significant increase in Budd-Chiari syndrome; among patients with DVT, G20210A heterozygotes had PE in 32%, compared with 19% in FVL carriers and 17% in those without thrombophilia [17]. In splanchnic thromboses, pooled prevalences of AT, PC and PS deficiencies were 3.9%, 5.6% and 2.6% in portal vein thrombosis and 2.3%, 3.8% and 3.0% in Budd-Chiari syndrome [15]. FVL + G20210A double heterozygosity is associated with a higher frequency of hepatic, mesenteric and cerebral thrombosis [17].

3.3. Childhood and the neonatal period

Paediatric VTE is multifactorial: more than 90% of patients have more than one risk factor, and central venous catheters account for more than 90% of neonatal and more than 50% of paediatric VTE [15]. Asymptomatic children heterozygous for FVL had no thrombotic complications during a mean follow-up of five years; FVL increases the risk of neonatal and paediatric cerebral venous thrombosis (OR 2.74) [16]. G20210A heterozygotes have a three- to fourfold higher relative risk of VTE, and the presence of two or more thrombophilias increases it to more than ninefold [17]. AT deficiency is the defect with the greatest expression in childhood: in a cohort of 968 individuals from 441 families, 7.5% had had thrombosis before 19 years, with an annual incidence approximately 300 times higher than in the general paediatric population (0.41%/year vs 0.0014%/year), two incidence peaks (neonatal, with idiopathic thromboses at atypical sites, and adolescence, with triggers similar to those in adults) and cerebral venous thrombosis in 17.8% of paediatric events, with six deaths [21]. OXF recommends thrombophilia and FVL testing in children with cerebral palsy attributed to perinatal stroke [1], but BSH does not recommend routine testing in neonatal stroke (Grade 2B) [15].

3.4. Neonatal purpura fulminans (severe PC and PS deficiencies)

Severe biallelic protein C deficiency (severe congenital protein C deficiency, SCPCD) usually manifests in the first hours or days of life as purpura fulminans: small ecchymoses rapidly progress to purplish-black purpuric lesions, with blisters, haemorrhagic necrosis and disseminated intravascular coagulation (DIC). These are accompanied by cerebral thrombosis (infarction, secondary haemorrhage and hydrocephalus, with neurological sequelae), renal vein thrombosis and retinal vascular thrombosis with vitreous haemorrhage and retinal detachment; bilateral blindness is frequent in published series [23]. The estimated incidence of the hereditary neonatal form is between one case per million and one per four million births [29]. Biallelic patients with residual activity may present later, in childhood or adulthood, with VTE or coumarin-induced skin necrosis [22, 23]. Biallelic protein S deficiency produces an overlapping presentation, with DIC (thrombocytopenia, prolonged prothrombin and activated partial thromboplastin times, low fibrinogen, elevated D-dimers), multifocal thromboses and intracranial haemorrhage, frequently in consanguineous families [9, 25]. Homozygosity for type IIb AT deficiency is the AT variant compatible with life that may manifest as severe childhood thrombosis [19].

3.5. Pregnancy and puerperium

Normal pregnancy increases VTE risk five- to tenfold, and the highest risk occurs in the first six weeks after delivery [15, 16]. Absolute pregnancy-associated VTE risk by defect, according to the Bayesian meta-analysis of 36 studies, is summarised in the following table [3].

GeneReviews adds that FVL heterozygotes have a five- to eightfold higher risk of VTE in pregnancy, with an absolute risk of approximately 1% per pregnancy (3% with a family history), and homozygotes have a 17- to 34-fold increase, with an absolute risk of 2.2–4.8% per pregnancy, rising to 14% with a positive family history or age over 34 years [16]. In G20210A heterozygotes without other factors, absolute risk is 1:200 to 1:300 pregnancies; in double heterozygotes, the probability of VTE in pregnancy and puerperium is 5.5% below 35 years and 8.2% above [17]. Women with previous unprovoked VTE and FVL had recurrence in 20% of pregnancies [16]. In OXF, 60% of pregnant women with venous thrombosis were FVL carriers [1]. In type I AT deficiency, population-based data point to risks of 15–50% per pregnancy, but with a very wide range [30].

3.6. Non-thromboembolic obstetric complications

The association between hereditary thrombophilias and placental complications is weak and inconsistent. OXF reports a two- to threefold risk of late pregnancy loss for FVL and an association with pre-eclampsia, placental abruption, intrauterine growth restriction and fetal death, with variation between studies [1]. The meta-analysis restricted to prospective cohorts showed pregnancy loss in 4.2% of FVL carriers compared with 3.2% (OR 1.52) and did not confirm an association with pre-eclampsia or placental abruption; a Danish study found ORs of 1.6 for severe pre-eclampsia, 1.5 for severe growth restriction and 1.7 for symptomatic abruption [16]. FVL homozygosity was associated with fetal death (OR 87.44) in a North American study but not in a regional Stockholm study [16]. For G20210A, the maximum plausible increase in pregnancy loss risk is two- to threefold [17]. In a Portuguese series of 100 women with three or more consecutive miscarriages and 100 controls, FVL prevalence was 5% in both groups and G20210A prevalence 3% vs 1%, with no association with embryonic loss before ten weeks [31]. AT deficiency is also associated with pregnancy loss [32, 33]. The therapeutic question was tested in randomised trials: in ALIFE2, involving 326 women with two or more pregnancy losses and hereditary thrombophilia, low-dose LMWH did not increase the live-birth rate (72% vs 71%), and in TIPPS antepartum dalteparin did not reduce a composite outcome of placental complications, pregnancy loss and VTE (see 7.11) [34, 35].

3.7. Arterial thrombosis

The most recent meta-analysis found, for FVL, ORs for cerebrovascular disease of 1.48 in heterozygotes and 2.76 in homozygotes, and ORs for coronary disease of 1.39 and 1.68, respectively [16]. The G20210A variant is not convincingly associated with arterial thrombosis [17], and PROS1 variants were not associated with myocardial infarction, peripheral arterial disease or non-cardioembolic ischaemic stroke [26]. BSH does not recommend hereditary thrombophilia testing in arterial thrombosis (Grade 1B) or stroke at any age (Grade 1A) [15].

3.8. Chronic sequelae

Post-thrombotic syndrome and chronic venous hypertension are sequelae of VTE and are themselves recurrence risk factors; OXF recommends looking for them on physical examination [1]. FVL heterozygosity is not associated with increased mortality or reduced life expectancy, even with a history of VTE [16].

4. Clinical Recognition and Warning Signs

History-taking is the principal stratification tool. OXF recommends a three-generation pedigree with targeted enquiries about venous thrombosis (age and site; young age suggests homozygosity, particularly for PC or PS deficiencies), PE, pregnancy loss and pre-eclampsia, myocardial infarction before 50 years (particularly in women), persistent leg ulcers and childhood stroke; for each event, the presence of precipitating factors (trauma, pelvic, vascular or orthopaedic surgery, malignancy, immobilisation, pregnancy, oestrogens) and acquired factors (smoking, diabetes, lupus) should be recorded [1]. Family history has value independently of genotype: a first-degree relative with thrombosis doubles risk (OR 2.2), and more than one affected relative raises it to an OR of 3.9; risk is fivefold higher with one relative affected before 50 years and 18-fold higher with two or more affected relatives [16].

Warning signs for a high-risk thrombophilia include VTE before 40–50 years that is unprovoked or associated with weak risk factors, with at least one affected first-degree relative; recurrent VTE; thrombosis at atypical sites without an obvious local cause; VTE in pregnancy, puerperium or during combined contraception; heparin resistance (inability to achieve the anti-Xa or activated partial thromboplastin time target with adequate doses), suggesting AT deficiency; skin necrosis in the first days of warfarin, suggesting PC or PS deficiency; and, in the newborn, rapidly progressive purpura with DIC in the first hours or days of life, particularly in children of consanguineous parents [1, 15, 19, 24, 29]. Neonatal purpura fulminans is an emergency: in this presentation, blood sampling for PC and PS measurement should precede plasma administration whenever possible, without delaying treatment [15, 29].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. When to test and when not to test

Current recommendations are predominantly conditional and based on evidence of very low certainty, because they derive from modelling rather than trials comparing strategies with and without testing [2]. The table summarises the 23 ASH 2023 recommendations and the principal positions of BSH 2022 and GeneReviews.

The 2001 ACMG consensus, reproduced in OXF, indicated FVL testing in VTE before 50 years, thrombosis at atypical sites (hepatic, mesenteric and cerebral veins), recurrent VTE, VTE with a strong family history, VTE in pregnancy or during oral contraception, relatives of patients with VTE before 50 years and myocardial infarction in female smokers younger than 50 years, and allowed it in VTE after 50 years without active malignancy, relatives of known carriers and women with recurrent pregnancy loss or severe placental complications; it did not recommend population screening or testing in arterial disease [1, 13]. Several of these indications were restricted by subsequent guidelines, particularly testing in unprovoked VTE, obstetric complications and arterial disease [2, 14, 15]. The 2024 GeneReviews recommends FVL genotyping when the APC resistance assay is low or borderline, in patients receiving direct thrombin or factor Xa inhibitors (which interfere with the assay), in the presence of lupus anticoagulant with a prolonged baseline activated partial thromboplastin time, in pregnancy-, puerperium- or COC-associated VTE and in VTE up to 40 years that is spontaneous or associated with weak factors and an affected first-degree relative [16].

5.2. Tests by defect

In the presence of FVL or G20210A, GeneReviews recommends testing for the other common defect and antiphospholipid antibodies (lupus anticoagulant using multiple phospholipid-dependent assays, anticardiolipin and anti-β2-glycoprotein I), adding PC activity, AT activity and free PS or PS activity only in high-risk patients (recurrent VTE at a young age or a strong family history of early VTE); it does not recommend homocysteine measurement, MTHFR genotyping or measurement of factor VIII or other coagulation factors [16, 17]. OXF, predating this review, suggested plasma homocysteine in FVL-positive individuals and recalled classical homocystinuria (autosomal recessive) as a cause of very high thromboembolic risk [1]. BSH recommends testing the natural anticoagulants only after three months of anticoagulation for acute thrombosis (Grade 2B), not measuring factor VIII routinely (Grade 2C), testing for antiphospholipid antibodies after unprovoked VTE (Grade 1B) and not testing MTHFR or SERPINE1 variants (Grade 2C) [15].

5.3. Molecular tests and panels

AT, PC and PS deficiencies are too heterogeneous for a targeted molecular test, and diagnosis begins with functional assays [1]. BSH recommends genetic testing to identify the causal variant of a phenotypically demonstrated deficiency when the result will influence management (Grade 2B) and does not recommend genetic testing to predict a first episode (Grade 2B) [15]. The Genomics England R97 panel, “thrombophilia with a likely monogenic cause”, includes 15 genes (among them SERPINC1, PROS1, PROC, F2, F5 and the fibrinogen genes) and is intended for patients with VTE before 40 years, spontaneous or associated with weak factors, and at least one affected first-degree relative, when the result has clinical impact [15]. Genotyping complements functional assays: it identifies variants not detected by classical assays and allows risk stratification, since risk varies between SERPINC1 variants; conversely, functional deficiencies without an identified variant exist [36]. Variant classification follows the five-class ACMG/AMP system; FVL and G20210A are low-penetrance risk variants and should not be communicated as Mendelian causes of disease [16, 17]. ClinGen assigns limited actionability to FVL heterozygosity, moderate actionability to FVL homozygosity and FVL + G20210A double heterozygosity, limited actionability to adult PC and PS deficiencies, and has no assertion for F2 or SERPINC1; the absence of an assertion for AT deficiency reflects only a lack of curation, not an absence of clinical consequences [2, 37].

5.4. Practical algorithm

Faced with a first VTE, the clinician begins by classifying the event (provoked by a major surgical or non-surgical transient factor, hormonal, gestational, unprovoked or at an atypical site) and deciding whether the testing result would change anticoagulation duration, according to ASH R1–R10 [2]. If testing is indicated, it is performed outside the acute phase and, for AT, PC and PS, after three months of anticoagulation and with attention to anticoagulant interference [15, 36]. Functional deficiencies are confirmed on a second sample and, when the result has consequences for the patient or family, the relevant gene is sequenced [15]. In asymptomatic relatives, testing is justified only when the familial defect is known and belongs to the high-risk group (AT, PC, PS, homozygous FVL or double heterozygosity), in the context of pregnancy, contraception, HRT or exposure to a minor risk factor [2]. In the newborn with purpura fulminans, urgent PC and PS measurement (using neonatal reference ranges) guides replacement [15].

5.5. Limitations of genetic tests and report content

Technical coverage depends on the test type. Targeted FVL and G20210A genotyping detects only these two positions; a negative result says nothing about other F5 or F2 variants (F5 Cambridge, F5 Hong Kong, prothrombin Yukuhashi) or AT, PC or PS deficiencies [16, 17]. SERPINC1, PROC or PROS1 sequencing (Sanger or a next-generation sequencing panel) covers exons and intron–exon junctions but does not reliably detect deletions and duplications of one or more exons, which require MLPA or validated copy-number analysis; deep intronic, regulatory or splicing variants outside the regions analysed, low-level mosaicism and abnormalities in regions with pseudogene homology (the PROS2P pseudogene requires specific design in PROS1 analysis) lie outside the scope of many assays [15, 25, 36]. A negative genetic test does not exclude a persistent functional deficiency confirmed in two samples outside known interference, and functional deficiencies without an identified variant exist [36]. Conversely, an identified variant does not obviate functional characterisation (type I or II, AT subtype IIb), which determines risk [19, 36].

The report should specify the gene, reference transcript with version (MANE Select transcripts: F5 NM_000130.5, F2 NM_000506.5, SERPINC1 NM_000488.4, PROC NM_000312.4, PROS1 NM_000313.4), HGVS nomenclature, zygosity, ACMG/AMP classification and technical limitations [38, 39]. Classical literature uses historical numbering that should not be mixed with standardised numbering: FVL is NM_000130.5:c.1601G>A, p.(Arg534Gln), historically Arg506Gln (mature protein numbering, without the signal peptide), and the prothrombin variant is NM_000506.5:c.*97G>A, historically 20210G>A (position in the gene's original reference genomic sequence) [16, 17]. In ClinVar, FVL (VCV000000642, assessed by an expert panel) has a “drug response” assertion and G20210A (VCV000013310) is classified as pathogenic with low penetrance and an established risk allele; both should be communicated as risk variants, not as Mendelian causes of disease [16, 17, 39]. Zygosity has practical consequences: FVL homozygosity, FVL + G20210A double heterozygosity and pseudo-homozygosity (FVL in trans with a factor V deficiency variant) are not equivalent, and the last can only be distinguished by functional and family studies [16]. A variant of uncertain significance in SERPINC1, PROC or PROS1 does not become pathogenic because it coexists with a low plasma level in a single patient, partially segregates in a small family or responds to anticoagulation; family segregation and functional studies are described as research, and classification changes only with new evidence meeting ACMG/AMP criteria [15, 36].

6. Differential Diagnosis

7. Treatments and Risk Management Strategies

7.1. General principles

The first episode of VTE is treated according to general guidelines, and the presence of a hereditary thrombophilia does not alter acute treatment [16, 17]. Guidelines suggest a direct oral anticoagulant (DOAC: dabigatran, edoxaban, rivaroxaban or apixaban) rather than warfarin, because of less bleeding and greater convenience, except in subgroups such as severe renal impairment, antiphospholipid syndrome or extreme body weights [16]. Duration is based on the balance between recurrence risk and bleeding risk: at least three months for VTE with a reversible transient factor; indefinite anticoagulation for unprovoked VTE with low or moderate bleeding risk, irrespective of genotype; and prolonged anticoagulation to be considered in FVL or G20210A homozygotes and carriers of combined thrombophilias, particularly with additional factors [16, 17, 40]. Isolated heterozygosity for FVL or G20210A is not an indication for prolonged anticoagulation, according to the American College of Chest Physicians and ASH [16, 17, 40]. OXF records that FVL homozygotes with a first VTE do not appear to benefit from prolonged full-dose oral anticoagulation but should receive short-term prophylaxis in risk situations, particularly pregnancy, as should FVL + G20210A double heterozygotes (present in 1:1000 of the population and 1:50 of patients with thromboembolism) [1]. Patients with two or more VTE episodes require lifelong anticoagulation [16].

7.2. Anticoagulant drugs: prescribing information doses

When warfarin is used, it is started simultaneously with LMWH or fondaparinux, with a minimum overlap of five days and until INR has remained in the therapeutic range for 24 hours; the INR target of 2.5 is effective even in FVL and G20210A homozygotes [16, 17]. In PC and PS deficiencies, warfarin must never be started alone or with high loading doses: initiation must take place under therapeutic heparin anticoagulation because of the risk of coumarin-induced skin necrosis [22, 24, 25]. In severe thrombophilias, the communication from the International Society on Thrombosis and Haemostasis (ISTH) physiological anticoagulants subcommittee concluded, based only on cohorts, that full-dose DOACs and vitamin K antagonists have similar efficacy and bleeding (recurrence HR for DOACs vs warfarin between 0.3 and 0.75), noted greater treatment failure in severe PS deficiency (< 20%) and possibly in AT Budapest 3 homozygosity (heparin-binding type II), and advised against reduced-dose DOACs because of lack of evidence [48].

7.3. Children

Treatment of paediatric VTE is not influenced by the presence of FVL or G20210A. A child with a first VTE receives unfractionated heparin or LMWH for at least five days; ASH suggests LMWH or warfarin for symptomatic DVT or PE, with frequent preference for LMWH in infants and patients with complex disease, and DOACs have obtained paediatric approval with similar efficacy and safety [16]. Paediatric indications differ, however, between drugs and jurisdictions: in the United States, rivaroxaban is indicated for VTE from birth to 18 years (after at least five days of parenteral anticoagulation), dabigatran pellets from three months to 12 years and dalteparin from birth (gestational age ≥ 35 weeks), whereas US apixaban prescribing information has no paediatric indication; in the European Union, apixaban is authorised for paediatric VTE from 28 days to 18 years and rivaroxaban has paediatric indications defined by weight and formulation [42, 44, 45, 49, 50]. DOAC use in a child outside these age, weight or jurisdictional limits is off-label use, even when trial evidence in nearby ages makes it plausible. Anticoagulation is continued for three months after VTE provoked by a resolved factor, for at least three months and until resolution of the factor for persistent potentially reversible factors, and for six to 12 months after a first unprovoked VTE [16, 17].

7.4. Primary prevention and risk situations

Prolonged anticoagulation is not indicated in asymptomatic FVL or G20210A heterozygotes because the annual major bleeding risk on warfarin (1–3%) exceeds the annual thrombosis risk (< 1%) [16, 17]. Approximately half of first thromboses in FVL heterozygotes occur in association with circumstantial factors, and short-term prophylaxis in those circumstances may prevent some episodes, although there is no direct evidence of benefit [16]. OXF recalls that only major surgery (abdominal under general anaesthesia, orthopaedic) constitutes a relevant risk, that minor surgery (dental, biopsies under local anaesthesia) is not a high-risk situation, and that hydration, exercise and compression stockings are recommended during long journeys [1]. ASH 2023 suggests thromboprophylaxis in the presence of minor risk factors only in carriers of AT, PC or PS deficiency from families with VTE [2]. Travel-associated risk is marked in FVL carriers (OR 8.1), particularly with non-O blood group and excess weight [16].

7.5. Contraception and hormone therapy

COC use has a supra-additive effect with FVL (VTE OR 11–41) and G20210A (OR 16–59); in FVL homozygotes or double heterozygotes, ORs range from 17 to 110 [16, 17]. Risk is highest in the first year of use (OR 62.2 in the first year vs 25.4 thereafter) and varies with the progestogen: gestodene OR 22.1, desogestrel OR 26.3, levonorgestrel OR 17.4 and cyproterone OR 31.8 in FVL carriers [16]. Absolute VTE incidence in COC users carrying FVL or G20210A ranged from 0.49 to 2.0 per 100 pill-years (0.86 in homozygotes or double heterozygotes), compared with 0.19 in non-carriers [17]. Progestogen-only contraception is associated with lower risk (OR 5.4 in FVL carriers) [16]. Transdermal and vaginal forms of combined contraception have a risk at least equal to that of COCs [17]. Oral HRT increases risk two- to fourfold in the general population and threefold more in FVL or G20210A carriers than in users without thrombophilia; transdermal oestrogens did not increase risk in observational studies (HR 1.1 vs 1.7 for the oral route in FVL carriers) [16, 17]. Selective oestrogen receptor modulators (tamoxifen, raloxifene) double risk [17].

The practical recommendations are as follows: heterozygous women with previous VTE and all homozygous women should avoid oestrogen-containing contraception and HRT; asymptomatic heterozygotes should be informed and encouraged to consider alternatives, avoiding third-generation and higher-risk progestogens if they choose COCs, and using low-dose transdermal preparations if they need short-term HRT [1, 16, 17]. ASH suggests avoiding COCs and HRT in women from families with AT, PC or PS deficiency who prove to be carriers [2]. OXF allows testing of adolescent daughters of patients with thrombophilia when the result will influence contraceptive choice [1].

7.6. Pregnancy: antepartum and postpartum prophylaxis

LMWH is the anticoagulant of choice in pregnancy; warfarin is teratogenic (recognisable embryopathy), and dabigatran and direct Xa inhibitors are contraindicated in pregnancy and breastfeeding because of absent fetal and neonatal safety data and reproductive toxicity in animals [1, 16, 24]. During breastfeeding, unfractionated heparin, LMWH, fondaparinux, danaparoid and warfarin are safe options [16]. ASH 2018 recommends (strong, low certainty) antepartum prophylaxis when there is previous unprovoked or hormonally associated VTE and suggests not providing it when previous VTE was associated with a resolved non-hormonal factor [51]. The table summarises recommendations for women without previous VTE.

In ASH 2023 modelling, baseline first VTE risk considered for each period (eight months antepartum or six weeks postpartum) was 37.5 per 1000 for FVL homozygosity, 18 per 1000 for AT deficiency, 4 per 1000 for PC deficiency, 8 per 1000 for PS deficiency and 20.25 per 1000 for double heterozygosity, with a relative reduction through prophylaxis of 0.41 (95% CI 0.32–0.54) and baseline major bleeding risk of 6.34 per 1000 antepartum and 8.46 per 1000 postpartum [2]. BSH, based on the Croles meta-analysis, considers that women with AT, PC or PS deficiency or homozygous FVL should be considered for thromboprophylaxis in pregnancy and puerperium, and that FVL or G20210A heterozygotes or double heterozygotes should generally not receive prophylaxis solely on the basis of thrombophilia and family history [3, 15]. Women with previous unprovoked or hormonal VTE receive prophylaxis throughout pregnancy and for six weeks after delivery, so thrombophilia testing does not change their management [15, 17]. Extending prophylaxis between six and 12 weeks postpartum does not appear to provide a relevant benefit [16].

LMWH doses in pregnancy according to the Royal College of Obstetricians and Gynaecologists (RCOG), Green-top Guideline 37a [30]:

The guideline does not define a maximum dose; above 170 kg the dose is calculated by weight [30].

These are standard prophylactic doses; GeneReviews, citing ASH 2018, suggests standard-dose LMWH antepartum and standard or intermediate dose postpartum [16]. For treatment of acute VTE in pregnancy, ASH 2018 recommends LMWH rather than unfractionated heparin (strong) and allows administration once or twice daily without routine anti-Xa monitoring [51]; the therapeutic enoxaparin doses in prescribing information are those given in point 7.2 [41]. Enoxaparin use in pregnancy outside these prescribing information indications constitutes guideline-supported practice; data from a cohort of 693 live births showed no increase in major malformations [41].

7.7. Antithrombin deficiency: particular considerations

Management of AT deficiency has two specific aspects. First, heparin resistance: patients may fail to achieve the anti-Xa or activated partial thromboplastin time target with usual doses, and reported responses are dose adjustment, AT supplementation or switching to a direct thrombin inhibitor (argatroban, bivalirudin) [19, 20]. RCOG recommends that pregnant women with previous VTE associated with AT deficiency (frequently on prolonged oral anticoagulation) receive higher-dose LMWH (50%, 75% or full therapeutic dose) during pregnancy and for six weeks after delivery, that management be shared with specialist haematology, that anti-Xa monitoring using an assay without added exogenous AT be considered (four-hour peak of 0.5–1.0 IU/mL), and that AT replacement at the onset of labour or before caesarean delivery be considered; asymptomatic carriers may require an intermediate dose [30]. Dedicated reviews confirm the scarcity of trials and the need for joint planning with obstetrics and anaesthesiology [32, 33].

Second, AT concentrate is available. Thrombate III® (human antithrombin III, FDA-approved in 1991) is indicated in adults and children with hereditary AT deficiency for treatment and prevention of thromboembolism and prevention of perioperative and peripartum thromboembolism. The loading dose is calculated as [(120% − baseline level in %) × weight (kg)] / 1.4, assuming recovery of 1.4% per unit/kg; adjustments use (target level − trough) × weight / 1.4, and maintenance is approximately 60% of the loading dose every 24 hours, to maintain AT between 80% and 120%, with measurements 20 minutes after injection (peak), at 12 hours and before the next dose (trough). In surgery or obstetric procedures, AT is raised to normal and maintained for two to eight days; the half-life shortens after surgery, bleeding, acute thrombosis and during heparin treatment. Infusion takes place over 10–20 minutes (500 U vials, 50 U/mL after reconstitution); the most common adverse effects (≥ 5%) are dizziness, chest discomfort, nausea, dysgeusia and cramp-like pain; there is a risk of hypersensitivity and transmission of plasma-derived infectious agents [52]. Recombinant antithrombin (ATryn®) was authorised in the European Union in 2006 for VTE prophylaxis in surgery in patients with congenital AT deficiency, and authorisation was withdrawn in 2018 [53]. AT concentrate is an option when anticoagulation must be discontinued or is insufficient (delivery, bleeding, surgery, VTE during therapeutic anticoagulation) and does not constitute maintenance therapy [33].

7.8. Severe protein C deficiency: neonatal purpura fulminans

Purpura fulminans due to SCPCD requires protein C replacement within hours. Ceprotin® (human protein C concentrate; authorised in the EU in 2001 and by the FDA in 2007) is indicated in newborns, children and adults with severe congenital PC deficiency for prevention and treatment of venous thrombosis and purpura fulminans, including coumarin-induced skin necrosis in the EU [54, 55]. The prescribing information regimen for acute episodes and short-term prophylaxis is an initial dose of 100–120 IU/kg, followed by three doses of 60–80 IU/kg every 6 hours and maintenance of 45–60 IU/kg every 6 or 12 hours; for prolonged prophylaxis, 45–60 IU/kg every 12 hours. The target is a PC activity peak of 100% and a trough above 25%, monitored by a chromogenic assay; the maximum injection rate is 2 mL/min (0.2 mL/kg/min in children weighing less than 10 kg). Reported adverse effects are hypersensitivity reactions (rash, pruritus, dizziness); the product contains traces of heparin (risk of heparin-induced thrombocytopenia) and mouse protein, and more than 200 mg of sodium per dose [54]. In the prospective phase 2/3 trial with 15 patients, 94.7% of the 19 treated episodes of purpura fulminans or coumarin-induced skin necrosis were classified as effective, without concentrate-related adverse events [56]. The 2022 ISTH communication recommends PC concentrate as the preferred option for prolonged prophylaxis and the subcutaneous route as the preferred route because of problems with central venous catheters [23, 57]; the subcutaneous route is not included in prescribing information and is therefore off-label use documented in case series [23]. Another concentrate is available in Europe (Protexel®), whose information recommends 100 IU/kg/day one to three times weekly for prevention in severe deficiency [23].

When concentrate is unavailable, fresh frozen plasma is the alternative, with reported doses of 10–15 mL/kg every 8 to 12 hours, combined with heparin and DIC support [29, 58]. After the acute phase, maintenance consists of anticoagulation (a vitamin K antagonist or LMWH), with or without PC concentrate, and liver transplantation is a curative option in selected cases [29, 58]. Introduction of a vitamin K antagonist should be gradual and under full cover [22]. Neonatal gene editing for expression of modified protein C cured purpura fulminans in a murine model, without human data [59].

7.9. Severe protein S deficiency

No licensed protein S concentrate exists; urgent replacement uses fresh frozen plasma, followed by maintenance anticoagulation [15, 25]. Warfarin-induced skin necrosis has been described in PS deficiency, including immediately postpartum, when free PS is physiologically low [25].

7.10. Trials and investigational therapies

There are no targeted therapies in advanced-phase trials for common hereditary thrombophilias; GeneReviews refers to ClinicalTrials.gov and the European trial registry [16]. For SCPCD, the most recent data come from studies of the pharmacokinetics and efficacy of PC concentrate in Japanese patients and reports of continuous subcutaneous administration [23]; in Japan, post-marketing surveillance of all cases treated with Ceprotin® is ongoing (NCT06590974; observational study, seven planned participants, estimated completion in 2030) [60]. In AT deficiency, the open-label, uncontrolled phase 3 trial NCT04918173 evaluates plasma-derived AT concentrate Atenativ® in patients with congenital deficiency undergoing surgery or delivery (38 planned participants, from 12 years, centres in the United States and 13 European and Middle Eastern countries; primary endpoint: incidence of thrombotic events; estimated primary completion in December 2026, no results yet) [60]. In October 2026, no advanced-phase trials of new anticoagulants (for example, factor XI inhibitors) specifically targeting patients with hereditary thrombophilia were identified in these searches; this absence in the sources consulted does not prove that ongoing studies do not exist.

7.11. Pivotal trials and limitations of comparisons between studies

These studies do not allow strategies to be ranked through indirect comparison. ALIFE2 and TIPPS are negative trials contradicting the still frequent practice of prescribing LMWH to women with pregnancy losses and hereditary thrombophilia; the ALIFE2 authors advise against both LMWH and thrombophilia screening in this context, in agreement with BSH [15, 34]. The populations included different hereditary thrombophilias, and results cannot be transferred to women with AT deficiency or previous VTE, in whom the prophylaxis indication derives from thromboembolic risk rather than the obstetric objective [2, 30]. Highlow included women with previous VTE irrespective of thrombophilia, compared two LMWH doses rather than a group without prophylaxis; absence of a significant difference in an endpoint with few events (27 in total) does not demonstrate equivalence, and the RR confidence interval is wide [61]. PC concentrate data come from a single-arm study in an ultrarare disease, with efficacy assessed by episode rather than patient, and the ISTH communication on DOACs summarises observational cohorts with a risk of selection bias; none of these studies provides an effect estimate comparable to those of randomised trials [48, 56].

7.12. Evidence hierarchy, regulatory status and off-label use

Four levels are distinguished in this article: peer-reviewed publication (the trials and cohorts cited), sponsor communications or trial registry entries without published results (for example, NCT04918173), regulatory opinions and authorisation decisions. FDA or European Commission authorisation does not guarantee marketing, reimbursement or access in each country; in Portugal and Brazil, these decisions fall respectively to INFARMED and ANVISA/CONITEC and were not verified in this review for AT and PC concentrates.

No drugs are approved specifically for FVL, G20210A or heterozygous PC and PS deficiencies; anticoagulants are used under the general VTE indication. Extrapolation of evidence and off-label use are distinct matters: LMWH prophylaxis in pregnancy in an AT deficiency carrier rests on guidelines and extrapolation from studies of women with previous VTE, but the use itself falls outside the specific prescribing information indication; DOAC use in pregnancy and breastfeeding is contraindicated in prescribing information; and in children, age, weight and jurisdiction determine whether a given anticoagulant is used within or outside its indication [2, 30, 41, 45].

8. Reproductive Options and Family Counselling

Hereditary thrombophilias are transmitted in an autosomal dominant manner; if both parents carry the same defect, the risk of a homozygous child is 1 in 4 [1]. Each child of a heterozygote has a 50% probability of inheriting the variant; if the partner is also heterozygous, the probabilities are 25% homozygosity, 50% heterozygosity and 25% no variant; all children of a homozygote inherit the variant [16, 17]. Because of the high frequency of FVL and G20210A, it is not rare for one parent to be homozygous or both to be heterozygous, and a negative family history can only be confirmed by parental genotyping; no de novo G20210A cases have been described [16, 17]. In severe PC and PS deficiencies (autosomal recessive in their neonatal form), heterozygous parents have a 25% recurrence risk in each pregnancy, and consanguinity is frequent in described families [25, 29].

Predictive testing of asymptomatic relatives requires a clear understanding, before testing, that the result will change management; OXF recommends discussion with haematology [1]. Routine testing of relatives for FVL or G20210A is not recommended because the increase in individual risk is mild and testing does not reduce morbidity or mortality; young children should generally not be tested because thrombophilia-associated thrombotic risk only increases from puberty [1]. EGAPP advised against testing asymptomatic adult relatives to decide primary prophylaxis [14], BSH does not recommend routine testing of first-degree relatives (Grade 2B) [15], and GeneReviews states that first-degree relatives of FVL carriers without risk factors and without VTE should not be tested [16]. Conversely, in families with AT, PC or PS deficiency, ASH suggests testing targeted to the familial defect in the presence of pregnancy, contraception, HRT or minor risk factors [2]. Testing is allowed in adults from families with a known variant when there is a concrete indication, such as pregnancy management or a decision about contraception or HRT, after consent [1].

Prenatal diagnosis is not offered for FVL or G20210A according to OXF [1]; GeneReviews allows that, once the variant is identified in the family, prenatal diagnosis and preimplantation genetic testing are technically possible, but emphasises differing perspectives, since these are common, predisposing rather than predictive variants [16, 17]. In severe biallelic PC or PS forms, prior identification of parental variants permits prenatal diagnosis, preimplantation genetic testing and delivery planning with immediate availability of PC concentrate or plasma [57]. The ideal time for counselling is before pregnancy, and it is appropriate to offer it to young adult carriers [16].

9. Special Considerations: Population Diversity and Epidemiology

FVL and G20210A are European founder variants. FVL heterozygosity occurs in 3–8% of European populations and North Americans of European ancestry (4.4% according to OXF), with 10–15% in southern Sweden and Greece and 2–3% in Italy and Spain; it is extremely rare in Asian, African and Aboriginal Australian populations. In the United States, it is present in 5.2% of Americans of European ancestry, 2.2% of Hispanics, 1.2% of African Americans, 1.25% of Native Americans and 0.45% of Asian Americans; homozygosity occurs in approximately 1:5000 [1, 16, 62]. FVL is present in 15–20% of patients with a first DVT and up to 50% of patients with recurrent or oestrogen-associated VTE [16]; OXF reports 20% of patients with a first idiopathic venous thrombosis [1]. G20210A heterozygosity occurs in 1.7–3% (3% in southern and 1.7% in northern Europe; 1–2% according to OXF), in 2–5% of Americans of European ancestry, 2.2% of Hispanics and 0–0.6% of African Americans; it is present in 6–14% of adults with a first VTE, 18–21% of patients with recurrent personal or familial VTE and 3.7% of children with a first spontaneous VTE; homozygosity occurs in 1:10,000 [1, 17].

Natural anticoagulant deficiencies have a different distribution. AT deficiency prevalence lies between 1:500 and 1:5000, and the upper limit includes type IIb deficiencies, which are more frequent and less thrombogenic [19]; Orphanet classifies worldwide point prevalence in the 1–5 per 10,000 category [63]. Heterozygous laboratory PC deficiency was found in approximately 1:200–1:300 healthy adults and blood donors, none of whom had a history of thrombosis, confirming that this is a largely asymptomatic biochemical prevalence [64]. OXF estimates that approximately 1:3000 individuals have hereditary AT, PC or PS deficiency [1], and GeneReviews a combined prevalence below 1–2%, with presence in 1–3% of patients with a first VTE [16]; ASH 2023 used median prevalences of 2.2% (AT), 2.5% (PC) and 2.3% (PS) for patients with VTE [2]. PS deficiency is the most frequent congenital thrombophilia in the Japanese population, with a prevalence of 0.48–0.63% in the general population, associated mainly with the NM_000313.4:c.586A>G p.(Lys196Glu) variant (protein S Tokushima; K155E in the historical numbering of the mature protein) [65, 66]. In East Asian populations, where FVL and G20210A are almost nonexistent, natural anticoagulant deficiencies therefore have greater relative importance in hereditary VTE [16, 66].

In Portugal, available data come from small hospital series: in a series of 100 women giving birth without pregnancy losses, prevalence was 5% for FVL and 1% for G20210A [31]. In Brazil, a study of 400 blood donors in Santa Catarina, a region of Portuguese, Italian and German settlement, found 2.5% FVL heterozygotes and no homozygotes, and the authors emphasise the absence of data for other regions of the country [67]. The sources consulted do not include national population-based studies of G20210A or AT, PC and PS deficiency prevalence in Brazil or Portugal, or equivalent data for most of Africa, the Middle East and Latin America; this absence in the sources does not prove that such studies do not exist but prevents extrapolation. The Portuguese series is hospital-based and measures frequency in women with and without pregnancy losses followed at one centre, rather than national prevalence. Cases of neonatal purpura fulminans due to biallelic deficiency are concentrated in consanguineous families, making these forms relevant in populations with high consanguinity rates [25, 29].

10. Illustrative Clinical Case

10.1. Type I antithrombin deficiency in pregnancy (published case)

A 35-year-old Caucasian woman with known AT deficiency, two previous VTE episodes and two miscarriages was referred during her third pregnancy. Her father and two brothers had AT deficiency and multiple VTEs at a young age. At 19 years she had had right popliteal vein thrombosis during COC use and, at 21, an unprovoked recurrence, leading to prolonged oral anticoagulation. In her first pregnancy, she switched to therapeutic-dose dalteparin and had a first-trimester miscarriage; in the second, on 200 IU/kg/day, she had superficial venous thrombosis and another miscarriage. In the third pregnancy, on dalteparin 230 IU/kg/day, anti-Xa levels remained below the therapeutic range (median 0.59 IU/mL) and, at 23 weeks, left popliteal thrombosis with intermediate-high-risk PE developed. Anticoagulation was switched to argatroban and then warfarin (INR 2–3) between 24 and 36 weeks. At 36 weeks, she resumed dalteparin 7500 IU every 12 hours combined with daily human AT concentrate (Kybernin®), adjusted to maintain AT activity between 80% and 120%, with a linear correlation between AT and anti-Xa. Induced vaginal delivery at 38 weeks was uncomplicated; LMWH and concentrate were reintroduced 12 hours after delivery, warfarin two days later (compatible with breastfeeding), and concentrate was stopped on day five. There was no recurrence or bleeding in two years of follow-up. Sanger sequencing of SERPINC1 revealed the heterozygous c.374G>A (p.Gly125Asp) variant, classified as pathogenic by the authors according to ACMG criteria, with reduced AT activity and antigen (type I) in the patient, her father and brother [20]. The article does not specify the transcript; in ClinVar, the variant is normalised as NM_000488.4(SERPINC1):c.374G>A (p.Gly125Asp) (MANE Select transcript), with a pathogenic classification from a single submitter, so classification rests primarily on the functional and familial evidence described [38, 39]. The course of anti-Xa levels during LMWH, the correlation between anti-Xa and AT activity, and the pedigree with laboratory results and sequence are shown in Figures 1–3 of the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12505717/), which are not reproduced here [20]. The case illustrates heparin resistance, the utility of anti-Xa measured without exogenous AT and the peripartum role of AT concentrate [20, 30].

10.2. Severe protein C deficiency in the newborn (published series)

Two male term newborns, born to consanguineous parents, developed ecchymotic lesions in the first days of life that rapidly progressed to necrosis and eschar, with DIC. Protein C activity was 4–8%, below the neonatal range, with normal PS and AT. Without access to PC concentrate, they were treated with fresh frozen plasma (10 mL/kg every 12 hours), continuous unfractionated heparin infusion and intensive support; both died of DIC and sepsis at 13 and 22 days of life, and genetic testing was not possible because of previous plasma transfusions [29]. The skin lesions, histology with intravascular thrombi and arterial Doppler are shown in Figures 1–5 of the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12999368/) [29]. Since diagnosis was not molecularly confirmed and PC activity was measured in the context of DIC (which also consumes it), the hereditary nature of deficiency in these patients is a clinical inference by the authors rather than a confirmed diagnosis. The series demonstrates the dependence of prognosis on access to specific replacement, the importance of collecting samples (including DNA) before plasma, and the value of parental genetic counselling, with a recurrence risk of 25% [29, 57].

10.3. Teaching points

Faced with a 20-year-old woman, sister of a patient with VTE at 30 years and heterozygous FVL, requesting testing before starting COC, ASH suggests not testing (R19), and the contraceptive decision should be based on family history and alternatives without oestrogens [2, 16]. If the family had AT, PC or PS deficiency, targeted testing would be indicated and, if positive, the young woman should avoid COC [2].

11. Prognosis and Long-Term Follow-Up

The prognosis of FVL and G20210A heterozygotes is that of the general population: most will never have thrombosis, and FVL heterozygosity does not reduce life expectancy, even after VTE [1, 16]. Lifetime VTE risk in FVL carriers is 17.1%; ten-year absolute risk ranges from 0.7% in young, non-smoking heterozygotes with a body mass index below 25 kg/m² to 10% in heterozygotes over 60 years who smoke and are obese (3% and 51%, respectively, in homozygotes) [16]. After a first unprovoked VTE, cumulative recurrence is 20% at two years and, although 27% of these patients have hereditary thrombophilia, testing cannot predict a high recurrence risk; postoperative VTE has a very low recurrence risk [1]. In a large family series, VTE recurrence in relatives with FVL was 7% at two years, 11% at five and 25% at ten, similar to that in the general population [16].

Follow-up comprises periodic reassessment of patients receiving prolonged anticoagulation, to confirm that benefit continues to outweigh bleeding risk; assessment of carriers without anticoagulation before risk exposures (surgery, pregnancy); counselling on modifying environmental factors; and instruction to recognise and report signs of thrombosis [1, 16]. In AT, PC and PS deficiencies, follow-up should include advance planning of each pregnancy and surgery, with written prophylaxis protocols and, in AT deficiency, replacement protocols [30, 52]. In SCPCD, prolonged prophylaxis with PC concentrate, anticoagulation or both requires surveillance of PC activity (trough above 25%), venous access, ophthalmological and neurological complications and development [23, 54]. Patient organisations include Thrombosis UK (https://www.thrombosisuk.org) and the National Blood Clot Alliance (https://www.stoptheclot.org) [1, 16]. In Europe, rare and severe forms (biallelic PC and PS deficiencies, AT deficiency with severe thrombosis) fall within the European reference network for rare haematological diseases, ERN EuroBloodNet, which includes rare coagulation disorders; common variants (heterozygous FVL and G20210A) are not rare diseases and are followed in general thrombosis clinics [68].

12. Summary and Concluding Remarks

Hereditary thrombophilias divide into two groups with distinct implications. FVL and prothrombin G20210A are common variants of European origin, with relative risks of first VTE of three- to eightfold and two- to fivefold, respectively, but low absolute risks; their detection rarely changes management, except in homozygosity and double heterozygosity, particularly during pregnancy [2, 16, 17]. AT, PC and PS deficiencies are rare and heterogeneous, with higher absolute risks — in AT deficiency, 7.3% antepartum and 11.1% postpartum in women from affected families — and targeted testing in families with a known defect guides prophylaxis in pregnancy, in the presence of minor risk factors and in contraceptive choice [2, 3].

Current guidelines advise against testing the general population before COC (strong recommendation), after unprovoked or surgical VTE to determine anticoagulation duration, in obstetric complications, in arterial thrombosis and in asymptomatic children, and allow it in pregnancy-, oestrogen- or major non-surgical factor-associated VTE and in relatives of carriers of high-risk defects [2, 15]. Acute VTE treatment does not depend on genotype; LMWH is the anticoagulant of choice in pregnancy, warfarin is teratogenic and DOACs are contraindicated in pregnancy and breastfeeding [16]. AT deficiency requires attention to heparin resistance and has a specific concentrate (Thrombate III®) for the peripartum and surgical period [30, 52]. Biallelic PC deficiency is a neonatal emergency treatable with PC concentrate (Ceprotin®), while PS deficiency relies on fresh frozen plasma [15, 54, 56]. The randomised ALIFE2 and TIPPS trials were negative for LMWH in preventing pregnancy losses and complications in women with thrombophilia, and AT and PC concentrates have different regulatory statuses in the United States and European Union [34, 35, 52, 55]. The geneticist contributes to the decision to test, proportionate interpretation of risk and reproductive counselling, including severe recessive forms in consanguineous families.

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