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Protein S Deficiency

Deficiencies Protein S

Protein S is an anticoagulant protein and patients with protein S deficiency have a higher risk for developing blood clots.


Presentation

The most common presentation for patients with protein S deficiency is venous thromboembolism (VTE) which may present as deep vein thrombosis (DVT) or pulmonary embolism (PE). In roughly half of the patients with DVT there are no evident symptoms. Patients with DVT that do display symptoms may experience leg swelling, pain, increased temperature and redness (in affected leg). When a VTE occurs in the lungs it is known as a PE. Patients with PE may experience chest pain which worsens upon inhalation or coughing, sudden dyspnea, rapid heartbeat, dizziness, fainting and coughing up blood.
Protein S deficiency can be classified into three different types based on the levels of free, total and functionally active protein S that patients display. Patients with type I protein S deficiency, or quantitative deficiency, will have decreased levels of both the free and total protein S levels. Patients with type II protein S deficiency, or functional deficiency, will have normal protein S levels but decreased activity of protein S. Finally, patients with type III protein S deficiency have decreased levels of free protein S but normal levels of total protein S.

Fishing
  • FISH (8 families) and MLPA analysis (20 families) failed to identify other types of rearrangements.[ncbi.nlm.nih.gov]
  • High protein diets include meals enriched with foods like eggs, meats, peanuts, milk, chicken, sea foods, soy products, and fish. For vegetarians, proteins from vegetables like legumes and nuts are ideal.[med-health.net]
Recurrent Pulmonary Embolism
  • PATIENT CONCERNS: In this report, we present a case of recurrent pulmonary embolism (PE) and deep venous thrombosis (DVT) due to PS deficiency.[ncbi.nlm.nih.gov]
High Fever
  • Patient came to India for high fever and further management. Patient developed proteinuria with high creatinine and urinary abnormalities. Renal biopsy revealed acute interstitial nephritis (AIN).[ncbi.nlm.nih.gov]
Tinnitus
  • Dural arteriovenous fistula (DAVF) may present with a variety of neurological symptoms, ranging from tinnitus to fatal hemorrhage.[ncbi.nlm.nih.gov]
  • Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure.[ncbi.nlm.nih.gov]
Pulsatile Tinnitus
  • Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure.[ncbi.nlm.nih.gov]
Scotoma
  • Two pregnant women in their 30s presented with a paracentral scotoma in their right and left eye, respectively. In both cases the only risk factor for vascular occlusion was pregnancy. Systemic diseases were excluded.[ncbi.nlm.nih.gov]
Stroke
  • In this case Protein-S deficiency seems to be the only risk factor responsible for stroke.[ncbi.nlm.nih.gov]
  • Stroke or cerebro-vascular disease is one of the most important causes of high morbidity and mortality throughout the world. Stroke in young individuals poses a major problem as these individuals are the earning members of the family.[ncbi.nlm.nih.gov]
  • BACKGROUND: The association between protein S deficiency (PSD) and ischemic stroke is controversial and warrants further investigation.[ncbi.nlm.nih.gov]
  • However, the correlation between PS deficiency and ischemic stroke requires further investigation.[ncbi.nlm.nih.gov]
  • Keywords: Protein S deficiency, recurrent ischemic stroke, young stroke How to cite this article: Hooda A, Khandelwal P D, Saxena P. Protein S deficiency: Recurrent ischemic stroke in young.[dx.doi.org]
Recurrent Headache
  • A 38-year-old man presented with recurrent headache, vomiting, altered sensorium and one episode of transient left hemiparesis.[ncbi.nlm.nih.gov]
Focal Neurologic Deficit
  • CVST should be suspected in a patient with acute features of raised intracranial pressure or focal neurological deficit, and a patient without obvious clinical predisposition for a prothrombotic state should be evaluated for underlying thrombophilic states[ncbi.nlm.nih.gov]
Focal Seizure
  • Our patient is a 35-year-old male who presented with focal seizures. MRI brain showed venous infarcts, and MR venogram showed extensive thrombosis of superior sagittal sinus.[ncbi.nlm.nih.gov]
Generalized Seizure
  • Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure.[ncbi.nlm.nih.gov]

Workup

There are both descriptive and functional laboratory tests that can be done to diagnose protein S deficiency [7]. Levels of total and free protein S can be measured in laboratories using an enzyme-linked immunosorbent assay (ELISA). Researchers can distinguish between the bound and free form of protein S due to the functional differences between these molecules. Functional assays performed in the laboratory take advantage of the anticoagulation properties of protein S and measure the ability of samples to prolong blood clotting. Functional assays are associated with a number of problems including their relative difficulty to perform and their association with false positive results. The presence of other common hereditary thrombophilia disorders, such as factor V Leiden genetic defect, may lead to the diagnosis of protein S deficiency using functional assays when in fact protein S activity is normal. Newer methods are available to test for factor V Leiden genetic defect in plasma which may help diminish false positive protein S deficiency diagnoses associated with these functional tests [10].

Erythrocytosis
  • Association of mild protein S deficiency with erythrocytosis could have precipitated the onset of priapism.[ncbi.nlm.nih.gov]
Staphylococcus Aureus
  • Staphylococcus aureus was isolated from peripheral blood, but not, the pleocytotic cerebrospinal fluid.[ncbi.nlm.nih.gov]
  • She had been admitted earlier in the month with methicillin-resistant Staphylococcus aureus (MRSA) endocarditis and signed herself out against medical advice without completing antibiotic therapy.[pharmacytimes.com]
Human Herpesvirus 6
  • Antiprotein S autoantibodies and active human herpesvirus-6 (HHV6) replication were demonstrated. Purpuric skin lesions spread very rapidly despite broad-spectrum antibiotics and right leg amputation.[ncbi.nlm.nih.gov]

Treatment

No single medication or treatment fits all cases of protein S deficiency. Prophylactic medications may be administered but physicians must assess the patient's bleeding risk before making any recommendations. Patients should avoid drugs that may increase their risk of developing thrombosis, such as combined oral contraceptives. During pregnancy protein S deficiency is associated with increased fetal loss, therefore, physicians should closely monitor pregnant women who have this condition.

Prognosis

Many individuals who are homozygous and heterozygous (approximately 60-80%) have an increased risk for developing thrombosis, specifically venous thromboembolism (VTE), however, some heterozygous individuals show no symptoms. Prognosis is dependent on early detection and diagnosis and subsequent administration of antithrombotic measures. For acquired protein S deficiency the prognosis is highly variable and depends on the underlying condition that caused protein S deficiency.

Etiology

Both acquired and hereditary forms of protein S deficiency exist. The acquired form of protein S deficiency is most commonly due to vitamin K deficiency or hepatic disease but it can also be caused by warfarin treatment, nephrotic syndrome, antiphospholipid antibodies, acute thrombosis and disseminated intravascular coagulation. During pregnancy protein S levels fall but not as much in women using oestrogen-containing oral contraceptives or hormone replacement therapy. The inherited trait responsible for the hereditary form of protein S deficiency may cause one of three types of this disease with varying levels of protein S activity.

Epidemiology

In the United States (US) and most other countries around the world (exceptions stated later) the heterozygous form of hereditary protein S deficiency occurs in roughly 2% (ranging from 1-7%) of patients that present with venous thromboembolism (VTE). Patients with a family history or thrombosis or recurrent thrombosis display increased chances of having protein S deficiency (3-6%). This disease is much rarer in healthy populations without VTE, with one study conducted on 9000 blood donors indicating a frequency of protein S deficiency in one out of every 700 [2]. Recently, studies have demonstrated an elevated frequency of protein S deficiency in Japanese populations. Compared to protein S deficiency rates in Caucasians of about 1-7% of patients with VTE, studies have reported a frequency of around 12.7% in Japanese populations with VTE. Likewise, in the general Caucasian population the frequency of protein S deficiency is around 0.03% compared to healthy Japanese populations of about 0.63%. Black Africans have also been shown to have an increased risk for thrombophilic disorders. The mutation most commonly observed in Caucasians is the factor V Leiden mutation which is thought to be a result of the founder effect that occurred nearly 30,000 years ago. No differences exist in the frequency of protein S deficiency in males and females and the age of onset varies depending on whether an individual is heterozygous or homozygous for the trait. Individuals heterozygous for protein S deficiency usually display symptoms of VTE earlier than 40-45 years of age. The homozygous from of this disease is rare and associated with thrombotic disorders very early in life (within the first year of life). Patients homozygous for the protein S deficiency gene usually develop purpura fulminans in the first year of life, which is characterized by small vessel thrombosis along with cutaneous and subcutaneous necrosis [3].
Approximately 60-80% of individuals heterozygous for the protein S deficiency develop VTE with the remaining patients showing no symptoms. Although a clear association of protein S deficiency and VTE exists no clear relationship between this condition and arterial thrombosis has been identified. Some small case reports have identified protein S deficiency as condition found in patients with arterial thrombosis, however, larger prospective and cohort studies have not been able to show a link.
Protein S deficiency, along with a number of other genetic thombophilic disorders, is linked to fetal loss in women. Mortalities associated with protein S deficiency are caused by pulmonary embolism. The general three month mortality rates from pulmonary embolism are 10-17%. Some studies have shown a higher mortality rate from pulmonary embolism in men (13.7%) than women (12.8%) and blacks (16.1%) compared to whites (12.1%).

Sex distribution
Age distribution

Pathophysiology

The link between protein S deficiency and thrombosis is through its role in normal anticoagulation. Protein S is one of many proteins that function to keep the blood in its liquid nonthrombotic state [4]. If coagulation proceeds unchecked the result will be thrombosis which is why protein S and the other proteins in its anticoagulation pathway are so important [5] [6] [7]. The primary function of protein S is to act as a cofactor for activated protein C (APC) and together these proteins are part of the anticoagulation system known as the protein C system. To form a blood blot multimolecular complexes, known as the tenase and prothrombinase complexes, form on membrane surfaces that are typically composed of activated platelets and/or negatively charged phospholipids. The tenase and prothrombinase complexes are vital to the activation of factor X and prothrombin, respectively. In order to function properly as clotting factors, tenase and prothrombinase require the active forms of the large anchor proteins factor VIII (FVIIIa) and factor V (FVa), respectively.
Since unrestrained clotting is harmful there are a number of anticoagulation mechanisms built in to the clotting pathway. For example, the clotting factor thrombin acts as an anticoagulation factor on the surface of endothelial cells by activating protein C to its active form, APC. As stated earlier APC requires protein S to perform its activities, which include the inactivation of FVa and FVIIIa through cleavage of these two proteins and subsequent dampening and reversing of the clotting mechanism. This provides a general explanation of protein S deficiency in thrombosis but there are various nuances associated with different forms of the disease. The inactivation of FVIIIa relies not only on protein S and APC but also on the cleaved (inactivated) form of FVa. This becomes evident in patients who have the mutant factor V Leiden gene which codes for a FVa protein that is not cleaved by APC and therefore cannot perform its anticoagulation functions to resolve clots. Along with the role of protein S as a cofactor for APC, protein S can directly inhibit factor X clotting factor-activating complex and prothrombin-activating complex. In addition to its anticoagulation functions, protein S has been shown to play an important role in the phagocytosis of apoptotic cells by binding to molecules on their surface and subsequently stimulating macrophages phagocytosis. It is not known whether this function of protein S has any physiological consequences in patients with protein S deficiencies.
Protein S is a glycoprotein that requires vitamin K in order to be processed from its immature (pro) form to its functional form. This cleavage is performed by a vitamin K–dependent gamma-carboxylase enzyme that modifies the immature protein S into the active form of protein S that contains a gamma-carboxyglutamic acid (Gla) residue that is important for protein S to bind to the surface of cell membranes. Both protein S and APC require negatively charged phospholipids and calcium to function properly during anticoagulation. Protein S may exist in a free form or a bound form to the complement regulatory protein C4b-binding protein (C4BP). The free form of protein S is responsible for its anticoagulant properties and normally around 30-40% of protein S exists in its free state. Decreased levels of free and total protein S are observed in type I protein S deficiency, whereas, a decrease in only the free form of protein S is type III protein S deficiency. Normal levels of protein S are detected in type II patients, however, the activity of protein S as a cofactor for APC is reduced.
Recent studies have demonstrated APC-independent anticoagulation activities of protein S through inhibition of the factor Xa/factor Va prothrombinase complex [8]. This APC-independent activity was shown to be dependent on the presence of zinc which had no effect on the APC-dependent activities of protein S [8].
The human genes for protein S are found on chromosome 3 at position p11.1-3q11.2. The active protein S gene (PROS1) is longer than 80 kb and has 15 exons and 14 introns. Along with the active protein S gene there is a nonfictional pseudogene (PROS-b) that makes genetic studies very difficult [9]. Deletions in the PROS1 gene have been associated with protein S deficiency including a large deletion that is also associated with thrombophilia [9] and a 5.3 kb deletion that results in the production of a truncated form of protein S.

Prevention

Patients diagnosed with protein S deficiency should avoid activities associated with long periods of sitting that lead to clots, such as long airplane or car rides. Other activities associated with clotting that should be avoided include prolonged bed rest, surgery or hospital stays which all lead to blood moving slowly through the veins.

Summary

Protein S was discovered in 1979 in Seattle, Washington. This protein is a vitamin K-dependent cofactor for activated protein C (APC) that plays an important role in the anticoagulation pathway. Protein S supports the action of APC on two of its substrates, activated factor V (FVa) and activated factor VIII (FVIIIa). However, the precise mechanism of protein S activity is yet to be determined [1]. Low levels of protein S, which are observed in protein S deficiency, are associated with increased risk of blood clots (thrombosis).
There are numerous forms of hereditary and acquired protein S deficiencies. Acquired protein S deficiency usually arises from vitamin K deficiency, hepatic disease or hormone imbalance. There are three hereditary forms of protein S deficiency which are caused by an autosomal dominant gene, meaning that both homozygous dominant and heterozygous individuals are affected. The clinical manifestations of protein S deficiency are most commonly venous thromboembolism (VTE) and fetal loss. There is only a weak connection between protein S deficiency and arterial thrombosis which is not associated with other anticoagulant disorders, including protein C deficiency, antithrombin III deficiency and factor V Leiden gene mutation [1].

Patient Information

Protein S deficiency is a hereditary or acquired disorder where affected patients have an increased risk of developing blood clots in their veins also known as venous thromboembolisms (VTE). Protein S is an anticoagulation factor that requires vitamin K to function properly. The mechanism by which protein S breaks up blood clots is through the activation of activated protein C (APC) which degrades certain proclotting factors (factor Va and factor VIIIa).
Protein S deficiency may be caused by an inherited trait or acquired through certain environmental circumstances. The trait that causes protein S deficiency is a dominant gene, therefore, patients with one diseased and one normal gene will still inherit the disorder and parents have a 50% chance of passing the disease gene to their children. Only half of patients diagnosed with the hereditary form of protein S deficiency will develop a VTE which usually occurs from the late teens and beyond. There are a number of causes for the acquired form of protein S deficiency which include liver disease, vitamin K deficiency, warfarin intake, hormone replacement therapy, pregnancy and chronic infections (eg. human immunodeficiency virus). Patients taking warfarin or displaying vitamin K deficiency may experience bleeding instead of VTE.
Symptoms of VTE include pain, tenderness, redness and swelling at the affected area. Diagnosis of protein S deficiency can be achieved through laboratory tests to measure levels and activity of protein S. Typically, blood thinning drugs are recommended for the treatment or prevention of blood clots but the specific type of drug will vary from patient to patient depending on a number of other factors. Patients usually respond very well to treatment but if blood-thinning drugs are stopped symptoms may return.

References

Article

  1. Ten Kate MK, van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia. 2008; 14(6):1222-8.
  2. Brouwer JL, Lijfering WM, Ten Kate MK, et al. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009; 101(1):93-9.
  3. Edlich RF, Cross CL, Dahlstrom JJ, et al. 3rd. Modern concepts of the diagnosis and treatment of purpura fulminans. J Environ Pathol Toxicol Oncol. 2008; 27(3):191-6.
  4. Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol. 2008; 15(5):529-36.
  5. Soare AM, Popa C. Deficiencies of proteins C, S and antithrombin and activated protein C resistance--their involvement in the occurrence of Arterial thromboses. J Med Life. 2010; 3(4):412-5.
  6. Castoldi E, Maurissen LF, Tormene D, et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica. 2010; 95(9):1563-71.
  7. Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011; 86(5):418-21.
  8. Heeb MJ, Prashun D, Griffin JH, et al. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J. 2009; 23(7):2244-53.
  9. Lijfering WM, Brouwer JL, Veeger NJ, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009; 113(21):5314-22.
  10. Tripodi A, Asti D, Chantarangkul V, et al. Interference of factor V Leiden on protein S activity: evaluation of a new prothrombin time-based assay. Blood Coagul Fibrinolysis. 2007; 18(6):543-6.

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Last updated: 2019-07-11 21:12