Protein S Deficiency

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Background

Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Washington in 1979 and arbitrarily named after the city of its discover. 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 deficiencies are associated with thrombosis.

Protein S deficiency may be hereditary or acquired; the latter is usually due to hepatic diseases or a vitamin K deficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE). The association of protein S deficiency with arterial thrombosis appears coincidental or weak at best. Arterial thrombosis is not evident with other hereditary anticoagulant abnormalities (eg, protein C or antithrombin III deficiency, factor V Leiden gene mutation).

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

For patient education information, see Deep Vein Thrombosis.

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.[1] 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.[2, 3, 4]

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.


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A simplified outline of 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 to directly inhibit the factor X clotting factor–activating complex and the prothrombin-activating complex.

Furthermore, protein S interacts with the complement system and may play a role in phagocytosis of apoptotic cells. It has been recently observed that protein S binds to phosphatidyl serine on apoptotic cells and stimulates macrophage phagocytosis of early apoptotic cells. The physiological impact of protein S deficiencies on these nonanticoagulant roles of protein S is not yet known.

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. The role of protein S in complement regulation by C4BP is not completely understood.

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.

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.

A recent study by Heeb et al reported protein S has APC-independent anticoagulant activity, termed PS-direct, that directly inhibits thrombin generated by the factor Xa/factor Va prothrombinase complex,[5] 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.[5]

Heeb et al 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.[5]

Researchers have identified 2 genes for human protein S and both are linked closely on chromosome 3p11.1-3q11.2. One gene is the active gene, PROS -b (ie, PROS1), and the other, PROS- a, is an evolutionarily duplicated nonfunctional gene, which is classified as a pseudogene because it contains multiple coding errors (eg, frameshifts, stop codons). 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 -a gene.

Molecular studies into the genetic causes of protein S deficiency are complicated by the presence of the pseudogene, PROS- b, and phenotypic variation. Deletions of large portions of the PROS- a gene are associated with protein S deficiency and thrombophilia.[6] Researchers located the first such deletion in the central portion of the PROS- a gene. The second deletion described (5.3 kb) was a deletion of coding exon XIII, which resulted in a truncated protein product.

Family members with either deletion exhibit protein S deficiency and thrombophilia; however, subsequent studies indicate that the most common genetic defects in the protein S gene are point mutations rather than gene deletions. Phenotypic variation has been observed in protein S deficiency. The coexistence of type I deficiency and type III deficiency in families with the same protein S mutation has been shown at least in one family to be due to an age-related increase in total protein S level. In this family, the apparent type III variant with only low free S blood levels, was explained by the age increase in total protein S. Younger persons in the family when tested for blood levels still had low total and free protein S.

Epidemiology

Frequency

United States

Congenital protein S deficiency is an autosomal dominant disease, and the heterozygous state occurs in approximately 2% of unselected patients with venous thromboembolism (VTE).

Protein S deficiency is rare in the healthy population without abnormalities. Frequency is approximately one out of 700 based on extrapolations from a study of over 9000 blood donors who were tested for protein C deficiency. When looking at a selected group of patients with recurrent thrombosis or family history of thrombosis, the frequency of protein S deficiency increases to 3-6%.[7]

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.[8]

International

Data for European studies indicated the same frequencies for protein S deficiency as in the United States. Recent studies have indicated that the prevalence of protein S deficiency is particularly high in the Japanese population. In several reported series of patients with VTE in the United States, protein S deficiency was seen in 1-7% of patients. The deficiency is rare in population surveys of Caucasians, at approximately 0.03%. However, Japanese patients with VTE have reported a frequency of approximately 12.7% protein S deficiency and similarly elevated population frequencies of approximately 0.63%.

Mortality/Morbidity

Race

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

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 rare and almost never found in Japanese or Asian populations. In general, black Africans and African Americans with VTE have a lower detection of any of the currently recognized thrombophilic disorders, especially factor V Leiden.

Sex

No difference exists in the male-to-female rate of occurrence.

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.

History

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,[9] cerebral sinuses) are rare (< 5%) but, when observed, characteristically suggest one of the inherited thrombophilias (eg, protein S deficiency)

Deep vein thrombosis

Pulmonary embolism

Causes

Hereditary causes of protein S deficiency are described in detail in the Pathophysiology section.

Rarely, an acquired disorder causes protein S deficiency. Acquired deficiencies of protein S occur with liver disease, vitamin K deficiency, or as a result of antagonism with oral warfarin anticoagulants.

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.

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. Type I deficiency is a reduction in both total and free protein S. Type III deficiency is isolated reduction in free protein S. 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.

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[4] :

Several clinical conditions affect the blood levels of protein S—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 the section on genetics of protein S, 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:

Although reports document a few type II deficiencies, they are rare. The most common types are I and III. The distinction between type I and type III has no clinical implications. In both type I and type III deficiencies, free protein S levels are reduced.

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.

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, administer heparin therapy and then transition to warfarin oral anticoagulation.

Heparin

Warfarin

Warfarin administration can start on day 1 or 2 of heparin therapy. After two consecutive therapeutic International Normalized Ratio (INR) clotting tests 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.

The question of whether to continue lifelong warfarin in patients with identified 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 did not meet the criteria of life threatening or multiple or unusual sites, some experts argue that these patients may have a lower risk of recurrence and deserve a trial without warfarin after 9 months.

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 or orthopedic injury occurs, prophylaxis with heparin is mandatory.

In pregnancy, experts recommend prophylaxis with heparin; however, the timing is controversial. Most experts would treat from the second trimester through 4-6 weeks postpartum.

Patient 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. Avoid foods that are rich in vitamin K.

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 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 based on the aPTT test result (eg, subtherapeutic, therapeutic, supratherapeutic).

A commonly used weight-adjusted unfractionated heparin regimen is termed 80/18: 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.

Heparin

Clinical Context:  Usually administered as CIV infusion for the treatment of acute thrombosis. For prevention of thrombosis, unfractionated heparin is administered SC.

Enoxaparin (Lovenox)

Clinical Context:  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)

Clinical Context:  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.

Fondaparinux sodium (Arixtra)

Clinical Context:  Only synthetic compound in this class of LMW heparins. 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.

Tinzaparin (Innohep)

Clinical Context:  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)

Clinical Context:  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.

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.

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.

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 SC 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 in controlled trials are available to answer this difficult question.

Author

John E Godwin, MD, MS, Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

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A simplified outline of the protein C system.

A simplified outline of the protein C system.