Protein S Deficiency 

Updated: Jan 03, 2021
Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD 

Overview

Practice Essentials

Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Washington in 1979 and arbitrarily named after that city. The major function of protein S is as a cofactor to facilitate the action of activated protein C (APC) on its substrates, activated factor V (FVa) and activated factor VIII (FVIIIa). 

Protein S deficiency usually manifests clinically as venous thromboembolism (VTE).[1]  Any association of protein S deficiency with arterial thrombosis appears coincidental or weak at best. Evidence for arterial thrombosis in other hereditary thrombophilias (eg, protein C deficiency, antithrombin III deficiency, or factor V Leiden gene mutation) also appears to be minimal.[2]

Protein S deficiency may be hereditary or acquired; the latter is usually due to hepatic disease, nephrotic sydrome, or vitamin K deficiency. Protein S and C levels are lower in sickle cell anemia and they decrease further significantly during crisis.[3]

Hereditary protein S deficiency is an autosomal dominant trait. Thrombosis is observed in both heterozygous and homozygous genetic deficiencies of protein S.

Protein S deficiency is primarily diagnosed using  laboratory tests that detect free protein S antigen, and less commonly by measuring functional protein S activity (based on clotting assays); see Workup. Management is required in the event of acute VTE and includes administration of a low molecular weight heparin (LMWH), a vitamin K antagonist, or a direct oral anticoagulant (DOAC). Prophylaxis may be used in selected patients who are asymptomatic carriers without a thrombotic event. (See Treatment and Medication.)

For patient education information, see the Deep Vein Thrombosis Health Center and What Is Thrombophilia?.

Pathophysiology

To understand how thrombosis occurs in protein S deficiency, its physiological function should be briefly reviewed. Protein S is part of a system of anticoagulant proteins that regulate normal coagulation mechanisms in the body.[4] Under most normal circumstances, the anticoagulant proteins prevail and blood remains in a liquid nonthrombotic state. Whenever procoagulant forces are locally activated to form a physiologic or pathologic clot, protein S participates as part of one mechanism of controlling clot formation.[5]

Protein S functions predominantly as a nonenzymatic cofactor for the action of another anticoagulant protein, activated protein C (APC). This activity occurs via a coordinated system of proteins, termed the protein C system. The image below shows a simplified outline of the function of protein S in the protein C system.

A simplified outline of the function of protein S A simplified outline of the function of protein S in the protein C system.

During the process of clotting, multimolecular complexes are formed on membrane surfaces. These membranes are usually negatively charged phospholipids and/or activated platelets. These multimolecular complexes are referred to as the tenase and prothrombinase complexes for their key activities of activation of factor X and prothrombin, respectively. Anchoring these two complexes are the activated form of factor VIII (FVIIa) used for the tenase complex and the activated form of factor V (FVa) for the prothrombinase complex. These two large proteins are homologous in structure and are cofactors, not enzymes, in the clotting process.

In one of many examples of nature's efficiency, the same enzyme that clots blood, thrombin, is converted from clotting to an anticoagulant mechanism on the surface of the endothelium and it then activates protein C to its active enzymatic form, APC. APC requires protein S as a cofactor in its enzymatic action on its 2 substrates, FVa and FVIIIa. Thus, this process is designed to dampen and shut off clotting by switching off the key cofactor proteins FVa and FVIIIa. Protein S and APC are sufficient to inactivate FVa. However, for the inactivation of FVIIIa, APC and protein S require the help of the nonactivated clotting protein, factor V. This is another example of dual use of a protein in this same process.

Factor Va as noted above is cleaved by APC to an inactive form. However, in assisting protein S to inactivate FVIIIa, it is the inactive FV that is cleaved by APC. An important consequence of this dual procoagulant and anticoagulant property of factor V, is that the mutant factor V Leiden, which resists APC cleavage, cannot be switched off but also cannot function here at this step as an anticoagulant protein (see factor V Leiden gene mutation in Race). In addition to its cofactor role in the protein C system, protein S functions independently of protein C by acting as a cofactor to Tissue Factor Pathway Inhibitor (TFPI). TFPI inhibits the Tissue Factor/FVIIa complex thus inhibiting activation of factor X as well as Prothrombin further downstream. Similarly, Protein S has also been shown to directly inhibit factor Xa.[6, 7]

Heeb et al reported that protein S has APC-independent anticoagulant activity, termed PS-direct, that directly inhibits factor Xa/factor Va prothrombinase complex, a process made possible by the presence of zinc (Zn2+) content in protein S. The investigators found Zn2+ content positively correlated with PS-direct in prothrombinase and clotting assays, but the APC-cofactor activity of protein S was independent of Zn2+ content. In addition, protein S that contained Zn2+ bound factor Xa more efficiently than protein S without Zn2+, and, independent of Zn2+ content, protein S also efficiently bound tissue factor pathway inhibitor.[8]  The study also suggested that conformation differences at or near the interface of 2 laminin G-like domains near the protein S C terminus may indicate that Zn2+ is necessary for PS-direct and efficient factor Xa binding and could have a role in stabilizing protein S conformation.[8]

Protein S is a single-chain glycoprotein, and it is dependent on vitamin K action for posttranslational modification of the protein to a normal functional state. Vitamin K–dependent proteins are synthesized with a unique recognition propeptide piece. The propeptide sequence serves as a recognition site for the vitamin K–dependent gamma-carboxylase enzyme that modifies the nearby glutamic acid residues to gamma-carboxyglutamic acid (Gla) residues. Gla residues are responsible for calcium-dependent binding to membrane surfaces. Structural studies indicate that protein S contains 10-12 Gla residues, a loop region sensitive to thrombin (ie, thrombin-sensitive region [TSR]), 4 epidermal growth factor (EGF)–like modules, and a carboxy-terminal portion that is homologous to a sex hormone-binding globulin (SHBG)–like region.

In blood plasma, protein S exists in both a bound and a free state. A portion of protein S is noncovalently bound with high affinity to the complement regulatory protein C4b-binding protein (C4BP). The C4BP molecule consists of 7 alpha chains that bind to the complement protein, C4b, and one beta chain. The beta chain of the C4bBP molecules contains the binding sites for protein S. There is emerging evidence in the role of Protein S in the complement pathway. It is now found to interact with the complement system and may play a role in phagocytosis of apoptotic cells. Protein S interacts with tyrosine kinase receptors of the TAM family, along with phosphatidyl serine on cell surface apoptotic cells which stimulates macrophage phagocytosis of these cells.[9, 10]  The physiological impact of protein S deficiencies on these nonanticoagulant roles of protein S is not yet known.

APC and protein S require negatively charged phospholipids (PL) and Ca2+ for normal anticoagulant activity. Studies of the structure and function relationships of protein S demonstrate that the APC interaction sites are located in the Gla, TSR, and first EGF-like modules of protein S. The binding site for C4BP is located in the SHBG-like region, which is also important for full anticoagulant activity.

In healthy individuals, approximately 30-40% of total protein S is in the free state. Only free protein S is capable of acting as a cofactor in the protein C system. This distinction between free and total protein S levels is important and gives rise to the current terminology regarding the deficiency states. Type I protein S deficiency is a reduction in the level of free and total protein S. Type III deficiency is a reduction in the level of free protein S only. Type II deficiency is a reduction in the cofactor activity of protein S, with normal antigenic levels.

Age affects total protein S but not free protein S levels. Generally, the total protein S level increases in persons older than 50 years. This rise is in association with total increases in the complement binding protein, C4BP. Free protein S levels do not increase with age. These factors may explain the observation that families with the same recognized genetic defect in protein S can have both type I and type III deficiencies. When families with the same genetic type I defect are surveyed, older individuals even with deficiency in protein S have an increase in total protein S and now appear to have type III deficiency.

Epidemiology

Frequency

United States

Protein S deficiency is rare in the healthy population without VTE. In a study of 3788 healthy blood donors, the prevalence of famililial protein S deficiency was 0.03 to 0.13%.[11]  When a selected group of patients with recurrent thrombosis or family history of thrombosis is analyzed, the frequency of protein S deficiency increases to 3-5%.[12, 13]

Studies evaluating the clinical significance of free protein S levels associated with risk of VTE suggest using a lower cutoff of protein S levels for the diagnosis, which would in turn affect the prevalance of the disease.[14]  The Multi Environmental and Genetic Assessment Study (MEGA) case control study used protein S levels of less than 2.5th percentile of controls to identify protein S deficiency; however, risk of unprovoked VTE was limited to patients with free protein S levels of less than 0.10th percentile (< 33 U/dL). The prevalence of patients in this subgroup was 0.4%.[15]

International

Data for European studies indicate the same frequencies for protein S deficiency as in the United States. In contrast, the prevalence of protein S deficiency is particularly high in the Japanese population, with a frequency of approximately 12.7% in patients with VTE and approximately 0.48%-0.63% in the general population.[16] In a Japanese study that evaluated patients with VTE for congenital thrombophilia, Ikejiri et al diagnosed congenital protein S deficiency in eight of 130 patients (6.2%).[17]

Mortality/Morbidity

Congenital protein S deficiency is an autosomal dominant disease, with variable penetrance and heterogeneous genetic basis. VTE develops in almost 50% of patients who are heterozygous for protein S deficiency. The remaining patients are asymptomatic and some heterozygous individuals never develop VTE. Annual incidence of venous thrombosis was found to be 1.90%, with median age of presentation being 29 yrs in a retrospective cohort study of 2479 relatives.[13]

Very rarely, protein S deficiency occurs as a homozygous state, and these individuals have a characteristic thrombotic disorder, purpura fulminans. Purpura fulminans is characterized by small-vessel thrombosis with cutaneous and subcutaneous necrosis, and it appears early in life, usually during the neonatal period or within the first year of life.[18]

Though it is controversial, no clear association exists between protein S deficiency and arterial thrombosis. Many case reports and small case series describe protein S deficiency as one factor in patients with arterial thrombosis, most commonly stroke. However, prospective and cohort studies have not shown convincing increased risk for arterial thrombosis.

Protein S deficiency is also associated with fetal loss in women, in the absence of VTE. Some authors suggest that as many as 40% of women with obstetric complications other than VTE may carry some form of thrombophilia. Protein S deficiency is one of these factors along with several other more common genetic thrombophilic states.

Cases of warfarin-induced skin necrosis have been reported in patients with protein S deficiency.[19]

Mortality is from pulmonary embolism. In several studies, the 3-month mortality rate of pulmonary embolism ranged from 10.0-17.5%. In a study of Medicare recipients with pulmonary embolism, men had a 13.7% mortality rate compared to 12.8% in women; the mortality rate was 16.1% in blacks, compared to 12.9% in whites.[20]

Race

Race-related variations exist in thrombophilic disorders, as one would expect with genetically based traits. In general, a significant difference exists in the frequency of thrombophilic disorders in whites compared with Japanese (Asian) persons and African Americans. Current research indicates that protein S deficiency is 5-10 times more common in Japanese populations than in whites. Protein C deficiency is estimated to be 3 times higher in Japanese populations as well. 

The factor V Leiden mutation is common in white populations and is now known to be the result of a founder effect estimated to be 30,000 years old. This mutation is almost never found in Japanese or Asian populations. In general, black Africans and African Americans with VTE have a lower detection rate of any of the currently recognized thrombophilic disorders, especially factor V Leiden.

Sex

Men have a higher level of both free and total protein S antigen, the clinic relevance of which is not clearly documented.[11]

Age

Protein S deficiency is a hereditary disorder, but the age of onset of thrombosis varies by heterozygous versus homozygous state. Most VTE events in heterozygous protein S deficiency occur in persons younger than 40-45 years. The rare homozygous patients have neonatal purpura fulminans, as described above; onset occurs in early infancy. As noted above in the discussion on genetics, age does affect total protein S antigen levels, but not free protein S levels. Older patients deficient in protein S have low free S levels, even if their total protein S level rises into the normal range.

 

Presentation

History

Signs and symptoms of protein S deficiency are those associated with deep venous thrombosis (DVT), thrombophlebitis, or pulmonary embolus. Some women may have fetal loss as their only manifestation of a thrombophilic disorder (eg, protein S deficiency).

With venous thrombosis of the lower limbs, lower limb swelling and discomfort are the usual symptoms. Occasionally, redness or discoloration also is present, with or without associated cellulitis.

A family history of thrombosis is an important finding, which suggests inherited thrombophilia. Thrombosis at an early age (eg, usually < 55 y) or recurrent thrombosis is also frequently indicative of an inherited thrombophilic state (eg, protein S deficiency).

Physical

Direct the examination to identify signs of venous thrombosis or pulmonary embolism. The results of the physical examination are nonspecific and often misleadingly indicate the diagnosis of DVT. Unusual sites of thrombosis (eg, mesenteric vein,[21] cerebral sinuses) are rare (< 5%) but, when observed, characteristically suggest one of the inherited thrombophilias (eg, protein S deficiency)

Deep vein thrombosis

See the list below:

  • The most common manifestation is venous thrombosis of the lower extremities, whichaccounts for approximately 90% of all events

  • Superficial veins that are obviously thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain

  • Superficial thrombophlebitis can be observed in some cases, with or without DVT

  • Suspect DVT if identifying signs of venous obstruction and local inflammation are present on examination

  • The classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (ie, Homan sign). However, less than a third of DVT cases exhibit these three findings; physicians observe unilateral leg or calf swelling with mild or moderate pain more often, which suggests DVT; rarely, calf discomfort without swelling is the only sign of DVT

  • Differential diagnoses for DVT include muscle strains and tears, passive swelling of a paralyzed or immobilized limb, Baker cyst, cellulitis, knee trauma or derangement, lymphatic obstruction, and postphlebitic syndrome

  • In postphlebitic syndrome, chronic swelling and pain are present in the limb, and the occurrence of a new venous thrombosis is often impossible to assess without Doppler or venography.

Pulmonary embolism

See the list below:

  • Some patients may have associated or isolated pulmonary embolism and may experience dyspnea, chest pain, syncope, or cardiac palpitations; dyspnea is the most frequent symptom of pulmonary embolism, and tachypnea is the most frequent sign

  • Some patients with massive pulmonary embolism can present with syncope or cyanosis

  • Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement

  • Acute right-sided heart failure occurs rarely and is associated with massive embolus

  • Findings of right ventricular dysfunction include bulging neck veins, a left parasternal lift, and an accentuated pulmonic component of the second heart sound; these findings are not specific for pulmonary embolism

Causes

Protein S deficiency may be hereditary or acquired.

Hereditary protein S deficiency

Researchers have identified 2 genes for human protein S; both are linked closely on chromosome 3p11.1-3q11.2.[22]  One gene is the active gene, PROS-α (ie, PROS1), and the other, PROS-β, is an evolutionarily duplicated nonfunctional gene, which is classified as a pseudogene because it contains multiple coding errors (eg, frameshifts, stop codons).[23]  The expressed (alpha) PROS1 gene is more than 80 kb long and contains 15 exons and 14 introns. The protein S pseudogene (beta) has 97% homology to the PROS-α gene.[24]  Molecular studies into the genetic causes of protein S deficiency are complicated by the presence of the pseudogene, PROS-β, and phenotypic variation.

Over 200 mutations in PROS1 have been identified as causes of protein S deficiency and thrombophilia. Most are point mutations, such as transversion mutations that generate a premature stop codon and thus result in a truncated protein S molecule.[25, 26, 27] A missense mutation in exon 7 of PROS1 in which glycine is replaced with arginine has been reported in a Chinese family. In addition, deletions of large portions of the PROS1 gene have been reported. Researchers located the first such deletion in the central portion of the gene.[28]  The second deletion described (5.3 kb) was a deletion of coding exon 13, which resulted in a truncated protein product.[29]

Acquired protein S deficiency

Acquired conditions associated with decreased protein S levels include the following:

  • Oral contraceptive use
  • Warfarin anticoagulant use
  • Nephrotic syndrome
  • Vitamin K deficiency
  • Chronic liver disease
  • Certain viral infections (eg, HIV, varicella)
  • Systemic lupus erythematosus
  • Myeloproliferative disorders

In addition, protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range. These low levels of protein S in pregnancy do not cause thrombosis by themselves.

Another seldom recognized cause for acquired protein S deficiency is sickle cell anemia. However, this condition alone does not produce a thrombophilic state.

 

DDx

Diagnostic Considerations

Given the rarity of inherited protein S deficiency, testing for this disorder should not be considered in unselected patients with venous thromboembolism (VTE). However, screening for inherited thrombophilia is appropriate in cases of the following[27, 13, 15] :

  • VTE without obvious cause in patients younger than 45 to 50 years
  • VTE in patients with a family history of thrombosis
  • Recurrent VTE
  • Thrombosis at an unusual location
  • VTE during pregnancy, use of oral contraceptives, or hormone replacement therapy

Patients who develop VTE in the absence of acquired risk factors may have protein S deficiency or some other congenital thrombophilia, or may have more than one congenital risk factor for VTE. In a retrospective analysis of prospectively gathered data on 58 outpatients with VTE (approximate mean age 39 years) without major acquired risk factors, 45 had at least one hereditary risk factor for VTE. Diagnoses in these patients were as follows[30] :

  • Protein S deficiency - 17 patients
  • Protein C deficiency - 18 patients
  • Factor V Leiden mutation - 30 patients (25 heterozygous and five 5 homozygous)
  • Prothrombin gene mutation - 16 patients
  • Methylenetetrahydrofolate reductase C677T mutation - 24 patients (19 heterozygous, 5 homozygous)
  • Antithrombin III deficiency - 14 patients
  • Hyperhomocysteinemia - 13 patients

Of the 17 patients with protein S deficiency, 13 also had protein C deficiency, hyperhomocystinemia, antithrombin III deficiency, or some combination of those conditions.

These authors concluded that thrombophilia testing should be performed in younger VTE patients without known acquired risk factors. Testing for protein C, protein S, and prothrombin gene mutations should be followed by additional molecular assessment in patients with suspicious findings.[30]

Similarly, in a cohort of 367 unselected pediatric patients with VTE, Klostermeier et al found that 30 children (8.2%) from 27 families had protein S deficiency. After adjustment for family status, the prevalence of protein S deficiency was 7.4 %. Mean age at first onset of VTE was 14.5 years. Of the 30 children with protein S deficiency, 18 (60%) had a concomitant risk factor for VTE. The factor V mutation at rs6025 and the homozygous factor II susceptibility variant at rs1799963 were observed along with protein S deficiency in one patient each, and the Heerlen polymorphism was found in five children with milder protein S deficiency. These researchers concluded that thrombophilia testing and consideration of appropriate interventions are warranted in this high-risk group of patients.[31]

Differential Diagnoses

 

Workup

Laboratory Studies

Protein S deficiency is diagnosed using laboratory tests for the protein S antigen and by using other tests for functional protein S activity (based on clotting assays), as follows[32] :

  • Protein S antigen: Laboratories can test protein S antigen as total antigen (ie, protein S bound to C4BP plus free protein) or free protein S antigen. The free form of protein S has functional activity, and researchers have developed assays specifically for the free protein S antigen. Both free and total protein S are measured by enzyme-linked immunosorbent assay (ELISA) methods in the laboratory.

  • Functional protein S: Assays for functional protein S are indirect and are based on prolongation of blood clotting by the generation of activated protein C (APC) and its function in the assay. These functional tests are difficult to perform. In addition, the tests introduce several other factors that can alter the interpretation of test results. Most importantly, a falsely low protein S functional assay value can be observed in patients with factor V Leiden, which is another common cause of hereditary thrombophilia that interferes with protein C function. Some new commercial methods for determining protein S deficiency can measure activity in factor V Leiden patients accurately after dilution of test plasma.[33, 34]

Several clinical conditions affect the blood levels of protein S on both antigenic and functional assays. As one would expect, vitamin K deficiency, liver disease, or antagonism with warfarin reduces protein S levels. In the setting of acute thrombosis, protein S levels fall, sometimes into the deficient range. Pregnancy also results in lower blood levels of protein S, especially as measured by functional assays. As noted previously, in Overview/Pathophysiology, total protein S levels actually rise with age. Free protein S levels are not affected by age.

Based on the measurement of free and total protein S antigen and functional protein S activity, scientists classify protein S deficiency into the following three phenotypes, using the classification proposed at the 1991 meeting of the Scientific Subcommittee of the International Society on Thrombosis and Haemostasis in Munich, Germany:

  • Type I deficiency is characterized by a decrease in the total protein S antigen and free protein S antigen together (quantitative deficiency)

  • Type II deficiency is characterized by normal total and free antigen levels but reduced protein S activity (functional deficiency, qualitative defect)

  • Type III deficiency is characterized by low free protein S levels, whereas the total plasma concentration of protein S is normal

Type II deficiencies are rare. The most common types are I and III. The distinction between type I and type III has no clinical implications, as free protein S levels are reduced in both.

Physicians should request free protein S antigen testing for any patient suspected of having deficiencies of protein S because this test detects most cases (ie, type I or III), and the use of a total protein S assay is not routinely needed. Consider use of the functional assay for protein S deficiency if the other test results are normal and a reliable assay can be performed after excluding other interfering defects.

 

Treatment

Medical Care

Management of protein S deficiency takes place in the event of acute venous thromboembolism (VTE). Prophylaxis may be used in selected patients with asymptomatic carrier states without a thrombotic event.

Following an acute thrombosis, inital management is the same as for all acute VTE episodes, based on the severity of disease, co-morbidities, and hemodynamic stability. Main agents in the acute period include intravenous unfractionated heparin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (DOAC).

The choice between a DOAC and a vitamin K antagonist (VKA) depends on factors such as patient preference, cost, and convenience. Historically, VKAs were the mainstay of treatment for VTE, including those caused by inherited thrombophilias. With the advent of DOACs, with their comparable efficacy as well as their safety profile, they are now increasingly used for VTE, including in patients with hereditary thrombophilias. 

In a prospective cohort study of patients with acute VTE diagnosed with inherited thrombophilias, DOACs had the same efficacy as heparin/VKAs and were shown to significantly reduce the 2-year VTE recurrence after anticoagulant discontinuation. DOACs did show an increased risk of clinically relevant non-major bleeding, while VKAs showed a slight increase in major bleeding.[35] A systematic review and meta-analysis conducted by Elsebaie et al also reported a low VTE recurrence and comparable rates of bleeding events between DOAC and VKA.[36]  These studies support the use of DOACs for acute VTE in the setting of inherited thrombophilias, including protein S deficiency.  

The question of whether to continue lifelong anticoagulation in patients with diagnosed protein S deficiency after their first thrombotic event is controversial. If the first thrombotic event was life threatening or occurred in multiple or unusual sites (eg, cerebral veins, mesenteric veins), most experts recommend lifelong therapy initially. If precipitated by a strong event (eg, trauma, surgery) and the thrombosis was not life threatening or involved multiple or unusual sites, some experts argue that these patients may have a lower risk of recurrence and deserve a trial without anticoagulation after 9 months.

Heparin

Heparin is administered as follows:

  • Initial heparin treatment may be with intravenous unfractionated heparin or subcutaneous low molecular weight heparin (LMWH)
  • Heparin should be given for a minimum of 5 days
  • Manage heparin with standard protocols; see Deep Venous Thrombosis or Pulmonary Embolism for additional details

Warfarin

Warfarin administration can start on day 1 or 2 of heparin therapy. After two consecutive clotting tests showing a therapeutic International Normalized Ratio (INR) and a minimum of 5 days of heparin therapy, the patient can continue on warfarin alone. In most patients, specialists recommend 6-9 months of initial treatment with warfarin.

Direct Factor Xa Inhibitors

These agents bind to factor Xa and prevent it from cleaving prothrombin to thrombin. These drugs are widely used in multiple hypercoagulable states, including protein S deficiency, with evidence of comparable efficacy versus VKAs. Currently the oral agents that are available are rivaroxaban, apixaban, and edoxaban.[37, 38, 39]

Direct Thrombin Inhibitors

Dabigatran is another option for treatment of hypercoagulable states. In a post hoc analysis of data from the RECOVER, RE-COVER II, and RE-MEDY trials, Goldhaber et al reported no significant differences in rates of symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia.[40]

Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lacking, but idarucizumab, an antibody fragment, is available for reversing the anticoagulant effects of dabigatran.

Prophylaxis

In patients who are asymptomatic carriers of protein S deficiency, the goal of therapy is prevention of the first thrombosis. In such patients, avoid drugs that predispose to thrombosis, including oral contraceptives. In these patients, if surgery is performed or orthopedic injury occurs, prophylaxis with heparin is mandatory.

Protein S deficiency is considered a high-risk thrombophilia during pregnancy, with absolute risks of pregnancy-associated VTE being 0.9% antepartum and 4.2% postpartum.[41] Experts recommend prophylaxis with LMWH. The timing is controversial, but most experts would treat from the second trimester through 4-6 weeks postpartum.

The patient's bleeding risks must be assessed on an individual basis for any of these prophylactic recommendations. No single prescription fits all cases.

Diet and Activity

Dietary issues relate to patients with protein S deficiency who are on oral anticoagulation with warfarin. Maintain the same amount of vitamin K in the diet.

Restrictions apply to activity shortly after acute venous thrombosis (ie, DVT, pulmonary embolism). See Deep Venous Thrombosis or Pulmonary Embolism for additional details concerning such restrictions. While on anticoagulation therapy, patients should avoid vigorous contact activities.

 

Medication

Medication Summary

Heparin is used for patients with acute thrombotic events or for the prevention of thrombosis. Heparin treatment currently is available in two forms: unfractionated (standard) heparin or low molecular weight heparin (LMWH).

Unfractionated heparin for treatment of thrombosis is administered properly by a weight-based dosing protocol, with a target heparin therapeutic range as monitored by the activated partial thromboplastin time (aPTT) test and for a minimum of 5 days. A heparin dosing protocol includes the specified weight-dosing regimen, the target therapeutic aPTT range, the time for measuring aPTT tests after bolus or adjustment in dose (4-6 h), and a standard means of adjusting the unfractionated heparin infusion on the basis of the aPTT (eg, subtherapeutic, therapeutic, supratherapeutic).

A commonly used weight-adjusted unfractionated heparin regimen is termed 80/18, and consists of an 80 U/kg IV bolus followed by 18 U/kg continuous IV infusion. The target therapeutic heparin range is ideally individualized to the institution's laboratory aPTT test instrument and reagent.

To obtain an institutional heparin therapeutic range, employ a method such as that described by Brill-Edwards or any other similar comparison of in vitro and ex vivo heparin levels with aPTT test results in multiple individuals. In the absence of an established institutional therapeutic range, an aPTT ratio of 1.5-2.0 is commonly used; however, aPTT reagents and patient responses to unfractionated heparin vary, and the ratio can be 1.8-3.0 for some reagents.

The pharmacodynamics of LMWHs are different from the parent unfractionated heparin. LMWHs are administered subcutaneously. The aPTT test is not affected significantly by LMWH and is not used to monitor LMWH therapy. Several different LMWHs are available in the United States, but they have different pharmacodynamic properties and are not considered interchangeable. Weight-based dosing regimens for each LMWH and for treatment or prophylaxis indications are available from each manufacturer.

LMWHs are approved for treatment of deep venous thrombosis (DVT) with or without pulmonary embolism in the inpatient hospital setting. LMWHs are approved for treatment of DVT without pulmonary embolism in the outpatient setting.

Warfarin is used for long-term oral anticoagulant management of patients with protein S deficiency after first or subsequent thrombosis.

Investigational Anticoagulants

Agents in the following classes are under development:

  • Tissue factor pathway inhibitor (TFPI)  –  TFPIs act in two ways: by directly inhibiting factor Xa and by forming a complex together with factor Xa that inhibits tissue factorTF/factor VIIa. Currently the recombinant form is being tested.
  • Factor VIII inhibitor – With an approximate 3-week half-life, TB-402 is a human IgG4 monoclonal antibody with a partial inhibitor activity. TB-402 has been found to be effective for a 10 days equivalent of LMWH in a randomized phase II trial in patients who have undergone total knee replacement.
  • Factor IXa inhibitor  – REG1 has two components: RB006, which binds and inhibits factor IXa; and RB007, which neutralizes its anti-IXa activity. Trials are still underway to determine its effect when combined with anit-platelet therapy in patients with coronary artery disease.
  • Factor XI inhibitor  – FXI-ASO is a factor XI antisense oligonucleotide that potentially reduces factor XI.
  • Factor XIIa inhibitor  – rHA-Infestin-4 is a factor XIIa inhibitor that is being investigated in the management of acute ischemic cardiovascular and cerebrovascular events.
  • Polyphosphate inhibitors Platelets, when activated, release polyphosphate, which impacts coagulation via the intrinsic pathway. Compounds that inhibit polyphosphate are being investigated.
  • Thrombomodulin  ART-123 is the recombinant part of the extracellular domain of thrombomodulin. It has been approved in Japan for the treatment of disseminated intravascular coagulation. It has a plasma half-life of 2-3 days and can be administered subcutaneously every five to six days.

 

Anticoagulants

Class Summary

Unfractionated IV heparin and fractionated low molecular weight SC heparins are the 2 choices for initial anticoagulation therapy. Warfarin therapy may be initiated after 1-3 days of effective heparinization.

Heparin

Usually administered as a continuous IV infusion for the treatment of acute thrombosis. For prevention of thrombosis, unfractionated heparin is administered subcutaneously.

Enoxaparin (Lovenox)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Dalteparin (Fragmin)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Tinzaparin (Innohep)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Warfarin (Coumadin)

Oral anticoagulant that antagonizes action of vitamin K in normal synthesis of clotting factors II, VII, IX, and X. Safe and effective for long-term oral management of thrombotic disorders. See articles on Deep Venous Thrombosis or Pulmonary Embolism (discussed in Treatment section) for additional details on dosing and monitoring of warfarin. Therapy is initiated without a loading dose at a dose range of 5-10 mg qd for 70-kg adult. Monitor PT/INR daily during initiation of therapy to measure anticoagulation effect. After initial 5-10 d and stabilization of warfarin dose, measure PT/INR 2-3 times qwk for 2-4 wk, then monthly thereafter.

Factor Xa Inhibitors

Class Summary

These agents bind to factor Xa and prevent it from cleaving prothrombin to thrombin.

Rivaroxaban (Xarelto)

Orally administered factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. 

Its anticoagulant action develops within 2-4 hours of ingestion and lasts for approximately 24 hours. It should be used if the creatinine clearance is < 15mL/min. 

Rivaroxaban does not require monitoring of PT and aPTT. However, its presence can be tested by the prothrombin time (PT) or anti–factor Xa activity.

Apixaban (Eliquis)

Factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It is metabolized in the liver via CYP3A4/5.

Used in patients with atrial fibrillation to prevent venous thromboembolism and stroke.

PT, aPTT and INR are prolonged but, routinely no monitoring is required. Anti-Xa assay can be used to rely upon if testing is necessary.

Edoxaban (Savaysa)

Orally active, with a half life of 6-11 hours. Undergoes hydrolysis, conjugation and oxidation by CYP3A4. Inhibits free Xa, prothrombinase activity and thrombin-induced platelet aggregation without requiring routine monitoring. 

Fondaparinux (Arixtra)

This compound is a novel pentasaccharide capable of inhibiting factor Xa via the action of antithrombin (AT) but devoid of anti-factor IIa (thrombin) activity. Interestingly, this compound does not appear to cross-react with HIT antibodies.

Approved for use in hip fracture surgery, knee replacement surgery, and hip replacement surgery. Only FDA-approved anticoagulant drug for hip fracture surgery. Also used and approved for extended prophylactic dosing for 21 d following hip fracture surgery.

Thrombin Inhibitors

Class Summary

Prevent thrombus development through direct, competitive inhibition of thrombin.

Dabigatran (Pradaxa)

Prevents thrombus development through direct, competitive inhibition of thrombin Plasma half- life is 12-14 hours and duration of action is 24 hours.

Dabigatran etexilate is a prodrug that is rapidly hydrolyzed to dabigatran (active form) in the liver by plasma and hepatic esterases. It undergoes hepatic glucuronidation to active acylglucuronide isomers. Routine monitoring is not required; however, the measurement of activated partial thromboplastin time (aPTT), ecarin clotting test (ECT) if available, or thrombin time may be useful to determine presence of dabigatran and level of coagulopathy. Also, reversal agent has

 

Follow-up

Deterrence/Prevention

In patients with heterozygous protein S deficiency and no history of thrombosis, physicians may administer prophylactic heparin during situations that present high risk for thrombosis. Such situations include surgery, orthopedic trauma (especially with a cast), pregnancy, and prolonged bed rest. Heparin may be administered subcutaneously in standard protocols for venous thromboembolism (VTE) prevention.

The risk of VTE during pregnancy and for the first 6 weeks postpartum varies among the hereditary thrombophilic states. Protein S and protein C deficiencies significantly elevate the risks for thrombosis when compared with the modest increase in thrombosis seen with factor V Leiden mutation. Protein S deficiency was also associated with a seven-fold increase in fetal loss. Many experts recommend that women with protein S deficiency and a history of fetal loss, and severe or recurrent eclampsia, receive low-dose aspirin and prophylactic-dose low molecular weight heparin (LMWH) therapy during pregnancy, with the LMWH prophylaxis extending for 6 weeks postpartum.

For women with heterozygous protein S deficiency and no prior VTE or history of fetal loss, treatment choices vary. Some experts recommend VTE prophylaxis only during the 6 weeks postpartum (the highest risk period for VTE) unless the pregnancy is complicated. Others recommend prophylaxis for the entire pregnancy and 6 weeks postpartum. Recommendations for other scenarios include the following:

  • For women with no prior history of VTE and protein S deficiency plus any other thrombophilic defect, active prophylaxis with LMWH should be given during pregnancy and for 6 weeks postpartum.

  • For women with a prior VTE history and confirmed protein S deficiency, experts recommend prophylactic or intermediate dosing of LMWH during pregnancy and for 6 weeks postpartum.

  • For women with a prior history of VTE who are already receiving oral anticoagulants at the time of pregnancy, full anticoagulant dosing of LMWH is recommended with transition back to oral anticoagulant postpartum.

  • Patients with recurrent thrombosis should remain on lifelong warfarin.

Interruption of anticoagulation

In patients with a history of thrombosis who are taking warfarin, no standard exists for "bridging" (ie, on and off use of warfarin for surgery or other procedures that require cessation of warfarin). Some institutions cover with subcutaneous heparin while holding warfarin for 3-4 days. In other situations, this temporary interruption of warfarin is not covered by heparin. Each clinician should weigh the thrombosis risk with the bleeding risk in the individual patient because no data from controlled trials are available to answer this difficult question.

 

Questions & Answers

Overview

What is protein S deficiency?

What is the pathophysiology of protein S deficiency?

What is the role of APC in the pathophysiology of protein S deficiency?

What is the role of vitamin K in the pathophysiology of protein S deficiency?

What is the role of C4BP in the pathophysiology of protein S deficiency?

What are the types of protein S deficiency?

What is the role of age in the pathophysiology of protein S deficiency?

What is the prevalence of protein S deficiency in the US?

What is the global prevalence of protein S deficiency?

What is the morbidity associated with protein S deficiency?

What causes morbidity in patients with protein S deficiency?

What is the racial predilection of protein S deficiency?

What is the sexual predilection of protein S deficiency?

Which age groups have the highest prevalence of protein S deficiency?

Presentation

What are the signs and symptoms of protein S deficiency?

Which clinical history findings are characteristic of protein S deficiency?

Which physical findings are characteristic of protein S deficiency?

Which physical findings are characteristic of deep vein thrombosis in patients with protein S deficiency?

Which physical findings are characteristic of pulmonary embolism in patients with protein S deficiency?

What are causes of protein S deficiency?

What are causes of hereditary protein S deficiency?

What are causes of acquired protein S deficiency?

What is the role of sickle cell anemia in the etiology of protein S deficiency?

DDX

When is screening for protein S deficiency indicated?

Which congenital thrombophilias should be included in the differential diagnoses of protein S deficiency?

What are the differential diagnoses for Protein S Deficiency?

Workup

How is protein S deficiency diagnosed?

What are the phenotypes of protein S deficiency?

What is the role of free protein S antigen testing in the diagnosis of protein S deficiency?

Treatment

How is protein S deficiency treated?

How is heparin administered in the treatment of protein S deficiency?

How is warfarin administered in the treatment of protein S deficiency?

What is the role of direct factor Xa inhibitors in the treatment of protein S deficiency?

What is the role of direct thrombin inhibitors in the treatment of protein S deficiency?

How is thrombosis prevented in patients with protein S deficiency?

What are the dietary modifications used treatment of protein S deficiency?

What are the activity modifications used treatment of protein S deficiency?

Medications

What is the role of medications in the treatment of protein S deficiency?

Which anticoagulants are being investigated as possible treatments for protein S deficiency?

Which medications in the drug class Anticoagulants are used in the treatment of Protein S Deficiency?

Which medications in the drug class Thrombin Inhibitors are used in the treatment of Protein S Deficiency?

Which medications in the drug class Factor Xa Inhibitors are used in the treatment of Protein S Deficiency?

Follow-up

When is prophylaxis indicated for patients with protein S deficiency?

How is protein S deficiency treated during pregnancy?

What are the options for bridging anticoagulation in patients with protein S deficiency?