Hereditary Thrombophilia and Venous Thromboembolism in Saudi Arabia

Risk factors, the pitfalls of protein S and other natural-anticoagulant testing, antiphospholipid antibodies as a separate question, and a review of guidelines on thrombophilia testing

Husain Alkhaldy

4 October 2026

1. Key messages

These points are written for the clinician who orders or interprets thrombophilia tests.

• Factor V Leiden and prothrombin G20210A are uncommon in healthy Saudis. In three studies of healthy Saudis, factor V Leiden (FVL) carriage was about 1–2% and prothrombin G20210A 0–2% [1–3], lower than in Levantine and some other Arab groups [2, 4]. Protein C, protein S and antithrombin deficiency have not been measured in a healthy Saudi population.

• Rates are higher among people who were tested, because they were selected. FVL was positive in 5.9% of samples referred for testing in Riyadh, of unstated nationality [5], and in one hospital series most FVL carriers were not Saudi (Section 4.1). Always check the denominator, and the nationality, before quoting a Saudi prevalence.

• Unprovoked VTE is not rare in Saudi series, and antiphospholipid syndrome is common. Unprovoked events were 58% of a Riyadh registry [6] and 47.6% of an Eastern Province series, in which primary antiphospholipid syndrome was about three times as common as hereditary thrombophilia (Section 6.1) [7].

• Saudi reports of very high protein S deficiency should not be read as hereditary prevalence. Of the figures of 14.5% in selected VTE patients, 47% in recurrent pregnancy loss and 57% in cerebral venous thrombosis, two report functional assays [8, 9]; the CVT series does not state the assay [10]. None reports a repeat test on a second sample, and timing is incompletely reported (Section 4.2). True familial protein S deficiency is estimated at 0.03–0.13% of the general population [11].

• A single low protein S result is often wrong, but a true genetic deficiency is a strong risk factor. Most first low results in healthy donors did not repeat [11], and free protein S below a population cut-off was not associated with VTE in the MEGA study [12]. Damaging PROS1 variants, by contrast, were rare but carried an odds ratio for VTE of 14.0 [13] (Section 5.3).

• Antithrombin deficiency is a different case from protein S deficiency. Its assays are more reproducible, it carries the highest pregnancy risk of the hereditary thrombophilias, and its diagnosis can change the choice and monitoring of anticoagulation and peripartum care, not only its duration (Section 5.5) [14–17].

• Many things alter measured protein S, protein C and antithrombin. They include the acute phase, warfarin, heparin, pregnancy, oral oestrogen, liver disease, nephrotic syndrome, DIC, sepsis and sickle cell disease. FVL and a raised factor VIII falsely lower clot-based protein S activity, and DOACs falsely raise clot-based results and can hide a true deficiency (Table 6) [16, 18, 19].

• Antiphospholipid syndrome is acquired and is tested on different rules. A positive result must persist on two occasions at least 12 weeks apart [16], lupus anticoagulant testing is unreliable on anticoagulants [20], and rivaroxaban should not be used in triple-positive antiphospholipid syndrome [21, 22]. Other DOACs were not assessed in the evidence reviewed here, so it should not be inferred that they are safe in triple-positive disease.

• There is no evidence that testing reduces recurrence. No randomised trial has tested it [23]. The one observational comparison found an odds ratio for recurrence of 1.2 (0.9–1.8) in tested against untested patients, an interval compatible with a small benefit or with harm, and open to confounding [24].

• Guidelines do not all say the same thing. BSH 2022 and NICE NG158 advise against routine heritable testing after VTE [16, 25]; ASH 2023 conditionally suggests testing in a few settings where anticoagulation would otherwise be stopped, on very low-certainty, modelled evidence [23]. It is not accurate to tell trainees that “all guidelines say do not test” (Section 8).

• There is no Saudi guideline on thrombophilia testing and no Saudi audit of how the tests are used. A local audit is proposed in Section 9.8.

2. Scope and methods

2.1 Questions

The review asked five questions. What are the risk factors for VTE in Saudi Arabia? How common are the hereditary thrombophilias in Saudis, and in which populations was each figure measured? Why are low protein S, protein C and antithrombin results so often unreliable, and when is a low result likely to be true? Where do antiphospholipid antibodies fit? And what do current guidelines recommend on whom, when and how to test?

2.2 Searches

This is a narrative review, not a systematic review. The searches were run up to 4 October 2026 in two parts.

The Saudi and Gulf search used Europe PMC and PubMed. Title, abstract and affiliation fields were searched with combinations of terms for venous thromboembolism, deep vein thrombosis, pulmonary embolism, cerebral venous thrombosis, thrombophilia, factor V Leiden, prothrombin G20210A, protein C, protein S, antithrombin, antiphospholipid, testing, ordering, utilisation and cost, together with “Saudi” or Gulf terms. A general web search was added to find Saudi guidelines and documents not indexed in either database.

The guideline search used the websites of the issuing societies, open-access repository copies of guideline texts, PubMed and Europe PMC. Targeted searches were then run for specific questions raised in review: antiphospholipid testing and treatment, PROS1 genetic data, homozygous protein C deficiency in Saudi children, consanguinity, travel and the Hajj, and ordering-appropriateness audits in Saudi laboratories.

Inclusion was by judgement rather than by a fixed protocol: any Saudi or Gulf study reporting VTE risk factors, thrombophilia prevalence or thrombophilia testing practice was included; international studies were included where they bore directly on the interpretation of a test or on a guideline position. The number of records screened was not recorded, so it cannot be reported. Searches were in English only. Arabic-language journals and Arabic abstracts were not searched, and this is a limitation for a review about Saudi practice. A finding of “not found” means only that these searches did not find it.

2.3 What was read

The following guidelines were read in full: BSH 2022 [16], ASH 2023 [23], NICE NG158 section 1.9 [25], RCOG Green-top Guideline 37a [17], ESHRE 2017 with the relevant text of the 2022 update [26, 27], the ASH Choosing Wisely page [28] and the Tang 2025 international practical guideline [29].

Full texts were also read for eight Saudi papers: Al-Ansari [7], Al-Otaiby [30], Daghriri [10], Al-Ghamdi [9], Algahtani [31], Bakhsh [32], Alamri [33] and the Saudi travel prophylaxis guideline [34]. Most other Saudi and Gulf studies, and most of the international cohort studies and meta-analyses, were read as abstracts only.

Where only the abstract was read, study quality cannot be judged beyond it, and a detail the abstract does not report is said to be not reported, not absent. The same standard is applied to Saudi and international sources. No formal risk-of-bias assessment or meta-analysis was done.

Table 1. Evidence-status tags used in this review.

Evidence is described by design in the tables: systematic review or meta-analysis, cohort, case-control, cross-sectional, registry, laboratory-records audit, case report, and guideline or expert consensus.

2.4 Status of this review

Section 9 offers a suggested local approach to testing. It is derived from the published guidelines reviewed here. It is not a guideline, and no Saudi body has reviewed or endorsed it. Where the guidelines differ, it says so rather than choosing between them silently.

3. VTE epidemiology and risk factors in Saudi Arabia

3.1 Registries and hospital cohorts

There is no population-based Saudi VTE incidence study. All the figures below are hospital or clinic denominators [6, 7, 35]. Table 2 summarises the main studies.

Table 2. Saudi studies of VTE epidemiology and risk factors.

Smaller studies of thrombosis in hospitalised COVID-19 patients and in an intensive care unit are not tabulated, because their settings and selection make them of little use for estimating risk factors in the general Saudi population [41–43].

3.2 Acquired risk factors

The Saudi data name the same acquired risk factors as the international literature: surgery, hospital admission and immobilisation, cancer, infection, ICU stay, pregnancy and the puerperium, obesity and antiphospholipid syndrome (Table 2). The pooled Saudi meta-analysis is less certain than its conclusion suggests: only age over 60 reached statistical significance in the figures reported in the abstract [36]. Under-use of prophylaxis is documented: only 38.4% of at-risk inpatients in one Madinah cohort received recommended prophylaxis [40]. Sickle cell disease is a local risk factor worth naming, with VTE in about 3% of patients at a single academic centre in Saudi Arabia [39]. Oral contraceptive use produced resistance to activated protein C and thrombomodulin in a thrombin-generation assay in Saudi women, mainly in those who were overweight or obese [44].

Two Saudi series report that more than half or nearly half of VTE events were unprovoked [6, 7]. This is a reason not to say that “most” Saudi VTE has an acquired context. It is not a reason to infer a high rate of hereditary thrombophilia, because “unprovoked” was not defined against a measured thrombophilia in either study, and in the one series that tested for both, antiphospholipid syndrome was commoner than hereditary thrombophilia (Section 6.1).

A Saudi expert consensus on cancer-associated thrombosis stated that “the comparatively high incidence of inherited thrombophilia among the Saudi population may account for a higher” thrombosis burden [45]. The abstract cites no data for this, and it sits poorly with the low FVL and prothrombin rates in healthy Saudis (Section 4). It is best treated as expert opinion.

3.3 Altitude and the Aseer region

A prospective study compared patients with clinically suspected VTE in Abha and Riyadh, 2011–2013 (n=234: 111 in Abha, 123 in Riyadh). The full text places Abha at about 2,200 m and Riyadh at about 600 m above sea level. VTE was confirmed in 81.9% of suspected cases in Abha against 21.9% in Riyadh; DVT alone 56.8% against 13.0%; PE alone 12.6% against 4.1% [31]. The denominator is patients suspected of VTE, so these are diagnostic yields, not population incidence. A higher yield could reflect a true difference in incidence, a different threshold for suspicion or referral, or both, and the study cannot separate them. Presenting features also differed sharply between the two cities (lower-limb swelling in 73.9% against 1.6%), which suggests different kinds of patient were recruited [31]. Abha is at moderate altitude, which the authors themselves describe as “moderately highly elevated”. An older Saudi paper on VTE at high altitude exists, but its content could not be read [46].

In the Aseer region, a review of JAK2 testing in two hospitals (2020–2022) found 2 positive of 40 tests done for thrombosis (5%), and 57.5% of tested patients had a normal blood count [47]. This study is by the author’s group. It is the closest Saudi study of the yield of a thrombosis test. No FVL or prothrombin prevalence study from Aseer was found.

3.4 Cerebral venous thrombosis

Saudi cerebral venous thrombosis (CVT) series point to acquired causes. In 40 adults in Riyadh, Behçet disease was the commonest cause (25%), with antiphospholipid antibodies in 4, protein S deficiency in 3 and antithrombin deficiency in 2 [48]. Oral contraceptive use was found in 69% of women in a King Fahad Medical City series [49], and dehydration during Ramadan fasting was named as a risk factor among women on oral contraceptives [50]. A university hospital series named iron-deficiency anaemia as a preventable predisposing condition and judged genetic factors “less important in this cohort” [51].

A Jazan series of 51 patients reported protein S deficiency as the commonest recorded risk factor (29 patients, 57%) [10]. The full text gives a mean interval of 2.8 months from the CVT to the protein S measurement in the deficient patients, which the authors take as evidence of true deficiency, and also records protein C deficiency in 15.7%, antithrombin deficiency in 13.7% and antiphospholipid syndrome in 21.7%. It does not state the assay, whether low results were repeated, or whether patients were anticoagulated when tested [10]. A mean of 2.8 months means that some patients were tested earlier than the 3 months advised by BSH [16]. The figure should therefore be read as the rate of low results in this setting, not as a rate of hereditary deficiency.

3.5 What is missing

• No population-based incidence of VTE in Saudi Arabia.
• No Saudi series on VTE in Hajj or Umrah pilgrims. The Saudi clinical practice guideline on VTE prophylaxis in long-distance travellers [34] was read in full: it does not address the Hajj or pilgrims as a group, and it makes no recommendation on thrombophilia testing before travel. Nothing found supports testing travellers or pilgrims for thrombophilia; pilgrims are listed in the research agenda (Section 9.9).
• No Saudi series on VTE in adults with nephrotic syndrome, or in Behçet disease outside the CVT series.
• No FVL or prothrombin prevalence data from the Aseer region.

4. Prevalence of hereditary thrombophilia in Saudis

The single most important point in reading this literature is the denominator. A prevalence in healthy blood donors, a positivity rate among samples sent for testing, and a rate among patients chosen because they had unprovoked or recurrent thrombosis measure three different things. Nationality is a fourth variable: some Saudi hospital series include non-Saudi patients, and in one of them most of the FVL carriers were not Saudi [30]. Table 3 sets the studies side by side.

Prevalence of FVL and prothrombin G20210A is given as carrier frequency, the percentage of people carrying at least one copy; where a paper reports only an allele frequency, the allele frequency is given and labelled as such. The variants are named by their legacy names, factor V Leiden (R506Q, G1691A) and prothrombin G20210A. Some Saudi papers use the HGVS protein name for FVL, p.(Arg534Gln), with the coding-DNA name c.1601G>A; it is the same variant [52, 53].

Table 3. Hereditary thrombophilia in Saudi and Gulf populations, by type of population studied. Carrier frequencies unless stated.

A dash means the source did not report it. “Not measured” means the study did not test for it.

4.1 Factor V Leiden and prothrombin G20210A

In healthy Saudis FVL carriage is about 1–2% and prothrombin G20210A 0–2% (Table 3A) [1–3]. The three studies differ for the prothrombin variant (0.7%, 0% and 2%), and their sampling is described only briefly in the abstracts, so a single national figure should not be quoted. A Kuwaiti study found no FVL among 105 Kuwaitis of Saudi origin and described FVL as “almost absent in Arabs in the Arabian Peninsula itself” [57], in contrast to 15–25% in some Levantine and Egyptian groups living in Kuwait [4].

Among tested or selected patients the rates are higher: FVL 5.9% and prothrombin 2.93% in referred samples of unstated nationality [5], and about 10% in idiopathic DVT in the Western Region [52]. This is what selection should produce. Nationality can also mislead: the overall FVL rate of 4.4% in a Riyadh hospital series is often quoted as a Saudi figure, but 14 of the 21 carriers were non-Saudi, and the rate among the 402 Saudi patients was 1.7% [30]. The statement “FVL is rare in Saudis” is true for healthy controls and for Saudi patients in that series. It should not be quoted against referral cohorts, nor the reverse.

The Riyadh laboratory audit found that 3.69% of samples had low APC resistance without the FVL mutation [5]. The abstract does not name the assay, and APC resistance can be acquired: in Saudi women, oral contraceptive use produced resistance to activated protein C in a thrombin-generation assay [44]. The modified clot-based test, in which the sample is first diluted in factor V-deficient plasma, is more specific for FVL than the first-generation test, and in one evaluation it separated carriers from non-carriers completely, whether or not patients were anticoagulated [61]. A low APC resistance ratio without FVL therefore suggests either a first-generation assay or an acquired cause; it is not evidence of a second inherited defect. A targeted sequencing study found candidate variants (including SERPINA10 p.R88*) in 22 of 29 FVL-negative Saudi patients with idiopathic VTE [62]; this is small and hypothesis-generating.

4.2 Protein C, protein S and antithrombin

The Saudi figures for natural-anticoagulant deficiency are strikingly high (Table 3B and 3C), and what the studies report about method is uneven. Al-Jaouni states that functional assays were used and that tests were done at reference laboratories abroad [8]. Al-Ghamdi’s full text describes “functional immunosorbent assays” for protein S, protein C and antithrombin [9]. Daghriri reports the interval between the CVT and the protein S measurement, but not the assay (Section 3.4) [10]. None of the four reports a repeat test on a second sample, and none states whether patients were on anticoagulation, pregnant or postpartum, or taking oestrogen when tested [8–10, 55].

For comparison, true familial protein S deficiency is estimated at 0.03–0.13% of the general population [11]; inherited protein C deficiency at 1.45 per 1,000 observed, or up to 1 in 500 after allowing for missed cases [63]; and congenital antithrombin deficiency at about 1 in 600, most of it type II [64]. Among patients with VTE, the ASH panel used a median prevalence of 2.3% for protein S deficiency and 2.5% for protein C deficiency [23]. Saudi rates of 14.5–57% would be several-fold to many-fold higher. The more likely reading is that a large share of these low results were acquired or analytical (Section 5). For the recurrent pregnancy loss series in particular, pregnancy itself lowers protein S [17, 65, 66], and the series does not report when the women were tested in relation to a pregnancy.

4.3 Consanguinity

Consanguinity is common in Saudi Arabia. In a national household survey of 2004–2005 it was 56%, with first-cousin marriage at 33.6%, and it varied by region from 42.1% in Al-Baha to 67.2% in Madinah [67]. It is often given as the reason for high natural-anticoagulant deficiency rates in the Gulf.

What consanguinity can do. Protein C, protein S and antithrombin deficiencies are usually inherited as heterozygous traits. Consanguinity raises the chance that a child inherits the same defect from both parents, giving homozygous or compound-heterozygous deficiency, which is rare and severe [18]. Saudi case reports show exactly this pattern for protein C: neonatal purpura fulminans with undetectable protein C activity in the child of a healthy consanguineous couple [68]; a novel homozygous PROC splice-site variant in a neonate from a consanguineous family, with segregation confirmed in relatives [69]; a series of children with homozygous protein C deficiency presenting after the neonatal period, sometimes with eye bleeding alone, in which the authors advise premarital counselling where the family history suggests it [70]; and an infant presenting at 8 weeks with vitreous haemorrhage and retinal detachment, with a homozygous likely pathogenic PROC variant on exome sequencing [71]. The ISTH protein C communication notes that affected infants are often born into families with no history of deficiency or thrombosis [18], so a negative family history does not exclude the diagnosis in a newborn.

The Kuwaiti study of 130 patients with recurrent DVT deserves fair weight here [59]. It found hereditary protein C deficiency in 11.52%, protein S deficiency in 6.1% and antithrombin deficiency in 3.8%, and it did family studies, which showed a dominant pattern in 14 of the 15 protein C-deficient patients and a recessive pattern in one. Family studies are the strongest evidence of inheritance in any study in Table 3, and the authors attributed the high frequency to consanguinity. The study is from 1996 and used antigen assays for protein S and antithrombin, so it may have missed some functional defects, but its central finding is not easily explained by acquired causes.

What consanguinity cannot do. In a selected group of patients with recurrent or unusual thrombosis from consanguineous families, a true deficiency is more likely than in an unselected patient, and the pre-test probability in Section 5.1 should be set higher. Consanguinity does not, however, explain population or patient-series rates of 15–57% for a heterozygous trait, because, in population-genetic terms, consanguinity raises the proportion of homozygotes rather than the number of carriers. In a Saudi community study, consanguinity was clearly associated with congenital heart disease, but no association was found for several other genetic conditions, and the authors conclude that its effect “is not uniform” [72]. No Saudi VTE study testing consanguinity against natural-anticoagulant deficiency was found.

What follows in practice.

• A neonate or child with purpura fulminans should be tested urgently for protein C and protein S deficiency [16]. The child’s levels must be read against age-specific ranges, because adult ranges do not apply to babies and protein C may not reach adult levels even in adolescence [18].
• Testing both parents helps to confirm an inherited cause. Heterozygous parents with low levels and no acquired explanation support the diagnosis, and identifying the familial variant allows carrier testing and, if the family wishes, prenatal or preimplantation diagnosis [69].
• Where a natural-anticoagulant deficiency is found in a patient from a consanguineous family, genotyping the proband and then testing relatives for the same variant (cascade testing) is a more reliable route to confirmation than repeated plasma assays, provided the result will influence management [16, 73]. Testing of relatives should be preceded by counselling about what a positive or negative result means for them [17].
• Thrombophilia should not be added to the national premarital screening panel. The premarital programme screens 1.87 million people for haemoglobinopathies (2011–2018) [74], but thrombophilia is a different case. The common variants are low-risk: heterozygous FVL or prothrombin carriers have a pregnancy-associated VTE risk below 3% and should generally not be given prophylaxis on that basis alone [15], and BSH does not recommend genetic testing to predict a first VTE [16]. The natural-anticoagulant deficiencies are diagnosed from plasma levels, which are unreliable on a single sample (Section 5). Severe homozygous deficiency is rare, and the families at risk are usually identifiable from an affected relative, which makes counselling and cascade testing in those families the targeted alternative [70]. And a label carries costs (Section 7.3). This is the author’s reasoning from the sources cited; no study has tested premarital thrombophilia screening.

4.4 MTHFR

The Saudi MTHFR data are homozygous C677T frequencies of 2.45% and 2.55% in healthy Saudis [1, 3] and a sickle cell case-control study with no significant association [75]; MTHFR was not associated with thrombosis in the Qatar Biobank [60]. Internationally, MTHFR C677T homozygosity was not associated with VTE in a large meta-analysis (OR 1.38, 0.98–1.93) [76]. BSH and the American College of Medical Genetics and Genomics advise against MTHFR testing, and ASH makes no recommendation because the polymorphisms “have been shown not to be associated with VTE” (Table 9) [16, 23, 77]. There is no Saudi evidence that would justify a different local practice.

5. Why low protein S, protein C and antithrombin results need confirmation

A low natural-anticoagulant result can be true and inherited, true and acquired, or an artefact of the assay. The clinician’s task is to tell these apart before a patient is labelled. Five lines of evidence explain why the label so often turns out to be wrong, and when it is likely to be right. Antithrombin behaves differently from protein S on almost every one of them, and it is treated separately in Section 5.5.

5.1 Pre-test probability and the false-positive rate

When a condition is present in about 1 in 1,000 people [11], even a test with a small false-positive rate will produce more false than true positive results in unselected people. Inherited protein C deficiency found by screening donors was “asymptomatic with regard to thrombosis” in every case [63], and type II antithrombin deficiencies found in donors did not appear to confer a high thrombotic risk [64].

Rarity alone, however, is not the main problem in patients. Among patients with VTE, the ASH panel used a median prevalence of 2.3% for protein S deficiency [23], twenty times the population figure. The false-positive rate then decides the result, and it is not fixed. A laboratory that sets its lower reference limit at the 2.5th percentile of healthy people will, by construction, flag about 2.5% of healthy people as low on a single test. Every acquired cause in Table 6 adds to that: a sample taken in the acute phase, on warfarin, in pregnancy or on oral oestrogen will be low more often.

Table 4 assumes, for simplicity, that the test detects every true deficiency. The prevalences are taken from the sources cited; the false-positive rates of 10% and 20% are illustrative, not measured, and stand for testing under conditions that lower protein S.

Table 4. Worked example: how many low protein S results are true, per 1,000 people tested. Illustrative.

In unselected people, most low results are false whatever the laboratory does. In patients with VTE, a correctly timed single test is right about half the time, and less often when acquired causes are present. The practical rule is therefore not “do not test because deficiency is rare” but “confirm before labelling”: test at the right time, exclude acquired causes, and repeat. In a thrombophilic or consanguineous kindred with a known proband, the pre-test probability is high and a low result is much more likely to be true (Section 4.3).

5.2 A first low protein S often does not repeat

In 3,788 healthy donors, 56 had a total or free protein S in the lowest percentile. Only 9 were low again on retesting, and 8 of these remained low over 4–7 years after acquired causes were excluded [11]. In other words, 47 of 56 first low results (84%) did not repeat.

This is largely what would be expected when a cut-off is applied to a measurement that varies. People selected because a single value fell in the tail of the distribution will, on average, be closer to the middle when measured again: regression to the mean. The size of the effect depends on how much the measurement varies. For protein S it varies a great deal. In the ECAT external quality assessment programme the long-term within-laboratory coefficient of variation was 17.2% for protein S activity, 14.1% for free protein S antigen and 13.4% for total protein S antigen, against 7.6% for antithrombin; and the variation between laboratories was significantly greater for antithrombin and protein S in samples with levels near heterozygous deficiency [14]. A single low value close to the cut-off is therefore weak evidence on its own.

The same donor study found that men have higher total and free protein S than women [11]. A single cut-off for both sexes will over-call deficiency in women. The study also found that the oral contraceptive pill lowered total protein S but had no effect on free protein S, and that hormone replacement therapy had no statistically significant effect on either [11]. BSH 2022, by contrast, lists oral oestrogen therapy among the causes of a reduced free protein S antigen [16]. The abstract of the donor study does not allow the two to be reconciled. The safe course is to record hormone use and to read a low free protein S in a woman taking oestrogen with that in mind.

5.3 Low protein S and thrombotic risk: three different questions

Three bodies of evidence seem to disagree about whether low protein S matters. They are answering different questions.

A level below a population cut-off, in unselected patients. In the MEGA case-control study (n=5,317), deficiency defined as a level below the 2.5th percentile of controls was not associated with venous thrombosis: free protein S <53 U/dL, OR 0.82 (0.56–1.21); total protein S <68 U/dL, OR 0.90 (0.62–1.31). Only at very low free protein S (<33 U/dL, below the 0.10th percentile) was there a signal, with a wide interval (OR 5.4, 0.61–48.8). PROS1 mutations were found in 5 patients and 5 controls among those investigated. The authors concluded that “protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis” [12].

A low level in a thrombophilic family. Among 1,143 relatives in a single-centre family cohort, only free protein S below the 5th percentile (<41 IU/dL) or the 2.5th percentile (<33 IU/dL) carried a higher risk of a first venous thrombosis, with annual incidences of 1.20% and 1.81% and adjusted hazard ratios of 5.6 (2.7–11.5) and 11.3 (5.4–23.6) against the upper quartile. The authors note that “the cutoff level lies far below the normal range in healthy volunteers” [78].

A confirmed damaging genetic variant. In the UK Biobank (n=426,436) and the US All of Us cohort (n=204,006), heterozygous PROS1 variants of the most damaging kind (nonsense, frameshift and essential splice-site) were rare, with an adjusted prevalence of 0.0091% in the UK cohort and 0.0178% in the US cohort. They carried an odds ratio for VTE of 14.01 (6.98–27.14), and carriers had total protein S levels about half of normal. Less damaging missense variants were commoner (about 0.2%) and carried a smaller risk (OR 1.98, 1.55–2.48). PROS1 variants were not associated with arterial thrombosis (myocardial infarction, peripheral artery disease or non-cardioembolic ischaemic stroke). The authors also report that PROS1 variants correlated poorly with low plasma protein S, and that low plasma protein S was associated with VTE, and with peripheral artery disease, whether or not a variant was present [13]. Only the abstract was read. It does not give the size of that last association, the cut-off used, or whether protein S was measured before or after the thrombotic events, and protein S was measured by a high-throughput proteomic platform rather than a clinical assay. That finding therefore cannot be set directly against MEGA.

A protein S level just below the laboratory’s reference limit in an unselected patient carries little demonstrated risk, and most such results are not genetic. Inherited protein S deficiency, confirmed by a damaging PROS1 variant or by a clearly low level in a thrombophilic family, is rare but is a strong risk factor. Confirmation therefore matters in both directions: it prevents false labels and finds the few patients in whom the label matters.

5.4 First-event risk, recurrence risk, and why protein S predicts recurrence weakly

The hereditary thrombophilias raise the risk of a first event more than the risk of a recurrence. In a meta-analysis of observational studies, the odds ratio for a first VTE was 16.26 (9.90–26.70) for antithrombin deficiency, 7.51 (3.21–17.52) for protein C deficiency and 5.37 (2.70–10.67) for protein S deficiency [79]. BSH 2022 gives an approximately 15-fold risk of a first VTE in heterozygous antithrombin deficiency, with most type II heparin-binding-site defects carrying a roughly 4-fold lower risk [16]. Among relatives of people with FVL, heterozygous carriers had an odds ratio for VTE of 3.5 (2.5–5.0) and homozygous carriers 18 (7.8–40) [80].

For recurrence, the effects are smaller. Table 5 gives the relative risks used by the ASH panel in its model.

Table 5. Prevalence in patients with VTE and relative risk of recurrence by thrombophilia: modelling inputs used by ASH 2023 [23].

Source: ASH 2023, Table 3 (full text). These are modelling inputs, not results of a trial. In its text the panel gives a relative risk of 1.56 (1.31–1.86) for any hereditary thrombophilia, with a median prevalence of 28.3%, before pooling with antiphospholipid antibodies.

Protein S deficiency has the weakest and least certain effect of the natural anticoagulants. A separate meta-analysis found a recurrence odds ratio of 2.52 (0.89–7.16) for protein S deficiency, from only two studies and 57 cases, against 3.61 (1.46–8.95) for antithrombin and 2.94 (1.43–6.04) for protein C deficiency [79]. In the thrombophilic family cohort, recurrence was higher at the lowest free protein S levels (adjusted HR 3.0 and 3.4 below the 5th and 2.5th percentiles) [78]. In the Leiden Thrombophilia Study, the hazard ratio for recurrence with any anticoagulant deficiency was 1.8 (0.9–3.7), and an unprovoked first event (HR 1.9) and male sex (HR 2.7) predicted recurrence better than any laboratory abnormality [81]. Part of the weakness of protein S as a predictor is probably the misclassification described above: a category that contains many false positives will show a diluted effect. This is an inference, not a finding of these studies.

5.5 Antithrombin is a different case

Antithrombin is often grouped with protein S and protein C as “the natural anticoagulants”, and the cautions above are then applied to all three alike. On most points antithrombin behaves differently, and the differences change practice.

The assay is more reproducible. Its long-term within-laboratory variation in the ECAT programme was about half that of the protein S assays (Section 5.2) [14].

A true deficiency carries more risk. Antithrombin deficiency carries the highest odds ratios of the natural-anticoagulant deficiencies for both a first VTE and a recurrence (Section 5.4) [23, 79]. In pregnancy without anticoagulation, the absolute risk of a first VTE was 7.3% antepartum and 11.1% postpartum, the highest of the hereditary thrombophilias [15]. In asymptomatic carriers from thrombophilic families, the highest incidence of a first event was seen with antithrombin deficiency or combined defects [82]. Risk differs by subtype: most type II heparin-binding-site defects carry a lower risk than other forms [16], and type II deficiencies found in blood donors did not appear to confer a high thrombotic risk [64].

The diagnosis can change management, not only its duration. BSH 2022 states that heritable thrombophilia does not influence the intensity, choice or monitoring of anticoagulation “except potentially in those with AT deficiency”: the diagnosis makes antithrombin concentrate available and helps in interpreting the laboratory monitoring of heparin [16]. BSH also advises testing for antithrombin when there is heparin resistance, meaning failure to reach a target level of anticoagulation despite an adequate weight- and renal-adjusted dose [16]. In pregnancy, RCOG advises that women with previous VTE associated with antithrombin deficiency receive higher-dose low-molecular-weight heparin (LMWH) antenatally and for 6 weeks postpartum, with consideration of anti-Xa monitoring and antithrombin replacement at the start of labour or before caesarean section; if anti-Xa levels are measured, the assay should not use added antithrombin [17]. ASH suggests testing women with a family history of VTE and a known familial antithrombin deficiency, and antepartum prophylaxis if they carry it [23].

This has one direct consequence for the approach in Section 9. The usual rule, “do not test when anticoagulation will continue indefinitely in any case”, is sound for decisions about duration. It does not hold where antithrombin deficiency would change the agent, the monitoring of heparin, peripartum care or the advice given to relatives. BSH does not advise routine antithrombin testing without a strong family history, defined as two or more first-degree relatives with VTE [16].

The assays have their own blind spots. The ISTH recommends an activity assay first, followed by an antigen assay and an activity-to-antigen ratio when activity is low, and paediatric reference ranges until 6 months of age [73]. Activity assays can miss some variants. In a UK NEQAS exercise, 77% of centres using human thrombin-based activity assays reported a normal antithrombin level in a patient with antithrombin Cambridge II [83], and the ISTH notes that molecular testing can identify mutations that activity assays miss [73]. Anticoagulants interfere in an assay-specific way. Argatroban, bivalirudin and dabigatran falsely raise antithrombin in factor IIa-based assays; rivaroxaban, apixaban and edoxaban falsely raise it in factor Xa-based assays [16, 73]. A normal antithrombin result in a patient taking a DOAC does not exclude deficiency unless the assay was chosen to avoid the drug. Heparin truly lowers antithrombin, so a low result on heparin cannot be used to diagnose deficiency [16].

Antithrombin activity stayed unchanged through the first 22 weeks of pregnancy in 440 women [65], but BSH lists late pregnancy and the early postpartum period as causes of a physiological reduction [16]. Antithrombin can therefore be measured with reasonable confidence in the first half of pregnancy, which matters when a pregnant woman’s relative has a known deficiency (Section 9.4).

5.6 The assays themselves

Protein S can be measured in three ways: free protein S antigen, total protein S antigen, and protein S activity, a clot-based functional assay. The ISTH notes that assessing protein S is difficult “because of its complex physiological interactions in plasma, sample-related preanalytical variables, and numerous acquired disease processes” [84], and a review of the assays called the diagnosis “difficult and complicated” [85]. BSH 2022 lists free protein S antigen as its protein S assay [16], and the Tang 2025 guideline suggests free protein S antigen with PROS1 analysis [29]. The specific assay recommendations of the ISTH communication were not confirmed from its full text and are not relied on here [84].

Protein C is usually measured by a chromogenic assay, which the ISTH recommends for its good specificity. The chromogenic assay misses the rare type IIb deficiency, which a clot-based assay can detect, but the clot-based assay is less specific [18]. FVL and APC resistance falsely lower clot-based protein C activity: in UK NEQAS, 18% of centres reported protein C deficiency in a patient homozygous for FVL [83]. DOACs falsely raise protein C in the clot-based assay and do not affect the chromogenic assay [18].

Variability between laboratories is large. In UK NEQAS exercises, an average of 21% of 280 centres reported an incorrect diagnosis on a series of samples, and some protein S-deficient subjects would have been called normal with one kit if the manufacturer’s reference range had been used instead of a locally determined one [83]. Method-related differences in free protein S antigen and protein S activity persist in pooled data from six EQA providers [86]. An ISTH survey published in 2026 found that testing “is not always performed according to published guidelines” and that the transfer of reference intervals from manufacturers or the literature “is often suboptimal” [87].

Factor V Leiden and clot-based protein S activity. In one evaluation of a prothrombin time-based protein S activity assay, plasmas from people with FVL gave lower results than those without FVL (86 against 93 IU/dL, p=0.06), and 8% of FVL carriers were classed as low on undiluted plasma against 4% after dilution [88]. A 2025 case report states that FVL can lower protein S activity by up to 15% without affecting the antigen assays [53]. Knowing the patient’s FVL status helps in reading a protein S activity.

Lupus anticoagulant and protein S activity

It is often taught that lupus anticoagulant falsely lowers clot-based protein S activity. The direction of its effect is not settled in the sources read for this review. The one study found that measured it directly (263 patients, 58 lupus anticoagulant-positive) reported that lupus anticoagulant positivity was associated with higher measured protein S activity and also with higher free protein S. In the same study, a raised factor VIII lowered protein S activity but raised free protein S, warfarin lowered activity, and argatroban, bivalirudin and rivaroxaban caused a concentration-dependent false rise in activity. Free protein S was unaffected by every anticoagulant tested [19]. Only the abstract was read.

A normal protein S activity in a patient with lupus anticoagulant does not exclude deficiency. Because free protein S also rose with lupus anticoagulant in this study, free protein S antigen is less affected by anticoagulants but is not shown to be free of interference from lupus anticoagulant. And a low free protein S in a patient with antiphospholipid antibodies may be real but acquired: antibodies against protein S have been reported in a patient with primary antiphospholipid syndrome [89], and an autoantibody after varicella caused severe acquired protein S deficiency with purpura fulminans in a child [90].

5.7 Acquired and artefactual causes: a practical table

Table 6 brings together the factors that alter measured protein S, protein C and antithrombin, and what to do about each. BSH 2022 states the general principle: acquired causes “should always be considered before testing and when interpreting results as, if present, it may not be possible to reliably diagnose a heritable deficiency” [16].

Table 6. Factors that alter measured protein S, protein C and antithrombin.

A dash means that the sources reviewed did not report an effect; it does not mean there is none. HIV has been linked to low protein S only in a case report and a small series, and it is not listed by BSH. The effects of cold activation, delayed centrifugation and freezing and thawing on protein S were looked for and not established.

5.8 Confirming a deficiency before labelling a patient

1. Exclude the acquired causes in Table 6 first [16, 23].
2. Test at the right time: at least 3 months after the acute event and after the initial course of anticoagulation [16, 91]. If the patient is still anticoagulated, choose assays the drug does not affect rather than stopping the drug (Section 9.5).
3. Use the assay that is least affected: free protein S antigen, with local sex-specific ranges; a chromogenic protein C assay, remembering that it misses type IIb deficiency; and an antithrombin activity assay matched to any anticoagulant the patient takes [11, 16, 18, 73].
4. Repeat a low result on a separate sample before calling it a deficiency [11, 29].
5. Where the result will change management, confirm it in the family or the genes (BSH, 2B) [16]. Genetic results need care in both directions. A damaging PROS1 variant is strong evidence [13]. A common missense variant may not be: one case report describes low protein S activity, FVL and a likely benign PROS1 variant in a woman whose free protein S was at the lower normal limit on repeat at 8 months, and who did not meet the criteria for deficiency [53]. In MEGA, PROS1 mutations were as common in controls as in patients among those with the lowest levels [12].
6. Report an unconfirmed result as unconfirmed. A suggested wording is “low protein S, not confirmed; acquired causes not excluded”. This is the author’s suggestion, not a guideline wording.

6. Antiphospholipid antibodies: a separate question

Antiphospholipid syndrome is often requested in the same “thrombophilia screen” as the hereditary tests. It should be thought about separately, because it is acquired, it is tested on different rules, and a positive result changes treatment in a way that most hereditary results do not.

6.1 Why it is separate

Antiphospholipid syndrome (APS) is an acquired thrombophilia. For that reason BSH recommends against screening family members of patients with thrombosis for antiphospholipid antibodies (1A) [16]. The laboratory tests are lupus anticoagulant, IgG or IgM anticardiolipin antibodies, and IgG or IgM anti-β2-glycoprotein I antibodies. The antibodies must be persistent, meaning present on two or more occasions at least 12 weeks apart. Of the three tests, a positive lupus anticoagulant appears to be the most strongly associated with recurrent thrombosis, and people positive on all three (“triple positive”) have the highest thrombotic risk [16].

In Saudi patients, antiphospholipid syndrome is at least as prominent as hereditary thrombophilia. In the Eastern Province clinic series, primary antiphospholipid syndrome was found in 20.6% of patients with VTE, against 6.5% for hereditary thrombophilia [7]. It was recorded in 21.7% of the Jazan CVT series [10] and in 11.9% of couples with recurrent pregnancy loss in Al-Khobar [9], and lupus anticoagulant was found in 8% of selected VTE patients in Jeddah [8]. The ASH model used a median prevalence of antiphospholipid antibodies of 9.7% among patients with VTE [23].

6.2 Whom to test

BSH 2022 recommends or suggests antiphospholipid testing in these settings [16]:

• after unprovoked VTE, because the result may alter management, including the choice of antithrombotic therapy (1B);
• after VTE provoked by a minor risk factor (2C);
• in thrombosis at an unusual site without clear provoking factors (1A);
• in arterial thrombosis without other vascular risk factors (1B);
• in stroke in patients younger than 50 without identifiable cardiovascular risk factors, where testing “should be considered” (1A);
• in suspected catastrophic APS (1A);
• in recurrent or late pregnancy loss, where it “can be considered” (2B).

Other guidelines differ on unprovoked VTE (Section 8.3), and ESHRE recommends screening after two pregnancy losses [26]. Note that the hereditary rule “do not test after stroke, at any age” (BSH 1A) must not be read as covering antiphospholipid antibodies, which BSH advises in young patients with stroke and no cardiovascular risk factors.

6.3 When and how to test

Pregnancy. BSH advises that antiphospholipid testing should be avoided during pregnancy, because levels can vary markedly and a negative or positive result in pregnancy neither excludes nor confirms the diagnosis (2B). Testing should be done at least 6 weeks after the end of pregnancy and repeated 12 weeks after the first test to confirm a positive result [16].

Anticoagulants. ISTH guidance states that anticoagulants can cause false-positive or false-negative lupus anticoagulant results, that VKAs may affect the result, and that lupus anticoagulant should not be tested in patients taking a DOAC; DOAC-adsorbing agents and Taipan snake venom or ecarin-based tests are promising but lack independent evidence and standardised kits [20]. The 2020 ISTH update adds more detailed advice on testing anticoagulated patients and on timing, including measuring heparin or DOAC levels when necessary [93]. A 2024 review names anticoagulant therapy as the main confounder of lupus anticoagulant measurement, stresses timing in relation to the clinical event, and notes differences between the solid-phase assays for anticardiolipin and anti-β2-glycoprotein I antibodies [94]. The abstracts read do not state whether the solid-phase assays are affected by anticoagulants, so that claim is not made here. An integrated laboratory report, with an interpretative comment, is advised [94].

6.4 Why the result matters

A positive and persistent result changes the drug, not only the duration. In the TRAPS trial, 120 patients with thrombotic APS who were triple positive were randomised to rivaroxaban or warfarin. The trial stopped early because of an excess of events with rivaroxaban: 11 events (19%) against 2 (3%), including thromboembolic events in 7 patients (12%: 4 ischaemic strokes and 3 myocardial infarctions) against none with warfarin, and major bleeding in 4 (7%) against 2 (3%) [21]. EULAR 2019 recommends long-term VKA treatment with a target INR of 2–3 for patients with APS and a first unprovoked venous thrombosis, and states that rivaroxaban should not be used in triple-positive APS [22]. TRAPS tested rivaroxaban only. Other DOACs were not assessed in the evidence reviewed here, so it should not be inferred that they are safe in triple-positive APS. An ISTH guidance on DOACs in thrombotic APS also exists [95]; its abstract does not state its recommendations, so it is not relied on here. In pregnancy, RCOG advises higher-dose LMWH for women with VTE associated with APS [17].

6.5 Classification criteria are not diagnostic criteria

The 2023 ACR/EULAR criteria were developed “for use in observational studies and trials”. They require at least one positive antiphospholipid test within 3 years of a qualifying clinical event, then weighted points across six clinical and two laboratory domains, with at least 3 points needed from each. In the validation cohort they had a specificity of 99% and a sensitivity of 84%, against 86% and 99% for the 2006 revised Sapporo criteria [96]. They trade sensitivity for specificity and should not be used on their own to decide whether an individual patient has APS for treatment purposes. The requirement for persistence over at least 12 weeks used in this review comes from BSH [16], not from the ACR/EULAR abstract, which does not state it.

7. Does testing change management, and what does it cost?

7.1 Outcomes

No randomised trial has tested whether thrombophilia testing improves outcomes. The ASH panel states that “no randomized controlled trials (RCTs) have directly addressed these questions”, and its recommendations rest on modelling [23]. The observational evidence is summarised in Table 7.

Table 7. Studies of thrombophilia and recurrence, and of the effect of testing.

Coppens’s interval (0.9–1.8) is compatible with a small benefit or with harm, and tested and untested patients may have differed in ways that affect recurrence; the study shows no benefit, not proof of harm.

The ASH model for unprovoked VTE shows the trade-off behind its first recommendation. Against a default of indefinite anticoagulation for all, testing and stopping anticoagulation in test-negative patients would prevent about 4 major bleeds per 1,000 patients per year at low bleeding risk, but would cause about 42 more recurrences per 1,000 per year. ASH therefore suggests not testing after unprovoked VTE to set the duration [23].

7.2 Utilisation and cost

Audits from other health systems show heavy use in situations where the result is of little help. In Utah, 63% of 1,451 tests were done in situations of minimal clinical utility, and stroke accounted for half of all tests [100]. In California, 42.7% of 1,817 inpatient orders were potentially inappropriate [101]. At Emory, results changed management in 16.9% of tested patients, at a direct cost of US$2,364 per patient tested and US$19,653 per patient whose management changed [102]. In New Zealand, one of 94 requests complied with BSH guidance [103].

Simple controls can work, but their effect varies. A rule requiring a pathologist’s second signature cut inpatient orders by 90% [104]. A New Zealand programme in which a haematologist screened every request reduced testing significantly, and the authors judged the screening step necessary for its success [103]. A hard-stop electronic alert reduced the number of tests by 13%, which its authors described as “only mild reductions” [105].

The closest comparator is a 2026 single-centre audit, apparently Turkish, judged against the 2011 Turkish Society of Hematology guideline: only 7 of 120 evaluable requests (5.8%) met its criteria, 32.0% were ordered during acute thrombosis, two of six low protein C results were confirmed, and “none of eight low protein S results remained valid after timing and confirmation criteria were applied” [106].

No Saudi or Gulf audit of thrombophilia ordering, timing, appropriateness or cost was found. The nearest Saudi work is the Riyadh laboratory audit of positivity rates [5], the Aseer review of JAK2 testing [47], and two audits of other haematology tests in which the author took part: serum folate at Aseer Central Hospital, where deficiency was found in 2.8% of 614 patients tested [107], and serum vitamin B12 at a single institution, where three-quarters of 1,000 reviewed requests gave normal results [108]. Both concluded that ordering was often inappropriate. They are not evidence about thrombophilia testing, but they show that an ordering audit of this kind is feasible locally (Section 9.8).

7.3 The harm of a label

The harms named by guidelines are mislabelling, inappropriate prolongation of anticoagulation, and cost [16, 23, 28]. Psychological harm is often claimed but is not proven: a systematic review could draw “no valid conclusions” [109], and a study of asymptomatic relatives did not find more distress in carriers than in non-carriers [110].

A false label has concrete medical consequences, and they fall mostly on women. Under ASH, a woman from a family with a high-risk thrombophilia who tests positive is advised to avoid combined oral contraceptives and HRT [23]. Women with protein C, protein S or antithrombin deficiency are considered for antepartum or postpartum prophylaxis [15, 16], which means months of daily LMWH injections. And a patient labelled with a deficiency after a provoked event may be kept on indefinite anticoagulation, with its bleeding risk; this is the scenario in which ASH acknowledged that it “did not account for the impact of false-positive test results” [23].

In Saudi practice a label may have social consequences as well, for example when a family considers a marriage, or when an insurer or employer asks about a chronic condition. No study of these effects in Saudi Arabia was found, and they are mentioned here as context, not as evidence. They are a reason for the counselling that both BSH and RCOG advise before testing. BSH states that “it is important that patients are counselled in advance of any decision on whether or not to undertake testing”, including the aims of testing and how it might alter management [16]. RCOG advises that women be counselled about the implications of a positive or a negative result for themselves and for their families, and that results be interpreted by clinicians with specific expertise [17].

8. Review of guidelines on thrombophilia testing

8.1 Summary of each guideline

Table 8. Guidelines and guidance on thrombophilia testing.

8.2 Who to test and who not: by clinical situation

Table 9. Recommendations by clinical situation. A dash means the guideline does not address the point.

8.3 Where the guidelines agree

Agreement is claimed here only among guidelines that address the point.

• Heritable testing is not advised after VTE provoked by surgery [16, 23, 25, 28].
• Protein C, protein S and antithrombin should not be measured in the acute phase or in the first 3 months of anticoagulation [16, 91]. NICE’s related rule is not to test people continuing anticoagulation [25].
• Testing should be done only when the result would change a decision [16, 17, 91].
• MTHFR testing is not recommended [16, 77].
• Heritable screening is not advised for recurrent pregnancy loss, while antiphospholipid testing is [16, 26].
• Acquired deficiencies must be considered before a heritable deficiency is diagnosed [16, 23].

On antiphospholipid testing after unprovoked VTE, BSH recommends it (1B), NICE says “consider” it if anticoagulation is to stop, and RCOG advises it for women [16, 17, 25]. On stroke, BSH is the only one of the main guidelines read that addresses heritable testing [16].

8.4 Where they disagree, and why

The main disagreement is between ASH 2023 on one side and BSH 2022 and NICE on the other, over VTE provoked by non-surgical major risk factors, pregnancy or hormones, and over CVT and splanchnic thrombosis. The difference comes largely from how ASH framed the question. ASH compared testing, and treating only those who test positive, against the default care for each scenario. Where the default is to stop anticoagulation, testing identifies a group in whom continuing might be justified, so the model favours testing. Where the default is indefinite anticoagulation, the model favours not testing [23].

The ASH model has a weakness that matters for protein S. ASH stated that it “did not account for the impact of false-positive test results”, and noted that false positives matter when the comparator is “treat none” [23]. Those are exactly the scenarios in which it suggests testing, and in them a false-positive label leads to indefinite anticoagulation. Nearly all its recommendations are of very low certainty.

The 2013 Choosing Wisely item and ASH 2023 are sometimes presented as in conflict. They agree about surgery. The Choosing Wisely item also names trauma and prolonged immobility, which ASH 2023 would class as non-surgical major transient factors, and for those ASH now suggests testing, but only where anticoagulation would otherwise be stopped [23, 28]. The later guideline is the more specific document and qualifies the earlier item rather than contradicting it.

For CVT, ASH suggests testing if anticoagulation would stop, ESO suggests not screening routinely, and BSH does not recommend heritable testing for unusual site alone [16, 23, 114].

9. Saudi gaps and a suggested local approach

9.1 Gaps in the Saudi evidence

• No Saudi guideline or consensus on thrombophilia testing.
• No Saudi or Gulf audit of thrombophilia test ordering, timing, appropriateness or cost.
• No measurement of protein C, protein S or antithrombin deficiency in a healthy Saudi population.
• No Saudi study of how often a low protein S, protein C or antithrombin result is confirmed on repeat testing.
• No Saudi reference intervals for the natural anticoagulants by sex, age or altitude.
• No population-based VTE incidence, and no FVL or prothrombin prevalence data from Aseer.
• High Saudi protein S deficiency figures with no reported repeat test and incomplete reporting of timing.

Sections 9.2 to 9.7 are a suggested approach, not a guideline (Section 2.4). They should be agreed with the local laboratory before use.

9.2 When not to test

• VTE provoked by surgery [16, 23, 25, 28].
• During the acute event, or in the first 3 months of anticoagulation, for the plasma assays of protein S, protein C and antithrombin [16, 91].
• When the result would not change a decision. The usual example is a decision about duration when anticoagulation will continue indefinitely in any case [23, 25]. This does not apply where antithrombin deficiency would change the choice of agent, the monitoring of heparin, peripartum care or advice to relatives (Section 5.5).
• Stroke at any age, and arterial thrombosis, for the heritable panel [16]. Antiphospholipid testing is a separate decision (Section 6.2).
• Recurrent pregnancy loss or other pregnancy complications, for the heritable panel [16, 26]. Again, antiphospholipid testing is separate.
• Women from the general population before starting a combined oral contraceptive (ASH, strong) or HRT (ASH, conditional) [23].
• Thrombosis at an unusual site, when the site is the only reason (heritable panel) [16].
• Children with venous access-associated thrombosis and no family history [112].
• MTHFR or PAI-1, in any setting [16, 77].
• Asymptomatic relatives, routinely [16, 25]; and antiphospholipid antibodies in relatives, at all [16].
• Before travel, including the Hajj or Umrah. No source found supports it, and the Saudi travel guideline does not recommend it [34].

9.3 When testing may be considered, with specialist input

• Unprovoked VTE with a first-degree relative who has had VTE, when stopping anticoagulation is planned (NICE) [25].
• VTE provoked by a non-surgical major factor, pregnancy or a combined oral contraceptive, when the plan would otherwise be to stop anticoagulation (ASH, conditional, very low certainty). BSH and NICE do not support this, and the decision belongs with a haematologist [16, 23, 25].
• CVT or splanchnic thrombosis, when anticoagulation would otherwise stop (ASH). ESO and BSH advise against routine heritable testing here [16, 23, 114].
• Antithrombin, when there is a strong family history (two or more first-degree relatives with VTE) [16], a known familial antithrombin deficiency, or heparin resistance [16, 17].
• Selected relatives of a proband with a confirmed protein C, protein S or antithrombin deficiency, where the result would influence management or life choices (BSH 2B; ASH Recs 11–14 and 17–22) [16, 23].
• Neonates and children with purpura fulminans: urgent protein C and S testing (BSH 1B), with testing of the parents (Section 4.3) [16].

Antiphospholipid, MPN and JAK2 testing are separate decisions (Section 6.2 and Table 9).

9.4 Women: contraception, pregnancy and assisted reproduction

Before a combined oral contraceptive or HRT. ASH recommends against testing women from the general population before a combined oral contraceptive (Rec 15, strong) and suggests against it before HRT (Rec 16). Where there is a family history of VTE but no known thrombophilia in the family, or a known FVL or prothrombin variant, ASH suggests not testing (Recs 17–20). Where a relative has VTE and a known antithrombin, protein C or protein S deficiency, ASH suggests testing for that defect and avoiding combined oral contraceptives or HRT if it is present (Recs 19–20) [23]. BSH adds that routine FVL testing is not needed before oestrogen in a woman whose relative has FVL without thrombosis, but that family history and the risk of oestrogen should be discussed with all women [16].

Planning pregnancy, or already pregnant, with a known high-risk defect in the family. To guide antepartum prophylaxis (Rec 21), ASH suggests testing for the known familial thrombophilia in women with a family history of VTE and a familial antithrombin deficiency, homozygous FVL, or combined FVL and prothrombin variants, and either testing or not testing where the familial defect is protein C or protein S deficiency. To guide postpartum prophylaxis (Rec 22), it suggests testing in women with a first-degree family history of VTE and any of these defects, protein C and protein S deficiency included; with a second-degree family history, it suggests testing for antithrombin deficiency or combined FVL and prothrombin variants, and either testing or not testing for protein C or protein S deficiency [23]. RCOG advises testing for antithrombin deficiency where there is a family history of antithrombin deficiency or of a thrombophilia that has not been identified, and considering testing in a woman whose first-degree relative had an unprovoked or oestrogen-provoked VTE before the age of 50 [17]. BSH suggests that antithrombin testing may be considered in pregnant women with a family history of the deficiency (2C) [16]. If a woman is already pregnant:

• FVL and prothrombin G20210A are DNA tests, and pregnancy does not change the result.
• Antithrombin can be measured with reasonable confidence in the first half of pregnancy, but not late in pregnancy or early postpartum (Section 5.5).
• Protein S falls in pregnancy [65, 66], and RCOG notes that pregnancy “affects the estimation of protein S in particular” [17]. A low protein S in pregnancy cannot be used to diagnose deficiency.
• Protein C rose through the first 22 weeks in one cohort [65]. Pregnancy-specific ranges would be needed to read a result.

For a woman who has already had an unprovoked or oestrogen-provoked VTE, BSH advises that routine thrombophilia testing in pregnancy is not indicated, because she will need prophylaxis through pregnancy and the puerperium whatever the result [16].

Assisted reproduction. RCOG treats in vitro fertilisation and ovarian hyperstimulation syndrome as risk factors when deciding on thromboprophylaxis in early pregnancy, not as indications for thrombophilia testing [17]. BSH includes VTE provoked by in vitro fertilisation among the events after which routine testing in pregnancy is not indicated [16]. No guideline read recommends thrombophilia testing before ovarian stimulation.

A label carries real consequences for women, so a deficiency should be confirmed before it is acted on (Section 7.3).

9.5 Timing, and testing a patient who is anticoagulated

What the guidelines say. BSH, the Anticoagulation Forum and NICE set the timing rules summarised in Table 9 [16, 25, 91]. None of these documents states how long after stopping a VKA, or how long after delivery, the plasma assays become reliable. One audit states that “recent guidelines suggest” testing at least 1 month after stopping anticoagulation or 3 months after the event, but it does not name those guidelines [104], and that interval is not adopted here.

A practical route. The following is the author’s suggestion, derived from the assay data in Sections 5.5 to 5.7.

• Do not stop anticoagulation only to obtain a test result. Where testing is meant to inform a decision about stopping, do it near the planned end of the initial treatment, after at least 3 months.
• On a DOAC: free protein S antigen was unaffected by the anticoagulants tested in one study [19]; the chromogenic protein C assay is unaffected by DOACs [18]; for antithrombin, choose an assay whose principle the drug does not affect (an anti-Xa drug falsely raises Xa-based assays, and a thrombin inhibitor falsely raises IIa-based assays) [73]; FVL and prothrombin are genotyped. Lupus anticoagulant should not be tested on a DOAC [20].
• On a VKA: protein C and protein S are truly lowered, so a deficiency cannot be diagnosed [16]. If the result is needed while anticoagulation continues, changing from the VKA to LMWH or a DOAC, with specialist advice, and then using the assays above is one route. Do not change to a DOAC where antiphospholipid syndrome is confirmed or has not yet been excluded, or where a VKA is otherwise required; use LMWH instead. Rivaroxaban caused excess events in triple-positive APS, EULAR advises against it there, and the safety of other DOACs in APS is not established by the evidence reviewed here (Section 6.4) [21, 22, 95]. On LMWH, antithrombin cannot be assessed, because heparin truly lowers it [16]. The interval needed after the change is not specified in the guidelines read.
• On heparin: antithrombin is truly lowered, and clot-based protein C and protein S are falsely raised [16].
• After pregnancy: test outside pregnancy and preferably before it [16, 17]. For antiphospholipid antibodies BSH gives at least 6 weeks after the end of pregnancy, with a repeat 12 weeks later [16]; no corresponding interval for the natural anticoagulants was found.

9.6 Which assays, and confirmation before labelling

• Protein S, protein C and antithrombin: free protein S antigen, a chromogenic protein C assay and an antithrombin activity assay matched to any anticoagulant, with the confirmation steps in Section 5.8. Where suspicion is strong and the first-line assay is normal, a clot-based protein C assay or genetic testing may find a variant that the first-line assay misses (Sections 5.5 and 5.6).
• FVL: genotyping, or a modified APC resistance test (with predilution in factor V-deficient plasma) followed by genotyping. A first-generation APC resistance test alone is not enough (Section 4.1) [5, 61].
• Prothrombin G20210A: can only be detected genetically [87].
• Do not enter “protein S deficiency”, or protein C or antithrombin deficiency, as a diagnosis on the basis of a single result.

9.7 Making it work in Saudi laboratories

Many Saudi hospitals, including Ministry of Health and regional hospitals, will not have every assay on site. The points below are practical suggestions by the author; they are not drawn from a guideline unless a source is cited.

If only clot-based activity assays are available. Read every result against Table 6. Record the patient’s FVL status, anticoagulant and lupus anticoagulant status with the request. A normal clot-based protein C or protein S result in a patient on a DOAC does not exclude deficiency [16, 18, 19]. A low clot-based protein S may be caused by FVL or a raised factor VIII [19, 88]. Before a patient is labelled, a low result should be repeated and, where possible, confirmed with a free protein S antigen or a chromogenic protein C assay at a reference laboratory.

If samples are sent out. Pre-analytical variables affect the measurement of protein C, and the effect depends on the assay; a partially clotted sample, for example, raises a chromogenic result and lowers a clot-based one [18]. The sending laboratory should follow the reference laboratory’s written requirements for collection, separation, freezing and transport, and should not send a sample that does not meet them. Each repeat costs money and time, so the indication should be checked before the first sample is sent, not after the result returns.

Reference intervals. No Saudi reference intervals for protein C, protein S or antithrombin were found, by sex, age or altitude, and transferred intervals are a known source of error (Section 5.6). Protein S differs between men and women [11], and children need age-specific ranges [18, 73]. Until local intervals exist, a reasonable interim step is to use a reference laboratory’s verified, sex-specific intervals and to state their source on the report. For lupus anticoagulant, the ISTH advises establishing cut-offs in-house on at least 120 normal subjects, with transfer of the manufacturer’s cut-offs as an alternative [93].

Who owns the requesting rule. Requesting rules work when someone is responsible for them. In New Zealand, success depended on a haematologist screening every request [103]; in the United States, a pathologist’s second signature cut inpatient orders by 90% [104]. In a Saudi hospital the rule should be agreed between haematology and the laboratory, and one of them should own it.

9.8 A proposed local audit

Because no Saudi audit exists, a retrospective audit at the Aseer hospitals would fill a real gap. The author’s group has run ordering-appropriateness audits of serum folate and vitamin B12 [107, 108], which shows the method is feasible locally. The questions it could answer:

1. What proportion of thrombophilia requests met BSH 2022, NICE NG158 or ASH 2023 criteria?
2. What proportion were sent during the acute event, during the first 3 months of anticoagulation, in pregnancy, or on a VKA or a DOAC?
3. Which assays were used for protein S, protein C and antithrombin, and against which reference intervals?
4. Of the low natural-anticoagulant results, how many were repeated, and how many were confirmed?
5. Was lupus anticoagulant tested on anticoagulants, and was a positive antiphospholipid result repeated after 12 weeks?
6. How often did a result change management, and at what cost?
7. Did patients labelled as deficient receive extended anticoagulation, or have contraception withheld, on the strength of an unconfirmed result?

A re-audit after a simple intervention, such as a requesting rule tied to haematology review, would show whether practice can be changed. Elsewhere such measures have reduced testing by between 13% and 90% [103–105].

9.9 Research agenda

• Sex-specific reference intervals for free protein S, protein C and antithrombin in healthy Saudis, including the highland population of Aseer.
• Prevalence of FVL and prothrombin G20210A in Aseer.
• The prevalence of protein C, protein S and antithrombin deficiency in healthy Saudis, with repeat testing and family or genetic confirmation.
• The confirmation rate of low natural-anticoagulant results in Saudi laboratories.
• Natural-anticoagulant deficiency in relation to consanguinity, with family studies and genotyping.
• VTE in Hajj and Umrah pilgrims.
• A search of Arabic-language journals, which this review did not cover.

10. Limitations

This is a narrative review, not a systematic review. The searches followed no registered protocol, the number of records screened was not recorded, and inclusion was by judgement (Section 2.2). Only English-language sources were searched, so Saudi work published in Arabic may have been missed.

Most of the evidence was read as abstracts. Each reference carries its evidence status, and where only the abstract was read the text claims nothing beyond it. Absence of a detail in an abstract, such as the assay, the timing or a repeat test, does not mean the study lacked it.

Several documents were identified but not read, and are not cited for any position: the CHEST antithrombotic guidelines of 2012, 2016 and 2021, the European Society for Vascular Surgery 2021 guideline, the AHA 2024 statement on cerebral venous thrombosis, the ASH 2018 paediatric VTE guideline, the Society for Vascular Medicine Choosing Wisely item, and the AHA/ASA 2021 secondary stroke prevention guideline, which was known only from secondary summaries. The ESC 2019 pulmonary embolism guideline was read for the original draft, but the publisher’s page could not be reopened for this revision, so its wording was not re-checked and it is left out of the comparisons [120]. An ISTH guidance on thrombophilia testing said to date from 2023, and a CLSI document numbered H59, were looked for and not found. BSH 2010 is superseded by BSH 2022 and is not cited as current guidance [111].

Some claims are reasoning rather than findings (Table 4, the premarital argument in Section 4.3, and the author’s suggestions in Sections 9.5 and 9.7); each is labelled where it appears.

The Saudi evidence itself is limited. There is no population-based VTE study, no measurement of natural-anticoagulant deficiency in healthy Saudis, and no Saudi reference intervals, so the central argument of this review, that many low results in Saudi series are acquired or analytical, is an inference from international data and from what the Saudi papers report. The studies in Section 9.9 would test it.

Disclosure and attribution

I have no conflicts of interest to declare. One of the studies cited [47] and two of the audits cited [107, 108] are by my group. This review was researched and drafted with the help of AI. Every reference in the list was checked against its PubMed record, its DOI record or the issuing body’s own document, and its tag states what was actually read; documents identified but not read are named in Section 10 and not cited for any position. It is written for clinicians and is not a substitute for a guideline, a specialist opinion, or the judgement of the physician treating the patient.

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