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. A deficiency in protein S characteristically demonstrates the inability to control coagulation, resulting in the excessive formation of blood clots (thrombophilia).
Protein S deficiency is usually congenital, caused by mutations in the PROS1 gene. More than 200 PROS mutations have been described and may result in three different forms of protein S deficiency:
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. The risk of VTE is also increased in patients using oral contraceptives and pregnancy.
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.
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). The anticoagulant activity of protein S is two-fold :
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.
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. Venous thrombotic events (VTE), including parenchymal thrombi, deep vein thrombosis (DVT), pulmonary emboli (PE) and a propensity to DIC are common clinical manifestations, 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.
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.
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.
Plasma protein S levels fluctuate with age, gender, and genetic or acquired influences such as hormonal status or lipid metabolism. 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.
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. 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. 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.
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.
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.
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.
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.
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.
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. [Level V]
|||Dahlbäck B, Vitamin K-Dependent Protein S: Beyond the Protein C Pathway. Seminars in thrombosis and hemostasis. 2018 Mar; [PubMed PMID: 28905350]|
|||Castoldi E,Hackeng TM, Regulation of coagulation by protein S. Current opinion in hematology. 2008 Sep; [PubMed PMID: 18695379]|
|||Rezende SM,Simmonds RE,Lane DA, Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood. 2004 Feb 15; [PubMed PMID: 12907438]|
|||van Vlijmen EF,Brouwer JL,Veeger NJ,Eskes TK,de Graeff PA,van der Meer J, Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects: results from a retrospective family cohort study. Archives of internal medicine. 2007 Feb 12; [PubMed PMID: 17296885]|
|||Seligsohn U,Lubetsky A, Genetic susceptibility to venous thrombosis. The New England journal of medicine. 2001 Apr 19; [PubMed PMID: 11309638]|
|||Brouwer JL,Veeger NJ,van der Schaaf W,Kluin-Nelemans HC,van der Meer J, Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification. British journal of haematology. 2005 Mar; [PubMed PMID: 15725093]|
|||ten Kate MK,van der Meer J, Protein S deficiency: a clinical perspective. Haemophilia : the official journal of the World Federation of Hemophilia. 2008 Nov; [PubMed PMID: 18479427]|
|||Brouwer JL,Veeger NJ,Kluin-Nelemans HC,van der Meer J, The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Annals of internal medicine. 2006 Dec 5; [PubMed PMID: 17146065]|
|||Pauls JE,Hockin MF,Long GL,Mann KG, Self-association of human protein S. Biochemistry. 2000 May 9; [PubMed PMID: 10820019]|
|||Hackeng TM,Fernández JA,Dawson PE,Kent SB,Griffin JH, Chemical synthesis and spontaneous folding of a multidomain protein: anticoagulant microprotein S. Proceedings of the National Academy of Sciences of the United States of America. 2000 Dec 19; [PubMed PMID: 11106381]|
|||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]|
|||Monagle P,Cuello CA,Augustine C,Bonduel M,Brandão LR,Capman T,Chan AKC,Hanson S,Male C,Meerpohl J,Newall F,O'Brien SH,Raffini L,van Ommen H,Wiernikowski J,Williams S,Bhatt M,Riva JJ,Roldan Y,Schwab N,Mustafa RA,Vesely SK, American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood advances. 2018 Nov 27; [PubMed PMID: 30482766]|
|||Cooper DN, The molecular genetics of familial venous thrombosis. Bailliere's clinical haematology. 1994 Sep [PubMed PMID: 7841604]|