LOW TOTAL PROTEIN S ANTIGEN BUT HIGH PROTEIN S ACTIVITY DUE TO DECREASED C4b-BINDING PROTEIN (C4b-BP) LEVELS IN NEWBORNS

1987 ◽  
Author(s):  
H P Schwarz ◽  
W Muntean
Keyword(s):  
Vitamin K ◽  
Limit Of Detection ◽  
Polyclonal Antibodies ◽  
Regulatory Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Bleeding Risk ◽  
Free Form ◽  
Classical Complement Pathway ◽  
Coagulation Proteins

Vitamin K-dependent coagulation proteins are known to be decreased in the neonatal period. So far no data have been published on protein S (PS), the vitamin K-dependent cofactor for the antithrombotic enzyme, activated protein C (APC) in this period. We determined, therefore, PS antigen, PS activity and C4b-BP,a regulatory protein of the classical complement pathway to which PS is complexed, in 36 neonates. Total PS antigen in newborns was below the range associated with thromboembolism in patients congenitally deficient in this protein (22±9.6%, mean±SD). None of these infants had clinical or laboratory evidence of thromboembolism or DIC. In contrast to the PS antigen level PS activity measured by the ability of APC to prolong the clotting time of a modified APTT assay using PS-immunodep1eted plasma was significantly higher (77.6±14%, mean±SD, p< 0,001), suggesting a shift in PS to the free form. In fact two dimensional immunoe1ectrophoresis studies revealed the absence of protein S-C4b-BP complexes and only one precipitation indicating free PS was seen in 15 out of the 36 infants. In these 15 neonates C4b-BP was below the limit of detection by sensitive quantitative immunob1otting techniques using monoclonal or polyclonal antibodies. In the remaining 21 infants PS-C4b-BP complexes were detected, but in contrast to adult normal plasma approximately 80% of PS was found in the free form. Mixing experiments with normal human plasma and newborn’s plasma indicate that PS in neonate deficient of C4b-BP can bind normally to C4bp. Absence of C4b-BP did not correlate to gestational age. If an equilibrium distribution of PS between bound and free form regulates the cofactor activity of PS for the anticoagulant and profibrino 1ytic properties of APC in normal adults, our study demonstrates that the absence of PS-C4b-BP complexes in newborns and the presence of free PS only may contribute to the increased bleeding risk of premature infants.

scholarly journals Vitamin K-dependent protein S in Leydig cells of human testis

1994 ◽  
Vol 302 (3) ◽  
pp. 845-850 ◽  
Author(s):  
J Malm ◽  
X H He ◽  
A Bjartell ◽  
L Shen ◽  
P A Abrahamsson ◽  
...  
Keyword(s):  
Vitamin K ◽  
Leydig Cells ◽  
Regulatory Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Northern Blotting ◽  
Human Testis ◽  
Liver Protein ◽  
Local Synthesis ◽  
Dependent Protein

Protein S is an anticoagulant plasma protein, functioning as a cofactor to activated protein C in the regulation of blood coagulation. In addition, protein S forms a complex with the complement regulatory protein, C4b-binding protein. Protein S is unique among the vitamin K-dependent proteins in being structurally similar to androgen binding proteins. Protein S immunoreactivity was demonstrated in Leydig cells of human testis. In Northern blotting experiments, the presence of protein S mRNA in human testis tissue could be shown. In situ hybridization experiments localized protein S mRNA to the Leydig cells, demonstrating transcription of the protein S gene in these cells. Five protein S clones were isolated from a human testis cDNA library, partially sequenced and characterized by restriction enzyme mapping. Three unique clones contained information for the entire coding sequence and approximately two-thirds of the 5′ and 3′ non-coding sequences. The results indicate the nucleotide sequences of testis and liver protein S mRNA to be identical. No binding of androgens to protein S could be demonstrated. In conclusion, we demonstrate the presence of protein S immunoreactivity as well as protein S mRNA in the Leydig cells of human testis. These results suggest local synthesis of protein S in Leydig cells of human testis which may be functionally important for local anticoagulation.

Familial Dysfunction of Protein S

1989 ◽  
Vol 62 (02) ◽  
pp. 763-766 ◽  
Author(s):  
P M Mannucci ◽  
C Valsecchi ◽  
A Krachmalnicoff ◽  
E M Faioni ◽  
A Tripodi
Keyword(s):  
Protein C ◽  
Autosomal Dominant ◽  
Activated Protein C ◽  
Protein S ◽  
Free Form ◽  
Laboratory Abnormality ◽  
Vein Thrombosis ◽  
Autosomal Dominant Fashion ◽  
Low Levels ◽  
Deep Vein

SummaryWe describe a previously unreported defect of protein S characterized by low levels of cofactor activity for activated protein C contrasting with low normal levels of total and free protein S antigen. The distribution of protein S between the free form and the form complexed with the complement component C4b-binding protein was normal on two-dimensional immunoelectrophoresis. The proband developed juvenile deep-vein thrombosis while taking oral contraceptives. Her defect was transmitted in an autosomal dominant fashion from her asymptomatic mother. Other relatives carrying the same laboratory abnormality (mother, maternal uncle, two sisters and one brother) were also asymptomatic. We postulate that the defect is due to a dysfunctional protein S present in plasma in normal amounts and with normal proportions of the free and complexed forms of the protein.

Vitamin K–Dependent Protein S: Beyond the Protein C Pathway

2017 ◽  
Vol 44 (02) ◽  
pp. 176-184 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Vascular System ◽  
System Development ◽  
Regulatory Protein ◽  
Protein S ◽  
Receptor Interaction ◽  
Fetal Life ◽  
High Molecular Weight Complex ◽  
Increased Risk

AbstractProtein S is a vitamin K–dependent plasma glycoprotein circulating in plasma at a concentration of around 350 nM. Approximately 60% of protein S in human plasma is bound to the complement regulatory protein C4b-binding protein (C4BP) in a high-affinity, high-molecular-weight complex. Protein S in plasma has multiple anticoagulant properties and heterozygous protein S deficiency is associated with increased risk of venous thrombosis. Homozygous deficiency in man and mice is associated with severe thrombosis in fetal life, defects in the vascular system development, and not compatible with life. Protein S has additional functions beyond being an anticoagulant. It affects the complement regulatory properties of C4BP, and moreover, protein S interacts with tyrosine kinase receptors of the TAM family, which comprises Tyro3, Axl, and Mer. The TAM receptor interaction is important for the ability of protein S to stimulate phagocytosis of apoptotic cells. This review will discuss the multiple functions of protein S, describing its role as cofactor to activated protein C with a subsequent focus on the other functions of protein S.

scholarly journals Successful Pregnancy Outcome in a Patient with Protein S Deficiency: A Case Report

2017 ◽  
Vol 6 (2) ◽  
pp. 134-135
Author(s):  
Khaleda Khanam ◽  
Rehnuma Karim ◽  
Shakila Khanum
Keyword(s):  
Case Report ◽  
Pregnant Woman ◽  
Vitamin K ◽  
Fetal Loss ◽  
Protein S ◽  
Protein S Deficiency ◽  
Successful Pregnancy ◽  
S Deficiency ◽  
Coagulation Proteins ◽  
History Of

Protein S is a vitamin K-dependent anticoagulant and has a central role in the regulation of coagulation. The mechanism of action of protein S has been one of the least understood amongst the vitamin K-dependent coagulation proteins. A deficiency of protein S predisposes to recurrent thromboembolism and fetal loss. Here we report a case of protein S deficiency in a 28- year-old pregnant woman, who had a history of complete abortion at 22 of weeks of gestation and her 2nd pregnancy was managed properly with a successful fetal outcome.Birdem Med J 2016; 6(2): 134-135

scholarly journals Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 562-565
Author(s):  
HP Schwarz ◽  
W Muntean ◽  
H Watzke ◽  
B Richter ◽  
JH Griffin
Keyword(s):  
Vitamin K ◽  
Total Protein ◽  
Protein C ◽  
Binding Protein ◽  
Anticoagulant Activity ◽  
Active Form ◽  
Activated Protein C ◽  
Newborn Infants ◽  
Protein S ◽  
High Level

Protein S, a vitamin K-dependent cofactor for activated protein C, exists in normal adult plasma in a free anticoagulantly active form and in an inactive form complexed to C4b-binding protein. Immunologic and functional levels of protein S and C4b-binding protein in plasma were determined for 20 newborn infants and compared with adult normal pooled plasma. Total protein S antigen levels averaged 23%, similar to other vitamin K-dependent plasma proteins. However, the protein S anticoagulant activity was 74% of that of adult normal plasma. This apparent discrepancy of activity to antigen was shown to be due to low or undetectable levels of C4b-binding protein, which results in the presence of most if not all of protein S in its free and active form. The relatively high level of anticoagulantly active protein S in infants may enhance the potential of the protein C pathway, thereby minimizing risks of venous thrombosis in this group.

scholarly journals Biosynthesis and secretion of factor VII, protein C, protein S, and the Protein C inhibitor from a human hepatoma cell line

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 64-70
Author(s):  
DS Fair ◽  
RA Marlar
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Polyclonal Antibodies ◽  
Hepatoma Cell ◽  
Protein S ◽  
Factor Vii ◽  
Hepatoma Cell Line ◽  
Single Chain ◽  
Human Hepatoma Cell ◽  
Protein C Inhibitor

Using specific radioimmunoassays, 8 day cultures of Hep G2 cells were shown to contain in their supernatants 16, 74, and 828 ng/mL and in their cell lysates, 8, 55, and 48 ng/2 X 10(8) cells of factor VII, protein C, and protein S, respectively. These proteins and the protein C inhibitor were functionally active, and each of these activities was neutralized by their respective polyclonal antibodies. Although vitamin K had a modest effect, warfarin decreased the activity of secreted factor VII, protein C, and protein S by 50% to 90%. Protein C and protein S antigens were reduced three- to fourfold by warfarin. The protein C inhibitor antigen and activity were unaffected by vitamin K or warfarin treatment. Intrinsic labeling and immunoprecipitation indicated that factor VII, protein S, and the protein C inhibitor were secreted as 52,000, 77,000, and 58,000 molecular weight (mol wt) proteins, respectively. Protein C was secreted as a single-chain protein of about 65,000 mol wt, indicating that all of the vitamin K- dependent proteins are translated and secreted as single-chain molecules. Each of the four proteins studied represented their plasma protein counterparts structurally, functionally, and immunochemically. Thus, all of the known soluble components of the protein C pathway are produced by liver parenchymal cells.

scholarly journals Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 562-565 ◽  
Author(s):  
HP Schwarz ◽  
W Muntean ◽  
H Watzke ◽  
B Richter ◽  
JH Griffin
Keyword(s):  
Vitamin K ◽  
Total Protein ◽  
Protein C ◽  
Binding Protein ◽  
Anticoagulant Activity ◽  
Active Form ◽  
Activated Protein C ◽  
Newborn Infants ◽  
Protein S ◽  
High Level

Abstract Protein S, a vitamin K-dependent cofactor for activated protein C, exists in normal adult plasma in a free anticoagulantly active form and in an inactive form complexed to C4b-binding protein. Immunologic and functional levels of protein S and C4b-binding protein in plasma were determined for 20 newborn infants and compared with adult normal pooled plasma. Total protein S antigen levels averaged 23%, similar to other vitamin K-dependent plasma proteins. However, the protein S anticoagulant activity was 74% of that of adult normal plasma. This apparent discrepancy of activity to antigen was shown to be due to low or undetectable levels of C4b-binding protein, which results in the presence of most if not all of protein S in its free and active form. The relatively high level of anticoagulantly active protein S in infants may enhance the potential of the protein C pathway, thereby minimizing risks of venous thrombosis in this group.

scholarly journals The gene encoding vitamin K-dependent anticoagulant protein S is expressed in multiple rabbit organs as demonstrated by northern blotting, in situ hybridization, and immunohistochemistry.

1995 ◽  
Vol 43 (1) ◽  
pp. 85-96 ◽  
Author(s):  
X He ◽  
L Shen ◽  
A Bjartell ◽  
B Dahlbäck
Keyword(s):  
In Situ Hybridization ◽  
Epithelial Cells ◽  
Vitamin K ◽  
Pyramidal Neurons ◽  
Activated Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Northern Blotting ◽  
Specific Gene

Vitamin K-dependent protein S is an anticoagulant plasma protein that functions as a co-factor to activated protein C in the degradation of coagulation factors Va and VIIIa. We investigated the tissue/cellular distribution of protein S synthesis by Northern blotting, in situ hybridization, and immunohistochemistry. Northern blotting together with in situ hybridization, using specific oligodeoxynucleotide probes, demonstrated protein S mRNA in liver, lung, testis, epididymis, ovary, uterus, and brain. In the reproductive system, protein S mRNA was present in the cytoplasm of Leydig cells, interstitial cells of the ovary, epithelial cells of the epididymis, and in the endometrium, including endometrial mucous glandular membrane in the myometrium. Bronchial epithelial cells and alveolar macrophages were positive in the respiratory system. In the central nervous system, pyramidal neurons in the cerebral cortex and in the hippocampal region, and dentate fascia neurons gave strongly positive signals. Immunohistochemistry with monoclonal antibodies yielded a staining pattern that correlated well with results of in situ hybridization. In conclusion, results from Northern blotting, in situ hybridization, and immunohistochemistry suggested that rabbit protein S is expressed in several extrahepatic tissues. The presence of protein S transcripts in these fully differentiated cells suggests a cell type-specific gene expression which may be related to local anticoagulation or to other as yet unknown protein S functions.

scholarly journals Transition From Argatroban to Oral Anticoagulation With Phenprocoumon or Acenocoumarol: Effect on Coagulation Factor Testing

2008 ◽  
Vol 14 (3) ◽  
pp. 325-331 ◽  
Author(s):  
Jeanine M. Walenga ◽  
Amanda F. Drenth ◽  
Myttle Mayuga ◽  
Debra A. Hoppensteadt ◽  
Margaret Prechel ◽  
...  
Keyword(s):  
Vitamin K ◽  
Coagulation Factor ◽  
Protein S ◽  
Coagulation Factors ◽  
Vitamin K Antagonist ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Treatment Regimens ◽  
Coagulation Proteins ◽  
Dose Dependent

Treatment with the thrombin inhibitor argatroban is often followed by vitamin K-antagonist treatment. In this study, the behavior of coagulation factors measured under these treatment regimens is shown. Healthy subjects received infusions of 1.0, 2.0, or 3.0 µg/kg/hr argatroban before and during phenprocoumon or acenocoumarol dosing. Quantitation of factors II, VII, IX, and X by clot-based assays resulted in dose dependent, approximately 20%, lower than expected values in the presence of argatroban. On the contrary, values for the inhibitors, protein C and protein S, were higher. Cotherapy exaggerated the effect by vitamin K-antagonist alone. However, testing by immunologic and chromogenic assays did not show any effect by argatroban. Coupled with a lack of bleeding in the subjects, these data suggests that argatroban does not affect coagulation proteins and that the observations are only an assay artifact. Assay interferences must be considered when measuring coagulation proteins in patients receiving thrombin inhibitors.

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