Abstract 548: Molecular Mechanism Behind Protein S Deficiency in Obese Patients

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Vijaya S Pilli
Keyword(s):  
Molecular Mechanism ◽  
Plasma Protein ◽  
Protein S ◽  
Factor Ix ◽  
Negative Regulator ◽  
Liver Protein ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
Increased Risk

Introduction: Protein S is a vitamin K-dependent plasma protein, produced mainly in the liver; Protein S circulates in the blood at a concentration of 450 nM. Protein S is an anticoagulant, serving as a cofactor for APC and TFPI, and as an inhibitor of Factor IX (FIXa). Protein S deficiency causes deep vein thrombosis (DVT), increased risk of inflammation and, because DVT is a complication commonly observed in obese individuals, Protein S deficiency might be associated with obesity. Aim: To identify a correlation between Protein S deficiency and obesity, and identify the probable molecular mechanism behind the Protein S deficiency in the obese subjects. Methods: Immunoblots, ELISA, EMSA, CHIP, aPTT assay, and thrombin generation assay. Results: By ELISA, we measured a decrease in Protein S level in obese mice compared with wild type mice. In obesity, the liver becomes hypoxic, thus, we hypothesized that hypoxia and hypoxia inducible factor 1 alpha (HIF1α) may regulate Protein S expression in obesity. We found that a high fat diet induced HIF1α stability in mice. HIF1α levels were inversely proportional to Protein S levels, suggesting that HIF1α is a negative regulator of Protein S expression. We further identified a putative HIF1α binding site in the Protein S promoter, and, by using in vitro and in vivo assays, we demonstrated that HIF1α binds directly to the Protein S promoter and suppresses transcription. We further confirmed HIF1α-mediated Protein S transcriptional regulation in vivo, Plasma Protein S levels are increased in the liver-specific HIF1α knockout mouse whereas, liver-specific overexpression of HIF1α reduced the concentration of Protein S in the plasma. Conclusion: We conclude that HIF1α regulates Protein S expression in mouse liver and in obesity. Inhibition of HIF1α or intravenous injection of Protein S may reduce the occurrence of DVT in obese individuals.

Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study

1989 ◽  
Vol 61 (01) ◽  
pp. 144-147 ◽  
Author(s):  
A Girolami ◽  
P Simioni ◽  
A R Lazzaro ◽  
I Cordiano
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Free Protein ◽  
Her Family ◽  
S Deficiency ◽  
Increased Risk ◽  
Patient Reported

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

Elevated Levels of Prothrombin Activation Fragment 1+2 in Plasma from Patients with Heterozygous Arg506 to Gin Mutation in the Factor V Gene (APC-Resistance) and/or Inherited Protein S Deficiency

1996 ◽  
Vol 75 (02) ◽  
pp. 270-274 ◽  
Author(s):  
Benget Zöller ◽  
Johan Holm ◽  
Peter Svensson ◽  
Björn Dahlbäck
Keyword(s):  
Plasma Concentration ◽  
Protein C ◽  
Protein S ◽  
Factor V ◽  
Protein S Deficiency ◽  
Apc Resistance ◽  
S Deficiency ◽  
Increased Risk ◽  
Factor V Gene ◽  
V Gene

SummaryInherited resistance to activated protein C (APC-resistance), caused by a point mutation in the factor V gene leading to replacement of Arg(R)506 with a Gin (Q), and inherited protein S deficiency are associated with functional impairment of the protein C anticoagulant system, yielding lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is often an additional genetic risk factor in thrombosis-prone protein S deficient families. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hyper-coagulable states, was measured in 205 members of 34 thrombosis-prone families harbouring the Arg506 to Gin mutation (APC-resistance) and/or inherited protein S deficiency. The plasma concentration of F1+2 was significantly higher both in 38 individuals carrying the FV:Q506 mutation in heterozygous state (1.7 ± 0.7 nM; mean ± SD) and in 48 protein S deficient cases (1.9 ± 0.9 nM), than in 100 unaffected relatives (1.3 ±0.5 nM). Warfarin therapy decreased the F1+2 levels, even in those four patients who had combined defects (0.5 ± 0.3 nM). Our results agree with the hypothesis that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

Resolution of possible acquired protein S deficiency after viral suppression in HIV infection

2021 ◽  
Vol 14 (11) ◽  
pp. e244983
Author(s):  
Leigh Cervino ◽  
Jillian Raybould ◽  
Patricia Fulco
Keyword(s):  
Viral Suppression ◽  
Treatment Guidelines ◽  
Protein S ◽  
People Living With Hiv ◽  
Protein S Deficiency ◽  
Anticoagulation Management ◽  
S Deficiency ◽  
Increased Risk ◽  
Undiagnosed Hiv ◽  
Living With Hiv

Current literature suggests an increased risk of venous thromboembolism (VTE) in people living with HIV (PLWH) with poorly controlled viraemia and immunodeficiency. VTE treatment guidelines do not specifically address anticoagulation management in PLWH. We report a case of a 33-year-old woman diagnosed with an unprovoked pulmonary embolism (PE) and deemed protein S deficient. Three years later, she was diagnosed with AIDS. Antiretroviral therapy (ART) was promptly initiated with viral suppression and immune reconstitution within 12 months. Eight years after her initial PE, the patient self-discontinued warfarin. Multiple repeat protein S values were normal. ART without anticoagulation has continued for 3 years with no thrombotic events. This case describes a patient with VTE presumably secondary to undiagnosed HIV with possible consequent acquired protein S deficiency. Additional research is needed to understand the characteristics of PLWH with VTE who may warrant long-term anticoagulation as opposed to shorter courses.

FAMILIAL TYPE I PROTEIN S DEFICIENCY ASSOCIATED WITH SEVERE VENOUS THROMBOSIS. A STUDY OF FIVE CASES

1987 ◽  
Author(s):  
C Boyer-Neumann ◽  
M Wolf ◽  
J Amiral ◽  
A M Guyager ◽  
D Meyer ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Plasma Protein ◽  
Active Form ◽  
Vena Cava ◽  
Protein S ◽  
Immunological Methods ◽  
Type I ◽  
Protein S Deficiency ◽  
Free Protein ◽  
S Deficiency

Protein S deficiency has been demonstrated in 5 members from the same family with a history of severe recurrent venous thrombosis over three generations. The propositus, a 16 year old female, had a first spontaneous thrombotic episode at age 15. Phlebography revealed a total obstruction of her left ilio-femoral vein with an extension to the vena cava. She was treated with heparin followed by oral anticoagulant therapy. The four other affected members (mother, aunts and uncle of the propositus) had also presented recurrent thrombosis with onset at a young age. The grandfather, not tested, had died from massive pulmonary embolism at age 54. The immunological assay of protein S was performed in plasma by Laurell, using a monospecific antiserum to human protein S, or by an ELISA, using a kit from Diagnostica Stago (Asserachrom Protein S). In order to separate free protein S, the functionally active form, from protein S complexed with C4-binding protein, plasma was adsorbed with 3.75 % polyethyleneglycol (PEG 6000). Following PEG precipitation, the levels of free protein S antigen remaining in the supernatant were quantitated by the usual immunological methods. In addition, two-dimensional immunoelectrophoresis (DDIE) also provided information on the distribution of both forms. In plasma protein S levels were decreased (40 to 55 % of the normal range) in two untreated patients and lower levels (17 to 20 96) were observed in the three others, including the propositus, who were under dicoumarol therapy. In PEG treated-plasma, protein S was undetectable (less than 5 %) in all patients, indicating a lack of free protein S. This was confirmed by DDIE : whereas protein S migrated as two distinct peaks, corresponding to free and complexed protein S in normal plasma, only a single peak of complexed protein S was observed in all affected patients. These results clearly demonstrate a total lack of free protein S which appears to be responsible for the thromboembolic disorder in this family as there was no deficiency of the other plasma inhibitors (antithrombin III, heparin cofactor II and protein C). According to the classification recently proposed by Comp et al., this family belongs to type I protein S deficiency, with an autosomal dominant mode of inheritance.

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1935-1941 ◽  
Author(s):  
Michael Makris ◽  
Michael Leach ◽  
Nick J. Beauchamp ◽  
Martina E. Daly ◽  
Peter C. Cooper ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein S ◽  
Structural Defects ◽  
Protein S Deficiency ◽  
Gene Defect ◽  
Thrombotic Risk ◽  
Free Protein ◽  
First Degree Relatives ◽  
S Deficiency ◽  
Increased Risk

Abstract Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

scholarly journals Deficiency of the natural anticoagulant proteins in women with pregnancy related venous thromboembolism

2009 ◽  
Vol 62 (1-2) ◽  
pp. 53-62 ◽  
Author(s):  
Gorana Mitic ◽  
Ljubica Povazan ◽  
Radmila Lazic ◽  
Dragan Spasic ◽  
Milana Maticki-Sekulic
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Protein S ◽  
Single Woman ◽  
Control Group ◽  
Protein S Deficiency ◽  
Clotting Factors ◽  
Protein C Deficiency ◽  
S Deficiency ◽  
Increased Risk

Inherited thrombophilia can be defined as a predisposition to thrombosis caused by heritable defects, such as mutations in genes encoding the natural anticoagulants or clotting factors. Pregnancy related risk of VTE is sixfold increased comparing to non pregnant age matched women. Pregnancy is an independent risk factor for the development of venous thromboembolism and this risk is further increased by the presence of thrombophilia. Aim of the study: The aim of the study was to evaluate the association between deficiency of natural anticoagulants: antithrombin, protein C and protein S and pregnancy related thromboembolism. We have determined the activities of antithrombin, proten C and protein S in 74 women with pregnancy related thrombosis and in 45 healthy women who had at least two uncomplicated pregnancies. Among the women with the history of venous thromboembolism antithrombin deficiency was found in 4 (5.4%), protein C deficiency in 2 (2.7%) and protein S deficiency in 5 (6.76%). The total of 11 (14.6%) women was found to be deficient. Not a single woman in the control group was found to be deficient in natural anticoagulants. Deficiencies of coagulation inhibitors are associated with an increased risk of venous thrombosis during pregnancy and puerperium (p= 0.006). Antithrombin, protein C and protein S deficient women are at higher risk of developing venous thromboembolism during antepartal period (p= 0.0097). Prophylactic treatment with heparin should be recommended from the very beginning of the following pregnancy in women with antithrombin, protein C or protein S deficiency.

Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency

1997 ◽  
Vol 77 (01) ◽  
pp. 014-020 ◽  
Author(s):  
Tomio Yamazaki ◽  
Akira Katsumi ◽  
Yoshihiro Okamoto ◽  
Toshio Takafuta ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein S ◽  
Mutant Protein ◽  
Compound Heterozygous ◽  
Protein S Deficiency ◽  
Acceptor Splice Site ◽  
Mrna Accumulation ◽  
S Deficiency ◽  
Heterozygous Patient

SummaryGenetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paternal mutation was a G-to-T transition at position -1 of the acceptor splice site of intron N (Mutation I), and the maternal mutation was a G-to-C transversion at position -1 of the donor splice site of intron C (Mutation II). Both splice site mutations decreased the mutated mRNA accumulation to the same extent, approximately 40% of the normal mRNA. However, the mutations were associated with different phenotypical expressions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced quantity. Because Mutation I caused a cryptic splicing in the mutated mRNA, resulting in a reading frameshift and premature termination, the predicted mutant protein S might be highly unstable. In contrast, Mutation II led to the substitution of Val46 by Leu, which might be much less deleterious for the synthesis, secretion and stability of the predicted mutant protein S. It was supposed that the different post-translational metabolisms produced the distinct phenotypical expressions of the mutations.

Insight in Protein S Deficiency From Mouse Models

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 529-529
Author(s):  
Sara Calzavarini ◽  
François Saller ◽  
Jose A. Fernandez ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
...  
Keyword(s):  
Mouse Models ◽  
Purpura Fulminans ◽  
Protein S ◽  
Negative Regulator ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Deficient Mice

Abstract Abstract 529 Protein S (ProS) is an important negative regulator of blood coagulation. Its physiological importance is evident in purpura fulminans and other life-threatening thrombotic disorders typical of ProS deficient patients. Our previous characterization of ProS deficiency in mouse models has shown similarities with the human phenotypes: heterozygous ProS-deficient mice (Pros+/−) had increased thrombotic risk whereas homozygous deficiency in ProS (Pros−/−) was incompatible with life (Blood 2009; 114:2307-2314). In tissues, ProS exerts cellular functions by binding to and activating tyrosine kinase receptors of the Tyro3 family (TAM) on the cell surface. To extend the analysis of coagulation defects beyond the Pros−/− phenotype and add new insights into the sites of synthesis ProS and its action, we generated mice with inactivated ProS in hepatocytes (Proslox/loxAlbCre+) as well as in endothelial and hematopoietic cells (Proslox/loxTie2Cre+). Both models resulted in significant reduction of circulating ProS levels and in a remarkable increased thrombotic risk in vivo. In a model of tissue factor (TF)-induced venous thromboembolism (VTE), only 17% of Proslox/loxAlbCre+ mice (n=12) and only 13% of Proslox/loxTie2Cre+ mice (n=14) survived, compared with 86% of Proslox/lox mice (n=14; P<0.001). To mimic a severe acquired ProS deficiency, ProS gene was inactivated at the adult stage using the polyI:C-inducible Mx1-Cre system (Proslox/loxMx1Cre+). Ten days after polyI:C treatment, Proslox/loxMx1Cre+ mice developed disseminated intravascular coagulation with extensive lung and liver thrombosis. It is worth noting that no skin lesions compatible with purpura fulminans were observed in any of the above-described models of partial ProS deficiency. In order to shed light on the pathogenesis of purpura fulminans, we exposed the different ProS-deficient mice to warfarin (0.2 mg/day). We observed that Pros+/−, Proslox/loxAlbCre+ and Proslox/loxTie2Cre+ mice developed retiform purpura (characterized by erythematous and necrotic lesions of the genital region and extremities) and died after 3 to 5 days after the first warfarin administration. In human, ProS is also synthesized by megakaryocytes and hence stored at high concentrations in circulating platelets (pProS). The role of pProS has been investigated by generating megakaryocyte ProS-deficient model using the PF4 promoter as Cre driver (Proslox/loxPf4Cre+). In the TF-induced VTE model, Proslox/loxPf4Cre+ (n=15) mice showed a significant increased risk of thrombosis compared to Proslox/lox controls (n=14; survival rate 47% and 86%, respectively; P<0.05). Furthermore, preliminary results suggest survival to be associated with higher circulating ProS levels. In order to evaluate the potential role of pProS in thrombus formation, we investigated the thrombotic response to intravenous injection of collagen-epinephrine in vivo and platelet function in vitro. Both in vivo and in vitro experiments showed similar results between Proslox/loxPf4Cre+ and Proslox/lox, indicating that platelet reactivity was not influenced by the absence of pProS. These data suggest that pProS is delivered at the site of thrombosis to inhibit thrombin generation. We further investigated the ability of ProS to function as a ligand of TAM receptors, by using homozygous and heterozygous deficient mice for both the TAM ligands ProS and Gas6. Gas6−/−Pros−/− mice died in utero and showed comparable dramatic bleeding and thrombotic phenotype as described for Pros−/− embryos. In conclusion, like complete ProS deficiency, double deficiency in ProS and Gas6 was lethal, whereas partial ProS deficiency was not. Mice partially deficient in ProS displayed a prothrombotic phenotype, including those with only deficiency in pProS. Purpura fulminans did not occur spontaneously in mice with partial Pros deficiency but developed upon warfarin administration. Thus, the use of different mice models of ProS deficiency can be instrumental in the study of its highly variable thrombotic phenotype and in the investigation of additional roles of ProS in inflammation and autoimmunity through TAM signaling. Disclosures: No relevant conflicts of interest to declare.

Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency

2007 ◽  
Vol 120 (3) ◽  
pp. 421-426 ◽  
Author(s):  
G. Castaman ◽  
E. Biguzzi ◽  
C. Razzari ◽  
A. Tosetto ◽  
G. Fontana ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Protein S ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
Normal Individuals

scholarly journals Protein S deficiency complicated with repetitive peripheral arterial thrombosis successfully treated by mechanical thrombectomy device with Rotarex system

2017 ◽  
Vol 5 (1) ◽  
pp. 5
Author(s):  
Wei-Sheng Liao ◽  
Wei-Tsung Wu ◽  
Nai-Yu Chi ◽  
Wen-Hsien Lee ◽  
Chun-Yuan Chu ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Mechanical Thrombectomy ◽  
Rare Complication ◽  
Protein S ◽  
Protein S Deficiency ◽  
Catheter Directed Thrombolysis ◽  
S Deficiency ◽  
Increased Risk ◽  
Thrombectomy Device ◽  
Peripheral Arterial

Protein S deficiency is an inherited thrombophilia associated with an increased risk of venous thromboembolism. However, arterial thrombosis is a relative rare complication of protein S deficiency and the prognosis of these patients was worse than those without protein S deficiency in the literature. Herein we reported a 43-year-old male with protein S deficiency experiencing several times acute peripheral arterial thrombosis of left leg. Surgical thrombectomy was performed initially but later endovascular treatment (EVT) was suggested. Although EVT was successfully performed by catheter-directed thrombolysis (CDT), arterial thrombosis still recurred three months later. CDT was tried again but thrombosis could not be treated by this strategy anymore. Therefore, we used mechanical thrombectomy device (Rotarex system) and successfully regained the straight-line blood flow to the foot after the procedure. Peripheral echo showed patent flow after 6 months follow-up. In conclusion, arterial thrombosis is a relative rare complication of protein S deficiency and prognosis was not well in the literature, our case reminds physicians that Rotarex system is a safe and highly efficient device for acute PAOD even in the patients with hypercoagulable state.

Sign in / Sign up

Export Citation Format

Share Document