Sandbox:Roukoz

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

Overview

Protein S deficiency is an autosomal dominant thrombophilia, which leads to an increased risk of thromboembolic events. Protein S is a vitamin K-dependent glycoprotein and plays a role in anticoagulation. It is mainly a cofactor to the activated protein C (APC), which inactivates coagulation factors Va and VIIa and thereby controlling the coagulation cascade.

Historical Perspective

• Protein S was first discovered and purified in Seattle, Washington in 1979, and it was arbitrarily named protein S after the city it was discovered in.
• The function of this protein was still unknown; however, it was hypothesized that protein S plays a role in activating protein C.
• Protein S deficiency was first discovered in 1984 when two related individuals with recurrent thromboembolic events and normal coagulation tests were studied. At the time, protein C deficiency was usually associated with recurrent familial thrombosis. These individuals were found to have diminished anticoagulation activity with normal coagulation tests (including a normal protein C level), and when purified human protein S was added to their plasma, effective anticoagulation was restored.

Classification

Protein S deficiency can be subdivided into three types depending on whether the abnormality affects total protein S level, free protein S level, and/or protein S function:

• Type I: Reduced total protein S, free protein S, and protein S function

It is the classic form of hereditary protein S deficiency. Total protein S levels drop to approximately 50% of normal values while free protein S levels collapse to almost 15% of the normal. On a genetic level, type I deficiency usually results from missense or nonsense mutations. On few occasions, microinsertions, microdeletions, and splice site mutations have occurred with this type.

• Type II: Normal total and free protein S, reduced protein S function

This form results from a qualitative defect and is very rare. The genetics behind this type isn't certain; however, some reports have linked it to missense mutations affecting protein S's ability to bind to the activated protein C.

• Type III: Normal total protein S, reduced free protein S and protein S function

This is a quantitative defect.

Type	Total Protein S	Free Protein S	Protein S Function
I	↓	↓	↓
II	↔	↔	↓
III	↔	↓	↓

Pathophysiology

Coagulation cascade - Source: Wikipedia

• Protein S is a natural anticoagulant that works with other proteins to regulate coagulation in the body.

• After it gets produced by the hepatocytes, endothelial cells, and megakaryocytes, protein S undergoes activation via vitamin K-dependent gamma-carboxylation.
  • The vitamin K-dependent gamma-carboxyalse enzyme acts by modifying the glutamic acid residues in protein S to gamma-carboxyglutamic acid residues.
  • These gamma-carboxyglutamic acid residues are needed to ensure calcium-dependent binding to membrane surfaces.
• The now mature and activated protein S will circulate in the blood in two states:
  • Free protein S
    • This form constitutes 30 to 40 percent of the total protein S in the body.
    • It is the only form that will take part in the coagulation cascade.
  • C4b-bound protein S
    • There is a high affinity interaction between protein S and C4b-binding protein.
    • C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
    • Around 70 percent of circulating protein S is in the bound form.

• The activated free protein S acts as a cofactor to activated protein C, and with the help of phospholipids and Ca²⁺, it inactivates procoagulant factor Va and factor VIIIa thereby reducing thrombin formation.
• Protein S deficiency is a hereditary disease that results from mutations in the PROS1 gene, located on chromosome 3.
• This disease usually occurs due to heterozygous gene mutations in the PROS1 gene; however, rare cases of homozygous protein S deficiencies have been reported.
• Although another gene, PROS2, has been isolated on the same chromosome 3, it does not seem to have any relevance and has since been classified as a pseudogene.

Causes

• In addition to the common hereditary form of protein S deficiency, there are rare circumstances in which acquired causes can result in diminished protein S levels. These situations arise due to different mechanisms:
  • Protein S consumption
    • Disseminated intravascular coagulation
    • Surgery
  • Decreased synthesis of protein S
    • Liver disease
    • Vitamin K deficiency
  • Redistribution of complexed protein S
    • Pregnancy
    • Oral hormonal contraceptives
    • Nephrotic syndrome

Differentiating Protein S deficiency from Other Diseases

Protein S deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:

• Factor V Leiden mutation
• Antithrombin III deficiency
• Protein C deficiency
• Prothrombin gene mutation
• Disseminated intravascular coagulation (DIC)
• Antiphospholipid antibody syndrome

For more information on differentiating protein S deficiency, click here.

Epidemiology and Demographics

• The prevalence of protein S deficiency in the general population is unknown.
• However, its prevalence in individuals with a history of venous thromboembolism is approximately 900 per 100,000 individuals worldwide.

Age

• Patients of all age groups may be diagnosed with protein S deficiency.
• It is; however, more commonly observed among patients younger than 40 to 50 years old.

Gender

• There is no difference in the prevalence of the disease between men and women.

Race

• Protein S deficiency usually affects individuals of the Asian race.
• Caucasian individuals are less likely to develop protein S deficiency.

Risk Factors

• There are no established risk factors for protein S deficiency.
• Family history of thrombosis pose increased risk for a mutation.

Screening

• There is insufficient evidence to recommend routine screening for protein S deficiency in the general population.
• A simple positive family history incident of thrombosis is not enough to recommend screening in an asymptomatic low risk individual.
• High risk patients with a positive family history (first degree relative with protein S deficiency or first degree relative with multiple venous thromboembolic events at an age younger than 50), warrant a screening preferably prior to initiation of the high risk event such as taking oral contraceptives or pregnancy.
• The free protein S antigen assay is the best screening test.

Natural History, Complications, and Prognosis

• If left untreated, patients with protein S deficiency are at high risk to develop life-threatening venous thromboembolic events.
• Specific complications and prognosis associated with pulmonary embolism can be found here and for those related to deep vein thrombosis, click here.

Diagnosis

Diagnostic Study of Choice

• There is no established criteria for a definitive diagnosis of protein S deficiency.
• The diagnosis of protein S deficiency is the toughest out of all the hereditary thrombophilias due to protein S's interaction with other proteins, its complex genetic regulation, and its biologic variation.
• The diagnosis is made even more strenuous due to the the prevalence of acquired protein S deficiency causes (pregnancy, liver disease, DIC...).
• Three tests are used to assess protein S in plasma:
  1. Free protein S antigen
     • Determines free protein S level in plasma
     • Most reliable of the three tests
     • Evaluates the function of protein S indirectly
     • ELISA technique
  2. Total protein S antigen
     • Determines both free and bound protein S
     • ELISA technique
  3. Protein S activity assay
     • Assesses protein S's function as a cofactor for activated protein C
     • Indirectly measured based on a coagulation assay and the time to clot
     • Not very reliable due to inability to differentiate from factor V Leiden mutation (resistance to activated protein C)

History and Symptoms

• The hallmark of protein S deficiency is venous thromboembolism.
• A positive history of a venous thromboembolic event prior to age 50, a strong family history of venous thromboembolic events, and/or a known protein S deficient family member is suggestive of a protein S deficiency.
• The most common sites of venous thromboembolism include deep vein thrombosis and pulmonary embolism. For detailed symptoms associated with protein S deficiency refer to deep vein thrombosis history and symptoms and pulmonary embolism history and symptoms.
• Less common sites of venous thromboembolism include cerebral, axillary, and mesenteric veins.

Physical Examination

• Physical examination of patients with protein S deficiency is usually remarkable for signs of venous thrombosis or pulmonary embolism.
• For detailed findings associated with protein S deficiency refer to deep vein thrombosis physical examination and pulmonary embolism physical examination

Laboratory Findings

• A reduced concentration of serum free protein S is diagnostic of protein S deficiency; however, there is no standard cutoff for diagnosis.
• The exact levels used to differentiate patients with protein S deficiency from those without this deficiency depends on the patient's associated risk factors in addition to the hospital and laboratory.
  • Free protein S levels < 65 IU/dL are diagnostic of protein S deficiency in patients with a history of thromboembolic events or a strong family history of these events.
  • Lower levels of free protein S are required to diagnose patients who are asymptomatic or have no strong family history.
• For specific laboratory findings in patients with associated pulmonary embolism click here or deep vein thrombosis click here.

Electrocardiogram

• There are no specific ECG findings associated with protein S deficiency.
• For ECG findings related to pulmonary embolism click here.

X-ray

• There are no specific x-ray findings associated with protein S deficiency.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with protein S deficiency.

CT scan

• There are no specific CT scan findings associated with protein S deficiency.
• For CT scan findings related to pulmonary embolism click here

MRI

• There are no MRI findings associated with protein S deficiency.

Other Imaging Findings

• There are no other imaging findings associated with protein S deficiency.

Other Diagnostic Studies

• There are no other diagnostic studies associated with protein S deficiency.

Treatment

Medical Therapy

• Patients with protein S deficiency that remain asymptomatic and have no history of venous thromboembolic events do not require medical therapy.
• Patients with an acute event of venous thrombosis require same initial medical therapy regardless of whether the cause was hereditary or not.
  • For management of patients suffering from pulmonary embolism click here.
  • For management of patient suffering from deep venous thrombosis click here.
• Patients with protein S deficiency that suffer from a venous thromboembolic event are advised to continue anticoagulation indefinitely especially if the event was unprovoked (occurred without a preceding major risk event like surgery, trauma, oral contraceptives, immobility...).

Surgery

• Surgical intervention is not recommended for the management of protein S deficiency.

Primary Prevention

• There are no established measures for the primary prevention of protein S deficiency.

Secondary Prevention

• Effective measures for the secondary prevention of protein S deficiency include:
  • Avoiding oral contraceptives in women
  • Prophylactic anticoagulation postoperatively
  • Considering anticoagulation during pregnancy
  • Education concerning signs and symptoms of venous thromboembolic events