Protein S deficiency: a clinical perspective

Kate, Min Ki ten; Meer, Jan van der

doi:10.1111/j.1365-2516.2008.01775.x

Cited by 165 publications

(147 citation statements)

References 39 publications

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“…24 The rest circulates as free protein S, which acts as APC cofactor, increasing its potency approximately 20 times. 25,26 This makes APC a major inhibitor of coagulation factors VIIIa and Va. 11 Furthermore, APC indirectly affects fibrinolysis by inhibiting the activation of both thrombin activiatable fibrinolytic inhibitor and plasminogen activator inhibitor 1.…”

Section: Introductionmentioning

confidence: 99%

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Negreva

Georgiev

Vitlianova

2016

Clin Appl Thromb Hemost

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Background: Increased coagulation activity has been established in paroxysmal atrial fibrillation (PAF), but data on the anticoagulant system are scarce. Purpose: To examine the protein C anticoagulant pathway in the early hours of the disease. Materials and Methods: Fifty-one patients (26 men and 25 women; mean age 59.84 + 1.60 years) and 52 controls (26 men and 26 women; mean age 59.50 + 1.46 years) were selected for the study. Protein C antigen and its activity, total protein S, free protein S and its activity, soluble forms of endothelial protein C receptor (sEPCR), and thrombomodulin (sTM) were examined in the plasma. Results: The indicators were studied in patients between the 2nd and the 24th hour after the onset of arrhythmia. Levels of protein C were significantly elevated in patients compared to controls (111.40% + 6.66% vs 94.83% + 4.47%; P ¼ .039). Protein C activity showed significant reduction in PAF (73.13% + 5.80% vs 103.3% + 3.80%; P < .001). Total protein S levels did not differ significantly (108.20% + 4.07% vs 102.40% + 3.65%; P ¼ .30). Free protein S (76.81% + 6.01% vs 122.10% + 3.97%; P < .001) and its activity (71.39% + 6.27% vs 119.50% + 6.54%; P < .001) were reduced in patients. Higher levels of sEPCR (203.10 + 10.33 vs 133.10 + 7.37 ng/mL; P < .001) and sTM (6.50+0.40 vs 4.48+0.28 ng/mL; P < .001) were measured in PAF. Conclusion: Protein C activity is reduced still in the first hours (until the 24th hour) of PAF clinical manifestation, determining reduced activity of the anticoagulant pathway as a whole. The established low levels of free protein S and its activity as well as low sEPCR and sTM levels are a possible explanation of the changes in protein C activity.

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Section: Introductionmentioning

confidence: 99%

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Negreva

Georgiev

Vitlianova

2016

Clin Appl Thromb Hemost

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“…Individuals with less-severe ProS deficiencies due to heterozygous mutations or polymorphisms, of which more than 200 forms have been documented, are at elevated risk for deep vein thrombosis (DVT) and other life-threatening thrombotic events (7,8). These same risks appear in the many SLE patients who display ProS deficiency (9).…”

Section: Introductionmentioning

confidence: 99%

Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis

Burstyn‐Cohen¹,

Heeb²,

Lemke³

2009

J. Clin. Invest.

148

170

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Protein S (ProS) is a blood anticoagulant encoded by the Pros1 gene, and ProS deficiencies are associated with venous thrombosis, stroke, and autoimmunity. These associations notwithstanding, the relative risk that reduced ProS expression confers in different disease settings has been difficult to assess without an animal model. We have now described a mouse model of ProS deficiency and shown that all Pros1 -/-mice die in utero, from a fulminant coagulopathy and associated hemorrhages. Although ProS is known to act as a cofactor for activated Protein C (aPC), plasma from Pros1 +/-heterozygous mice exhibited accelerated thrombin generation independent of aPC, and Pros1 mutants displayed defects in vessel development and function not seen in mice lacking protein C. Similar vascular defects appeared in mice in which Pros1 was conditionally deleted in vascular smooth muscle cells. Mutants in which Pros1 was deleted specifically in hepatocytes, which are thought to be the major source of ProS in the blood, were viable as adults and displayed less-severe coagulopathy without vascular dysgenesis. Finally, analysis of mutants in which Pros1 was deleted in endothelial cells indicated that these cells make a substantial contribution to circulating ProS. These results demonstrate that ProS is a pleiotropic anticoagulant with aPC-independent activities and highlight new roles for ProS in vascular development and homeostasis.

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“…2,3 Numerous studies have shown an association between protein S deficiency and an increased risk for thrombosis. [4][5][6][7][8][9] The importance of protein S in vivo has been confirmed in mouse models where mice die in utero of coagulopathy and hemorrhages after knocking out the gene-encoding protein S (PROS1). 10,11 Protein S is a 635-amino acid vitamin K-dependent glycoprotein.…”

Section: Introductionmentioning

confidence: 99%

Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue

Ahnström

Andersson

Canis

et al. 2011

Blood

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Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/ E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the -loop that mediates Ca 2؉ -dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is ␥-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca 2؉ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693) IntroductionProtein S is an anticoagulant plasma protein recognized as a member of the protein C anticoagulant pathway, in which it acts as a cofactor for activated protein C (APC). 1 Protein S mediates its APC cofactor activity by enhancing the inactivation of activated coagulation factors V (FVa) and VIII (FVIIIa). Protein S also inhibits thrombin generation independently of APC, which has recently been attributed to an enhancement of the activity of tissue factor pathway inhibitor (TFPI). 2,3 Numerous studies have shown an association between protein S deficiency and an increased risk for thrombosis. [4][5][6][7][8][9] The importance of protein S in vivo has been confirmed in mouse models where mice die in utero of coagulopathy and hemorrhages after knocking out the gene-encoding protein S (PROS1). 10,11 Protein S is a 635-amino acid vitamin K-dependent glycoprotein. It circulates in plasma at a concentration of 350nM, with approximately 60% being in complex with C4b-binding protein. 12 It has generally been accepted that only free protein S can mediate cofactor function for APC, 13,14 but this has recently been questioned by Maurissen et al who showed that the protein S-C4b-binding protein complex impairs APC-catalyzed proteolysis of FVa at Arg506, whereas it enhances the APC-catalyzed proteolysis at Arg306. 15 Protein S is divided into a number of structural domains composing an N-terminal vitamin K-dependent Gla domain, a thrombin-sensitive region (TSR), 4 epidermal growth factor (EGF)-like domains, and a region homologous to sex hormone binding globulin domain. 1,13 In vitamin K-dependent proteins, ␥-carboxylation of glutamic acid residues leadin...

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Protein S deficiency: a clinical perspective

Cited by 165 publications

References 39 publications

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis

Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue

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