Protein S Deficiency

Article Author:
Ashish Gupta
Article Author (Archived):
Aung Tun
Article Editor:
Faiz Tuma
Updated:
7/13/2019 11:33:39 AM
PubMed Link:
Protein S Deficiency

Introduction

Protein S deficiency is a rare disorder, characterized by reduced activity of protein S, a plasma serine protease with complex roles in coagulation, inflammation, and apoptosis.[1] A deficiency in protein S characteristically demonstrates the inability to control coagulation, resulting in the excessive formation of blood clots (thrombophilia).

Etiology

Protein S deficiency is usually congenital, caused by mutations in the PROS1 gene.[2] More than 200 PROS mutations have been described and may result in three different forms of protein S deficiency:

  • Type I: quantitative defect presenting with low levels of total protein S (TPS) and free protein S (FPS), with reduced levels of protein S activity
  • Type II (also known as Type IIb): Decreased protein S activity, with normal levels of TPS and FPS antigens
  • Type III (also known as Type IIa): quantitative defect presenting with normal levels of TPS, but reduced levels of FPS and protein S activity

Protein S deficiency is an autosomal dominant pathology. Mutations in a single copy in heterozygous individuals cause mild protein S deficiency, whereas individuals with homozygous mutations present with severe protein S deficiency. Causes of temporary acquired fluctuations in protein S levels may include vitamin K-antagonist therapy, chronic infections, severe hepatic disease, nephritic syndrome, and DIC.[3] The risk of VTE is also increased in patients using oral contraceptives and pregnancy.[4][5]

Epidemiology

Estimates of the incidence of mild congenital protein S deficiency are between 1 in 500 individuals. Severe protein S deficiency is rare, and its prevalence in the general population remains unknown, due to difficulty in diagnosing the condition.

Pathophysiology

Protein S is a vitamin K-dependent protease that circulates in plasma at low concentrations and serves a crucial role in the regulation of coagulation. In circulation, approximately 40% of protein S is free, and about 60% is in a high-affinity complex with the complement regulatory factor C4b-binding protein (C4BP).[2] The anticoagulant activity of protein S is two-fold [1]:

  • Protein S operates as a cofactor for activated protein C (APC), and inactivating coagulation Factor Va and Factor VIIIa
  • Protein S is also a cofactor for the tissue factor pathway inhibitor (TFPI) protein, resulting in the inactivation of Factor Xa and tissue factor (TF)/Factor VIIa

Protein S is a complex protein with multiple structural moieties. The 3-dimensional structure is yet to be resolved but is expected to contribute to the understanding of the complex functional nature of PROS1 mutations.

History and Physical

The symptoms in patients with heterozygous protein S deficiency and mild reductions in protein S activity can range in severity. Almost half of all individuals with protein S deficiency will become symptomatic before the age of 55.[6] Venous thrombotic events (VTE), including parenchymal thrombi, deep vein thrombosis (DVT), pulmonary emboli (PE) and a propensity to DIC are common clinical manifestations,[7] with some patients also experiencing cerebral, visceral or axillary vein thrombosis. Approximately half of these recurrent VTE episodes occur in the absence of common risk factors for thrombosis. The variability in risk of thrombotic events in carriers of protein S mutations may be due to different functional consequences of PROS1 mutations, incomplete gene penetrance, exposure to thrombotic risk factors, environmental or other genetic influences.[8]

Severe protein S deficiency resulting from congenital homozygous mutations presents in neonates soon after birth and has a characteristic presentation of purpura fulminans (PF). Affected individuals rarely survive childhood without early diagnosis and treatment.[9]

Evaluation

Diagnostic testing for protein S deficiency is performed using functional assays, including clotting assays and enzyme-linked immunosorbent assays (ELISA) to determine levels of protein S activity. Total protein S tests have excellent performance but are not able to detect Type II and III protein S deficiency. Free PS assays may be a useful alternative, although they lack reproducibility. Measurement of APC cofactor activity could be used as a proxy indicator of protein S deficiency, although these assays have a high false-positive rate.[9]

Plasma protein S levels fluctuate with age, gender, and genetic or acquired influences such as hormonal status or lipid metabolism.[10] Total and free protein S levels are lower in women than in men, although total protein S levels increase with age, and this is more pronounced in women due to deviations in hormone levels.

Mutational analysis of the PROS1 gene can be an important tool in diagnosing protein S deficiency, and the International Society of Thrombosis and Haemostasis (ISTH) maintains a registry of documented mutations

Hemostasis analysis (per ISTH): Diagnosis of PROS1 mutations is performed using DNA sequencing or amplification and analysis by polymerase chain reaction (PCR) followed by gel electrophoresis.

Treatment / Management

VTE management is by the administration of anticoagulation therapies such as heparin (low-molecular-weight heparin or unfractionated) with warfarin. Patients with congenital protein S deficiency normally receive anticoagulation therapy for a longer duration, until coagulation activity has stabilized for at least two consecutive days.[7] Prophylactic anticoagulation therapy with warfarin is sustained for 3 to 6 months following a thrombotic episode and should be for longer durations in patients with coexisting coagulation conditions.[7] Prophylactic treatment should also be administered to patients with protein S deficiency exposed to thrombotic risk factors such as air travel, surgery, pregnancy, or long periods of immobilization. During pregnancy, patients in the first trimester or after 36 weeks, should be treated with low-molecular-weight heparin rather than warfarin, to reduce the risk of fetal and maternal bleeding.[7][11]

Differential Diagnosis

Patients who present with thrombophilia without other risk factors may suffer from protein S deficiency. Alternative causes of thrombophilia include other congenital coagulation abnormalities or a combination of protein S deficiency with other VTE risk factors. Protein S deficiency may also be an acquired condition, rather than congenital, as a result of conditions including pregnancy, vitamin K deficiency, oral contraceptives, severe hepatic dysfunction, and chronic infections.

Prognosis

Patients with mild protein S deficiency, are prone to recurrent episodes of VTEs, including DVT. VTE induces significant morbidity and mortality. However, there is little evidence to suggest that thrombophilia related to protein S deficiency results in deteriorated prognosis for VTE. The development of recurrent thrombotic events in individuals with thrombophilia can contribute to increased morbidity. Furthermore, extended periods of anticoagulation treatment with warfarin can lead to increased risk of bleeding.

Neonates presenting with severe protein S deficiency have a poor prognosis. Complications from frequent infusions of plasma, such as fluid overload contribute to a high rate of infant death. There is limited data regarding the long-term outcome of patients with severe congenital protein S deficiency.

Complications

In adolescents and adults, long-term anticoagulation therapy increases the cumulative likelihood of severe bleeding complications. Skin necrosis is a complication associated with warfarin treatment and is manageable with short-term heparin administration.[7]

Deterrence and Patient Education

At home, patient monitoring using point-of-care testing for fluctuations in international normalized ratios (INR) has eased the care of individuals with protein S deficiency. When combined with the use of short-term anticoagulation therapy, proactive, patient-directed management can prevent recurrent episodes of thrombotic events requiring hospitalization. The use of compression stockings can also aid in preventing VTE events.

Enhancing Healthcare Team Outcomes

Protein S deficiency is a rare pathology that can be acquired or is congenital. The most significant morbidity of protein S deficiency is that it predisposes patients to blood clots in the legs, brain, intestine, and lungs. Also, the condition can lead to premature birth and other complications during pregnancy. Because of its varied presentation, the disorder is best managed by an interprofessional team that includes nurse practitioners and pharmacists.

These patients are initially first managed by a hematologist and then followed up by the primary care provider or nurse practitioner. All healthcare workers participating in the care of these patients should refer to published guidelines and recommendations developed by organizations such as the American Society of Hematology for guidance in the treatment and management of children with coagulation abnormalities.[12]

Since many patients present with a first time thrombotic event, the key is to have a suspicion of the disorder to make the diagnosis. Once diagnosed, the pharmacist should educate the patient on anticoagulation compliance; otherwise, there is a risk for devastating thrombotic complications.

Because deep vein thrombosis can lead to post-thrombotic phlebitis, the nurse and pharmacist should coordinate education of the patient on the importance of wearing compression stockings.

Additionally, the interprofessional team should regularly monitor the levels of PT and INR on patients managed with warfarin. Any deviation from therapeutic levels should be communicated to the hematologist who should be the only one in charge of changing the dose and frequency. For those on oral anticoagulation who need elective surgery, an internist should have input because these patients may require bridge therapy with heparin. Females of childbearing age who want to get pregnant should consult with a hematologist first and be closely followed by a hematology nurse practitioner if she decides to conceive.

Only with an interprofessional team approach can the morbidity of protein S deficiency be reduced, and outcomes improved.[13] [Level V]


References

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[11] Folkeringa N,Brouwer JL,Korteweg FJ,Veeger NJ,Erwich JJ,Holm JP,van der Meer J, Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. British journal of haematology. 2007 Feb;     [PubMed PMID: 17223916]
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