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Protein S deficiency

Protein S deficiency
Author:
Kenneth A Bauer, MD
Section Editor:
Lawrence LK Leung, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 16, 2021.

INTRODUCTION — Protein S deficiency is an inherited thrombophilia associated with an increased risk of thromboembolism. Establishing a diagnosis of hereditary protein S deficiency may be difficult, particularly in the setting of an acute thrombosis or anticoagulant administration.

This topic review discusses the diagnosis and management of protein S deficiency.

Separate topic reviews address the appropriate use of thrombophilia testing in various clinical settings:

Children – (See "Thrombophilia testing in children and adolescents".)

Patients with venous thromboembolism – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Patients with stroke – (See "Overview of the evaluation of stroke", section on 'Blood tests'.)

Patients with pregnancy loss – (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for screening'.)

Asymptomatic patients with a positive family history – (See "Screening for inherited thrombophilia in asymptomatic adults".)

PATHOPHYSIOLOGY

Biology of protein S — Protein S is named for Seattle, Washington, where it was originally discovered and purified. Protein S is a vitamin K-dependent glycoprotein, but it is not a zymogen of a serine protease enzyme. It serves as a cofactor for activated protein C, which inactivates procoagulant factors Va and VIIIa, reducing thrombin generation (figure 1) [1]. Protein S also serves as a cofactor for activated protein C in enhancing fibrinolysis and can directly inhibit prothrombin activation via interactions with other coagulation factors [2-6].

Protein S deficiency impairs this normal control mechanism, increasing the risk of thrombosis. (See "Overview of hemostasis", section on 'Activated protein C and protein S'.)

Protein S is primarily synthesized by hepatocytes, but there is also evidence that it can be made in endothelial cells and megakaryocytes. It undergoes vitamin K-dependent gamma-carboxylation, which is required for its activity. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".)

Mature gamma-carboxylated protein S circulates in two states: free, and bound to the complement component C4b-binding protein (C4b-BP) [7]. The free form comprises 30 to 40 percent of total protein S and is the only form of protein S that has cofactor activity for activated protein C [7,8]. The average plasma concentration of total protein S in adults is 23 mcg/mL [9].

Total protein S levels change with age, but free protein S levels are more constant:

Total protein S levels in healthy newborns at term are 15 to 30 percent of that in adults, while C4b-binding protein is markedly reduced to less than 20 percent. Thus, free protein S predominates and functional protein S levels are only slightly reduced compared with those in adults [10].

Protein S levels increase with advancing age and are significantly lower and more variable in females than males [11,12]. In women, the increase with age is seen with total protein S but not free protein S; a finding that has been explained by an increase in C4b-BP levels during normal aging [11,13].

Free and total protein S levels appear to be higher in men than in women, although no clinical significance has been ascribed to this minor difference. In a series of 3788 healthy blood donors in Scotland, protein S levels in men were approximately 10 to 20 percent higher than in women [13].

Serum lipids may affect protein S levels. In one series of 150 adults in a community practice, total protein S levels were increased as much as 10 percent between those with the lowest versus the highest cholesterol levels, and free protein S rose as much as 30 percent between those with the lowest versus the highest triglyceride levels [14].

Genetics of protein S deficiency — Protein S deficiency (MIM 612336) is an autosomal dominant condition due to mutations in the PROS1 gene, a large gene on chromosome 3. The first descriptions of familial protein S deficiency were reported in 1984 [15-17]. Subsequently, a number of additional families and familial mutations have been described [18-23].

The majority of individuals with hereditary protein S deficiency are heterozygous for a PROS1 mutation, although rare homozygous or compound heterozygous individuals with much more severe clinical features have been reported (see 'Clinical features' below). A pseudogene (noncoding gene), PROS2, is located on the same chromosome but does not appear to have any clinical relevance [24,25].

The large size of the PROS1 gene and the presence of the pseudogene have complicated the identification of mutations, although an increasing number are being reported. Mutations have been identified in 70 percent of protein S-deficient probands, and a database of known PROS1 mutations has been published [26,27]. Molecular analysis also has identified a few cases of large PROS1 gene deletions [26,28-30].

Inherited protein S deficiency can be subdivided according to whether the abnormality affects total protein S antigen level, free protein S antigen level, and/or protein S function (activity) [27]:

Type I – Type I deficiency (reduced total protein S, free protein S, and protein S function) is the classic type of inherited protein S deficiency. Typical findings include total protein S of approximately 50 percent of normal and free protein S as low as 15 percent of normal [15,19]. Most of the mutations responsible for type I deficiency are missense or nonsense mutations [31]. Microinsertions, microdeletions, and splice site mutations have also been reported.

Type II – Type II deficiency (normal total and free protein S; reduced protein S function) is rare (case reports only). This is also referred to as a qualitative defect. Five mutations described in the original reports were missense mutations located in the aminoterminal end of the protein, which includes the domains that interact with activated protein C [32-35]. These mutations may alter the conformation of protein S or interfere with carboxylation of the gamma-carboxyglutamic acid domain of the protein [33]. In a series of 118 French patients with thromboembolism associated with protein S deficiency, 26 had a serine to proline substitution at amino acid 460 (the Heerlen polymorphism), which affects protein S metabolism [36,37]. The low free plasma protein S may result from increased binding of the abnormal protein S to C4b-binding protein [38,39]. The thrombophilic risk with this polymorphism has been questioned [37].

Type III – Type III deficiency (selectively reduced free protein S and protein S function; normal total protein S) is another type of quantitative defect.

In some families, different individuals have either type I or type III protein S deficiency, suggesting that the same mutation can cause different laboratory patterns [11,40-42].

Distinction among types is important for research purposes but does not affect disease severity or clinical management [43]. In the Protein S Deficiency Database, patient phenotypes are described as quantitative (types I or III) or qualitative (type II) [27]. Additional information on these mutations and their associated thrombotic risks can be obtained from the International Society on Thrombosis and Haemostasis (ISTH).

Causes of reduced protein S — In addition to PROS1 gene mutations (see 'Genetics of protein S deficiency' above), reduced protein S levels have been seen in the following settings:

Pregnancy [44]. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Coagulation and fibrinolysis'.)

Oral hormonal contraceptive use [12,45]. However, postmenopausal hormone replacement therapy does not appear to alter protein S levels [13].

Disseminated intravascular coagulation [46,47].

Acute thrombosis (table 1) [48].

Human immunodeficiency virus (HIV) infection (significantly reduced total and free protein S) [49]. A correlation with increased thromboembolism risk has not been established.

Nephrotic syndrome (typically characterized by increased total protein S levels but reduced protein S function) [50,51]. This pattern is in part due to urinary loss of free protein S and elevated plasma C4b-binding protein.

Liver disease (moderate decrease in total and free protein S) [38,45].

L-asparaginase chemotherapy [52].

In a boy recovering from chickenpox (varicella-zoster virus infection) transient isolated deficiency of protein S induced by an autoantibody directed against protein S was associated with renal and spermatic vein thrombosis [53].

C4b-binding protein is an acute phase reactant. Thus, several of the conditions listed above may be associated with a shift of protein S from the free form to the bound (inactive) form, potentially leading to an erroneous diagnosis of protein S deficiency [47]. (See "Acute phase reactants" and 'Diagnosis' below.)

The clinical implications of these protein S reductions may differ from inherited protein S deficiency; some of these conditions are associated with multiple coagulation factor deficiencies, making it difficult to establish whether the increased risk of thrombosis is attributable to protein S deficiency or to the combination of abnormalities.

EPIDEMIOLOGY — The prevalence of hereditary protein S deficiency has been challenging to establish due to the variability of protein S levels among different individuals, the use of different tests that may measure different pools of protein S, and the lack of a clear threshold below which protein S deficiency can be diagnosed reliably (table 2). (See 'Choice and interpretation of protein S assay' below.)

Data from the 2013 MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) suggest that protein S deficiency may be much less common than previously thought [54]. As noted below (see 'Venous thromboembolism' below), the individuals in this series included 2331 adults with a personal history of venous thromboembolism (VTE) without a strong family history and 2872 controls. When protein S deficiency was defined by the level of free protein S that correlated with an increased likelihood of VTE (<33 units/dL), the frequency of protein S deficiency in this population was quite low (approximately 48 of 5317; 0.9 percent). Only 10 of these individuals had a PROS1 mutation. Earlier studies had reported frequencies of protein S deficiency in the range of 2 to 8 percent among individuals with VTE [18,20,55].

CLINICAL FEATURES

Venous thromboembolism — Venous thromboembolism (VTE) including deep vein thrombosis and pulmonary embolism is the major clinical manifestation of protein S deficiency.

The absolute risk of VTE, typical age of presentation, and recurrence risk varies depending on the study population, with greater risks and younger age of presentation typically seen in thrombophilic families and individuals with combined inherited or inherited plus acquired VTE risk factors. Hereditary protein S deficiency is a rare risk factor for VTE in the absence of a family history. Available studies involving thrombophilic families and the general population include the following:

In a series of 30 children with protein S deficiency who presented with VTE, the median age of the first thromboembolic event was 14.5 years [55]. There was an additional thrombophilic risk factor in 18 (60 percent) of the children, such as oral contraceptive use, chemotherapy, or prolonged immobilization. The remaining 12 events (40 percent) were unprovoked. Sites of thrombosis were deep veins of the leg (DVT; 12 events; 40 percent), cerebral veins (8 events; 27 percent), DVT and pulmonary embolism (PE; 5 events; 17 percent), calf vein (3 events; 10 percent), intracardiac veins (1 event), and purpura fulminans (1 event). There was a positive family history of thrombophilia in 17 (57 percent). As noted above, these 30 children represented 8 percent of children referred to the center for VTE. (See 'Epidemiology' above.)

In a series involving 12 thrombophilic families, 71 of 136 individuals tested (52 percent) had protein S deficiency, consistent with autosomal dominant transmission [22]. Of these, 39 (55 percent) had VTE. Most were DVT or PE, although there were five in unusual sites (eg, mesenteric or cerebral veins). The mean age of first thrombotic event was 28 years (range, 15 to 68 years). Approximately half the events were spontaneous and half were considered to be provoked.

In a 2013 meta-analysis of studies involving patients with portal vein thrombosis (PVT) or hepatic vein thrombosis (Budd-Chiari syndrome [BCS]), inherited protein S deficiency was found in 3 percent of each group [56].

In a general population of individuals with a first VTE but without a strong family history of thrombophilia, the risk of VTE attributed to protein S deficiency appears to be lower than that in thrombophilic families.

The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) case control study compared protein S levels in 4956 individuals with a first episode of VTE and 6297 controls (partners of patients or individuals identified by random digit telephone calls) [54]. Protein S levels below the 2.5th percentile (<53 units/dL for free protein S; <68 units/dL for total protein S), did not correlate with an increased risk of VTE (eg, odds ratio [OR] for free protein S 0.82; 95% CI 0.56-1.21). Only when the cutoff was set at a free protein S level below the 0.1th percentile (ie, levels in the bottom one-tenth of one percent; <33 units/dL) did the odds of VTE increase, although this did not reach statistical significance (OR 5.44; 95% CI 0.6-48.8). Total protein S levels did not correlate with thrombosis, even below the 0.1th percentile. As noted above, the clinical implications of MEGA are that hereditary protein S deficiency is a rare risk factor for VTE if testing is carried out in the absence of a family history.

Some individuals with protein S deficiency and VTE also have a second thrombophilic defect. This was illustrated in a series of families with protein S deficiency, in which slightly over a third of families also had the factor V Leiden (FVL) mutation [57]. The risk of VTE was greater in those with both defects (13 of 18 [72 percent]; versus 4 of 21 with protein S deficiency alone and 4 of 21 with FVL mutation alone). Similar findings of increased VTE risk in individuals with combined protein S deficiency and FVL mutation have been reported by others [36,58,59].

In addition to DVT and PE, thrombosis has also been reported in the axillary, mesenteric, and cerebral veins in patients with protein S deficiency.

Complications typically associated with protein C deficiency such as purpura fulminans and warfarin-induced skin necrosis have also been described with protein S deficiency [55,60]. (See 'Neonatal purpura fulminans' below and "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Our approach to deciding which patients with VTE should be tested for inherited thrombophilias is presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Arterial thrombosis — Several case reports have described young patients with arterial thrombosis in the setting of inherited protein S deficiency [61-63]. However, larger studies have not convincingly demonstrated that protein S deficiency is a risk factor for arterial thrombosis [64-66].

Examples of available data include the following:

Protein S deficiency in patients with stroke – In a series of 127 consecutive patients admitted for an acute ischemic stroke, abnormally low levels of protein S were found in four (3 percent) [65]. Three were attributed to pregnancy and not to an inherited defect; the finding of protein S deficiency did not alter patient management in any case. In another series of 120 patients with cerebral ischemic events, 20 (17 percent) had decreased protein S levels, but on repeat testing protein S levels were only low in two (2 percent) [66].

Arterial thrombosis in patients with protein S deficiency – In a cohort of 3052 healthy men ages 49 to 64, a reduced free protein S level was not associated with an increased risk of stroke; however, it was associated with a modest increase in coronary artery disease (hazard ratio [HR] 1.85; 95% CI 1.1-3.2) [67].

Our approach to deciding which individuals with stroke should be tested for inherited thrombophilias is presented separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Overview of the evaluation of stroke", section on 'Blood tests'.)

Neonatal purpura fulminans — Severe thrombotic complications, including neonatal purpura fulminans, have been reported in newborns with very low protein S levels; this is rare and typically due to homozygous deficiency [68,69]. An animal model of complete absence of protein S demonstrated late embryonic death due to intracerebral thrombosis and hemorrhage, as well as abnormal blood vessel development [70,71].

Obstetrical complications — Data are mixed regarding the role of protein S deficiency in miscarriage. The increased risk, if any, is small. (See "Inherited thrombophilias in pregnancy".)

As noted above, however, pregnancy and the postpartum period increase the risk of maternal VTE over and above that attributable to protein S deficiency. (See 'Venous thromboembolism' above.)

DIAGNOSIS

Overview of evaluation and diagnosis — As with other inherited thrombophilias, protein S deficiency may be suspected in an individual with venous thromboembolism (VTE) in association with one or more of the following:

Strong family history of VTE

Known familial protein S deficiency

First VTE event before age 50

VTE in an unusual site such as portal, mesenteric, or cerebral vein

Recurrent VTE

For some individuals such as those with recurrent or life-threatening VTE for whom indefinite anticoagulation is indicated, the diagnosis of protein S deficiency may not alter management. However, there may be a role for identifying a familial defect to allow testing and counseling of first degree relatives such as women considering the use of hormonal contraceptives, or individuals who would benefit from additional counseling and/or interventions to reduce VTE risk. (See "Screening for inherited thrombophilia in asymptomatic adults" and "Contraception: Counseling for women with inherited thrombophilias".)

Unless the specific familial defect is known, individuals with VTE who warrant testing should be evaluated for other inherited thrombophilias and in some cases for acquired thrombophilias such as antiphospholipid syndrome (especially if the activated partial thromboplastin time [aPTT] is prolonged) or a myeloproliferative neoplasm (if there is erythrocytosis or thrombocytosis). (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

In contrast, we generally do not perform routine testing for protein S deficiency in the setting of VTE that is provoked or occurs in an individual over 50 years of age in the absence of a positive family history of VTE.

Once a decision is made to pursue testing, choosing the appropriate assay and criteria for diagnosis are challenging. (See 'Choice and interpretation of protein S assay' below.)

Additional information regarding the role of thrombophilia testing in specific clinical settings is discussed separately:

Portal vein thrombosis – (See "Epidemiology and pathogenesis of portal vein thrombosis in adults".)

Stroke – (See "Stroke: Etiology, classification, and epidemiology", section on 'Blood disorders'.)

Children – (See "Thrombophilia testing in children and adolescents".)

Choice and interpretation of protein S assay — Protein S deficiency is the most difficult of the hereditary thrombophilias to document with certainty. As previously noted, protein S levels in the general population vary more widely than those of protein C or antithrombin. (See 'Biology of protein S' above.)

Free protein S is our preferred approach to screening as it appears to be the best test for true deficiency [72,73]. Combining free protein S levels with other testing such as a functional assay does not appear to improve diagnostic accuracy.

Free protein S – Free protein S level is measured using an immunoassay. Various monoclonal antibody-based or ligand-based (eg, C4b-binding protein) detection methods are available [31,74-76]. Earlier assays used polyethylene glycol precipitation to remove protein S bound to C4b-binding protein [38].

Total protein S – Total protein S level is measured using an immunoassay. Polyclonal antibody-based methods are often used [77].

Protein S functional assay – Protein S function is measured in a coagulation-based assay in which the time to clot formation is proportional to the plasma protein S activity [78,79]. One problem with the functional protein S assay is the large coefficient of variation. Another problem is that some of these assays are also sensitive to the defect characterized by resistance to activated protein C (aPC) such as seen in individuals with the factor V Leiden (FVL) mutation. As a result, their use can lead to an erroneous diagnosis of functional protein S deficiency in a patient who has another cause of aPC resistance [80]. A strategy of first screening plasma samples for aPC resistance prior to performing a functional protein S assay can obviate this potential problem. As noted above, however, measurement of free protein S level is our preferred approach.

There is no ideal cutoff level that distinguishes between individuals with and without protein S deficiency. The value used depends on the assay, the clinical setting, and the age of the patient:

For patients who have had a VTE or those with a strong family history of VTE, plasma levels of total or free protein S antigen less than 60 to 65 international units/dL are considered to be in the deficient range [81].

For individuals who are asymptomatic or who have a first VTE in the absence of a strong family history, lower levels of free protein S (eg, <33 units/dL) are more predictive for an increased risk of VTE [81].

For newborns, it is important to use age-based norms for the specific laboratory performing the test, as these may differ from normal adult values, especially for total protein S levels. (See 'Biology of protein S' above.)

For most patients it is necessary to perform repeat testing and take into account the family history of thrombosis when making the diagnosis, regardless of which test is used.

In contrast to these plasma-based tests, genetic testing for protein S deficiency is neither feasible nor readily available outside of a research setting.

Timing of testing and effect of anticoagulants — The timing of thrombophilia testing relative to a VTE event and/or anticoagulation administration is an important consideration in laboratory testing for suspected protein S deficiency (as is also the case for suspected deficiency of antithrombin [AT] or protein C). (Related Lab Interpretation Monograph(s): "Low protein S in adults".)

Liver disease, acute thrombosis, pregnancy, and any comorbid illness that causes an acute phase response can lower the level of free protein S, resulting in erroneous diagnosis of protein S deficiency. (See 'Causes of reduced protein S' above.)

Vitamin K antagonists can cause reduced protein S levels. A finding of a normal protein S level in the setting of warfarin therapy excludes protein S deficiency; however, a low protein S level in the setting of warfarin therapy must be repeated when the individual is no longer receiving a vitamin K antagonist.

In practice, it is preferable to investigate patients suspected of having protein S (or protein C) deficiency after a vitamin K antagonist has been discontinued for at least two weeks. If it is not possible to discontinue warfarin due to the severity of the thrombosis or thrombotic risk, it may be possible to assay protein S levels while the patient is receiving heparin, which does not alter protein S concentration. Another option that was proposed in the setting of vitamin K antagonist therapy many years ago is to measure the ratio of protein S to prothrombin or other vitamin K-dependent coagulation factor, and to infer a diagnosis of protein S deficiency if this ratio is low; however, this method has not been validated [15,19].

Direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) can affect the functional assays for protein S (which use a clotting endpoint) [82].

Heparin and low molecular weight heparin do not interfere with testing for protein S deficiency [82].

Differential diagnosis — The differential diagnosis of VTE includes other inherited thrombophilias and acquired risk factors for thrombosis. For individuals without clinical findings, a borderline protein S value may simply represent a level below the lower limit of the normal range, which is established in such a way that a small percentage of unaffected individuals will have a level below "normal."

Other inherited thrombophilias – Other inherited thrombophilias include factor V Leiden (FVL) mutation, protein C deficiency, antithrombin (AT) deficiency, and prothrombin G20210A mutation; of these, FVL is the most common. Like protein S deficiency, patients may present with a positive personal or family history of VTE or other thromboembolic complications. Unlike protein S deficiency, individuals with these other inherited thrombophilias will have laboratory evidence of the other specific defect and will have normal protein S levels, unless tested in the setting of acute illness, thrombosis, or interfering anticoagulant. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

Acquired VTE risk factors – A number of acquired risk factors for VTE have been described, including immobility, surgery, trauma, cancer or myeloproliferative neoplasms (MPN), certain drugs, the antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria (PNH), disseminated intravascular coagulation (DIC), and hormonal changes including hormonal contraceptives, pregnancy, and the postpartum period. Like protein S deficiency, these patients may have VTE in typical or atypical locations. Unlike protein S deficiency, these acquired risk factors are often obvious from the patient's history and/or laboratory studies; the family history typically does not reveal thrombophilia in these acquired disorders. (See "Overview of the causes of venous thrombosis", section on 'Acquired risk factors'.)

MANAGEMENT

Patients with VTE — The initial management of acute venous thromboembolism (VTE) in patients with inherited protein S deficiency is not different from that in patients without an inherited thrombophilia and typically includes anticoagulation for at least three to six months (algorithm 1). Protein S deficiency does not alter the choice of anticoagulant or dosing, which are discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

The choice between a direct oral anticoagulant (DOAC) versus warfarin is based on a number of factors including the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions. We are more likely to use a DOAC for individuals with typical VTE presentations and more likely to use warfarin for individuals with extremely high or low body weights, concerns about adherence, or a potential benefit from maintaining an INR in the high end of the therapeutic range (eg, those with a submassive or massive pulmonary embolism [PE] with severe clinical presentations such as hypoxemia/shock or those with deep vein thrombosis [DVT] with proximal clot burden).

The decision to continue anticoagulation beyond three to six months or indefinitely depends on whether the thrombosis was provoked or unprovoked and other factors. Indefinite anticoagulation is recommended for many patients with an unprovoked thromboembolic event, regardless of whether an inherited thrombophilia is identified; the documentation of protein S deficiency may strengthen the case for indefinite anticoagulation, particularly if there is a strong family history of VTE. Other factors that make us more likely to advise indefinite anticoagulation include recurrent thrombosis, life-threatening thrombosis, thrombosis at an unusual site, or more than one inherited prothrombotic defect. These issues are discussed in more detail separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

If it is decided to use a DOAC for the long-term prevention of recurrent VTE, we generally continue a higher dose regimen (eg, rivaroxaban 20 mg once daily or apixaban 5 mg twice daily rather than rivaroxaban 10 mg once daily or apixaban 2.5 mg twice daily), assuming the individual's bleeding risk is not excessive. This is because protein S deficiency is one of the more thrombophilic of the hereditary thrombophilias. The prescribing physician and patient should understand that evidence for the optimal dose in such patients is lacking.

Asymptomatic individuals (obstetrical/surgical prophylaxis) — Individuals with protein S deficiency who have not had a thromboembolic event are not treated with routine anticoagulation. (See "Screening for inherited thrombophilia in asymptomatic adults".)

We generally avoid oral contraceptives in women with inherited protein S deficiency. However, there may be settings in which an individual with protein S deficiency may be treated with oral contraceptives if this is in the best interest of the patient based on the judgment of the treating clinician. An example would be a patient who strongly wishes to avoid pregnancy and cannot or will not use another method of birth control, especially if the family history of thrombosis is absent or weak. A comprehensive discussion of contraceptive counseling that addresses other scenarios is presented separately (see "Contraception: Counseling for women with inherited thrombophilias"). We also provide education regarding conditions that increase thrombotic risk (eg, prolonged immobility).

Individuals with protein S deficiency may also benefit from the judicious use of prophylactic anticoagulation in certain settings, especially if they have a strong family history of thrombophilia or other VTE risk factors (algorithm 1). The greatest benefit is likely to be seen in those at greatest risk of VTE such as those with a strong family history of thrombophilia or surgery/pregnancy associated with prolonged immobility; benefit may be lower (or absent) in those with less VTE risk such as those with an absent or weak family history of thrombosis and a briefer period of immobility. Recommendations for anticoagulation in specific settings are presented in separate topic reviews:

Pregnancy – (See "Inherited thrombophilias in pregnancy".)

Surgery – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Acute medical illness – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Testing of first degree relatives — The testing of asymptomatic first degree relatives can be delayed until after puberty and is generally most helpful in settings in which the risk of thrombosis is increased, such as initiation of oral hormonal contraceptives or pregnancy. This subject is discussed in more detail separately. (See "Screening for inherited thrombophilia in asymptomatic adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY AND RECOMMENDATIONS

Protein S function – Protein S (for Seattle) is a negative regulator of coagulation. It circulates free and bound to C4b-binding protein; only the free form is active. Free protein S is a cofactor for protein C, which inactivates procoagulant factors Va and VIIIa (figure 1). Protein S deficiency is autosomal dominant; most individuals are heterozygous for a PROS1 mutation. Reduced protein S occurs in several acquired conditions for which its clinical significance is unclear. (See 'Pathophysiology' above.)

Prevalence – The prevalence of hereditary protein S deficiency has been difficult to establish and may be <1 percent of individuals with venous thromboembolism (VTE). (See 'Epidemiology' above.)

VTE risk – Protein S deficiency increases VTE risk. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are most common, but thrombosis also occurs in other sites (cerebral and mesenteric vein). Younger age of presentation is typically seen in thrombophilic families and individuals with combined VTE risk factors. Data are limited regarding risks of arterial thrombosis and obstetric complications. (See 'Clinical features' above.)

Evaluation – Protein S deficiency may be suspected in an individual with a strong family history of thrombophilia or known familial protein S deficiency, first VTE before age 50, VTE in an unusual site, or recurrent VTE. For some individuals, the diagnosis of protein S deficiency may not alter management. There may be a role for identifying this disorder to allow testing and counseling of first-degree relatives (especially females) considering estrogen-containing contraceptives. (See 'Overview of evaluation and diagnosis' above.)

Diagnosis – Protein S deficiency is difficult to document with certainty. Free protein S (measured by immunoassay) is probably the best screening test. The cutoff value depends on the assay, clinical setting, and patient age. For most patients, it is necessary to repeat testing and incorporate family history of thrombophilia when making the diagnosis. An erroneous diagnosis can be made with acute VTE or during pregnancy certain illnesses, or treatment with certain anticoagulants, especially vitamin K antagonists (table 1). (See 'Choice and interpretation of protein S assay' above and 'Timing of testing and effect of anticoagulants' above.)

VTE treatment – Acute VTE management is not different from VTE in the general population and typically includes anticoagulation for at least three to six months (algorithm 1). Extended anticoagulation beyond three to six months depends on whether the thrombosis was provoked or unprovoked and other factors. Documented protein S deficiency may strengthen the case for indefinite anticoagulation, particularly if there is a strong family history of VTE. (See 'Patients with VTE' above and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

VTE prevention – We generally avoid oral contraceptives in women with inherited protein S deficiency, with rare exceptions. Individuals with protein S deficiency may also benefit from the judicious use of prophylactic anticoagulation in certain settings such as pregnancy or hospitalization, especially if they have a strong family history of thrombophilia or other VTE risk factors (algorithm 1). (See 'Asymptomatic individuals (obstetrical/surgical prophylaxis)' above and "Contraception: Counseling for women with inherited thrombophilias" and "Inherited thrombophilias in pregnancy" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

General thrombophilia approach – Our approach to screening for inherited thrombophilia is discussed separately. (See "Screening for inherited thrombophilia in asymptomatic adults" and "Thrombophilia testing in children and adolescents" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 1357 Version 36.0

References