PROTEIN C : ROUEN - A NEW HEREDITARY PROTEIN C ABNORMALITY WITH LOW ANTICOAGULANT BUT NORMAL AMIDOLYTIC ACTIVITIES

1987 ◽  
Author(s):  
J Y Borg ◽  
M Vasse ◽  
M Monconduit
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Protein S ◽  
Functional Assay ◽  
Type I ◽  
Functional Abnormality ◽  
Oral Anticoagulant Treatment ◽  
Crossed Immunoelectrophoresis ◽  
Deficiency Type ◽  
Hydrolysis Of

During the last three years, we could detect hereditary quantitative protein C (PC) deficiency in 43 patients belonging to 18 families. In those defects type I without oral anticoagulant treatment, the values of PC measured either by an ELISA method (PC:Ag) or by a chronometric functional assay were very closed and well correlated. (Results expressed in % of normal pooled plasmas PC:Ag m=44,l %, SD = 15,3 ; PC : activity m = 49,5, SD = 13,5 - correlation r = 0,82). In a 32 year#old man with a severe thrombo-embolic disease and in 11 related people, we could diagnose a hereditary qualitative PC deficiency type II, because of a discrepancy between normal PC:Ag levels (m = 105 %, SD = 20,3, range = 78-143) and low PC anticoagulant activities (m = 46 %, SD = 9,5, range = 30-60). FunctionalpC studies included assays, with or without preliminary adsorption on baryum citrate or aluminium hydroxide, with various PC activators (thrombin, PROTAC venom), in chronometric and amidolytic assays.(Normal protein S levelswere first tested).As shown by those results, PC activity is normal in amidolytic assays even after preliminary adsorption whatever the activation is. On the contrary, the PC anticoagulant activity is reduced in any technique. We can conclude that the activation is normal. Crossed immunoelectrophoresis (CIE) with or without calcium showed normal migration as compared to controls. Normal adsorption on insoluble salts and normal Ca-binding in CIE allow us to say that the abnormal PC is not completely acarboxylated. As amidolytic assays (normal in patients) do not assess the ability of activated PC to interact with protein S (PS) and phospholipids via calcium, 3 hypothesis can explain the functional abnormality:- abnormal binding to PS- abnormal binding to phospholipids due to partially carboxylated glutamic acids (which would be sufficient to promote adsorption)- defective inhibition of Va and Villa because a conformational change allowing only hydrolysis of little synthetic peptides.

Two Cases of Inherited Triple Deficiency in a Large Kindred with Thrombotic Diathesis and Deficiencies of Antithrombin III, Heparin Cofactor II, Protein C and Protein S

1991 ◽  
Vol 66 (03) ◽  
pp. 295-299 ◽  
Author(s):  
F Jobin ◽  
L Vu ◽  
M Lessard
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Large Family ◽  
Protein S ◽  
Type I ◽  
Heparin Cofactor Ii ◽  
First Case ◽  
Cofactor Activity ◽  
Deficiency Type

SummaryThirty-three subjects, belonging to a large family with functional antithrombin III (ATIII) deficiency (type IIa) and recurrent thromboembolism, were investigated for ATIII, heparin cofactor II (HCII), protein C (PC) and protein S (PS). We report the exceptional finding of two cases of triple deficiency: ATIII combined with HCII and PC in the first case aged 15 and ATIII combined with HCII and PS in the second case aged 27. Interestingly, both are asymptomatic thus far. Twenty-five other deficient members were found, among which seven are affected with a double deficiency. Totally, the results of our study show 38 deficiencies of four distinct antithrombotic protein: ATIII (n = 9), HCII (n = 9), PC (n = 7) or PS (n = 13). Two types of HCII deficiency were observed and type I PC deficiency was found. Functional PS deficiency was characterized by reduced levels of cofactor activity for activated PC. Our report demonstrates that combined deficiencies should be sought in a family already known to be deficient in one antithrombotic protein.

The Use of a Functional and Immunologic Assay for Plasma Protein C in the Study of the Heterogeneity of Congenital Protein C Deficiency

1984 ◽  
Vol 51 (01) ◽  
pp. 001-005 ◽  
Author(s):  
R M Bertina ◽  
A W Broekmans ◽  
C Krommenhoek-van Es ◽  
A van Wijngaarden
Keyword(s):  
Plasma Protein ◽  
Protein C ◽  
Functional Assay ◽  
Type I ◽  
Autosomal Dominant Disorder ◽  
Protein C Deficiency ◽  
Oral Anticoagulant Treatment ◽  
Congenital Deficiency ◽  
Congenital Protein C Deficiency ◽  
Protein C Activity

SummaryProtein C is a vitamin K dependent protein involved in blood coagulation. A congenital deficiency in protein C antigen - which inherits as an autosomal dominant disorder - has been reported to be associated with a high risk for thrombo-embolic disease at relatively young age. In the present paper we report on the development of a functional assay for plasma protein C. In this assay protein C is adsorbed to Al(OH)3, eluted and activated by thrombin, after which the concentration of the activated protein C is measured with a peptide substrate (S2366). Normal values for protein C activity and protein C antigen were determined in healthy volunteers and patients on stable oral anticoagulant treatment. Protein C activity and antigen levels were compared in 28 patients from 9 different pedigrees with both congenital protein C deficiency and thrombotic disease. Two types of protein C deficiency could be recognized: in type I the deficiency is due to the absence or reduced presence of protein C molecules, while in type II the deficiency is caused by the presence of an abnormal protein C molecule with strongly reduced functional activity.

STUDY OF A SPANISH FAMILY WITH INHERITED PROTEIN S DEFICIENCY

1987 ◽  
Author(s):  
J Fontcuberta ◽  
R M de los Inocentes ◽  
N Sala ◽  
M Borrell ◽  
J Félez
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Activated Protein C ◽  
Protein S ◽  
Hepatic Function ◽  
First Episode ◽  
Oral Anticoagulant Treatment ◽  
Free Protein ◽  
Spanish Family

Protein S (PS) is a plasma glycoprotein that serves as a cofactor for activated protein C (PC) anticoagulant activity. Inherited PS deficiency has been found to be associated to thrombotic disease in several families. In the present study, we report on a Spanish family with type II PS deficiency.The propositus is a 40 year-old male that was referred to our center for study after having suffered from multiples thrombotic events since he was 20 year-old. After his first episode of deep vein thrombosis (DVT) he had 4 recurrences, three of them complicated with pulmonary embolism. It should be remarked that one of the episodes occured while the patient was under oral anticoagulant treatment. The basic screening of haemostasis and hepatic function were normal for a patient that was being treated with oral anticoagulants. Functional and antigenic levels of antithrombin III, protein C and plasminogen were also normal. When total and free protein S levels (method of Comp et al.) were measured using both an electroimmunoassay and an ELISA assay ,almost indetectable levels of free protein S (between 0 and 10%) and very low levels (20%) of total plasma PS, were found. These results were also confirmed by crossed-electriimnunophoretic studies.When the family of this patient was studied it was found that his two sons, aged 15 and 8 years, as well as one of his sisters, aged 35 years, and her daughter of 4 years, were also affected (free PS levels between 38-60% and total PS between 35 and 39%). All these members had been assymptomatic up to now and are not under oral anticoagulants.

The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

1988 ◽  
Vol 59 (01) ◽  
pp. 018-022 ◽  
Author(s):  
C L Gladson ◽  
I Scharrer ◽  
V Hach ◽  
K H Beck ◽  
J H Griffin
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Young Patients ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Low Protein ◽  
S Deficiency

SummaryThe frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

A Novel Functional Assay of Protein C in Human Plasma and fts Comparison with Amidolytic and Anticoagulant Assays

1992 ◽  
Vol 67 (01) ◽  
pp. 046-049 ◽  
Author(s):  
H A Guglielmone ◽  
M A Vides
Keyword(s):  
Oral Anticoagulant ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Normal Subjects ◽  
Test Sample ◽  
Functional Assay ◽  
Fast Method ◽  
Factor Va ◽  
Protein C Activity

SummaryA simple and fast method for the quantitative determination of protein C activity in plasma is here described. The first step consists in the conversion of protein C in the test sample into activated protein C by means of an activator isolated from Southern Copperhead venom. Subsequently, the degradation of factor Va, in presence of protein C-deficient plasma, is measured by the prolongation of the prothrombin time which is proportional to the amount of protein C in the sample. The dose-response curve showed a linear relationship from 6 to 150% protein C activity and the inter- and intra-assay reproducibility was 3.5% and 5.6% respectively. In normal subjects, a mean of protein C level of 98 ± 15% of normal pooled plasma was found. Comparison with the anticoagulant assay in samples of patients with oral anticoagulant, liver cirrhosis, disseminated intravascular coagulation and severe preeclampsia revealed an excellent correlation (r = 0.94, p <0.001). Also, a similar correlation (r = 0.93, p <0.001) existed between amidolytic assay and the method here proposed for all the samples studied without including the oral anticoagulant group. These results allowed us to infer that this method evaluates the ability of protein C to interact with protein S, phospholipids, calcium ions and factor Va.

A Mutation in the Protein S Pseudogene Is Linked to Protein S Deficiency in a Thrombophilic Family

1989 ◽  
Vol 62 (03) ◽  
pp. 897-901 ◽  
Author(s):  
Hans K Ploos van Amstel ◽  
Pieter H Reitsma ◽  
Karly Hamulyák ◽  
Christine E M de Die-Smulders ◽  
Pier M Mannucci ◽  
...  
Keyword(s):  
Total Protein ◽  
Protein S ◽  
Southern Analysis ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
The Family ◽  
Dna Pattern ◽  
Deficiency Type ◽  
S Genes

SummaryProbands from 15 unrelated families with hereditary protein S deficiency type I, that is having a plasma total protein S concentration fifty percent of normal, were screened for abnormalities in their protein S genes by Southern analysis. Two probands were found to have a deviating DNA pattern with the restriction enzyme Mspl. In the two patients the alteration concerned the disappearance of a Mspl restriction site, CCGG, giving rise to an additional hybridizing Mspl fragment.Analysis of relatives of both probands showed that in one family the mutation does not co-segregate with the phenotype of reduced plasma protein S. In the family of the other proband, however, complete linkage between the mutated gene pattern and the reduced total protein S concentration was found: 12 heterozygous relatives showed the additional Mspl fragment but none of the investigated 26 normal members of the family. The mutation is shown to reside in the PSβ gene, the inactive protein S gene. The cause of type I protein S deficiency, a defect PSα gene has escaped detection by Southern analysis. No recombination has occurred between the PSα gene and the PSβ gene in 23 informative meioses. This suggests that the two protein S genes, located near the centromere of chromosome 3, are within 4 centiMorgan of each other.

Protein S mRNA in Patients with Protein S Deficiency

1995 ◽  
Vol 73 (05) ◽  
pp. 746-749 ◽  
Author(s):  
E Sacchi ◽  
M Pinotti ◽  
G Marchetti ◽  
G Merati ◽  
L Tagliabue ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Total Protein ◽  
Restriction Analysis ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Phenotypic Analysis ◽  
S Deficiency ◽  
Deficiency Type ◽  
S Genes

SummaryA protein S gene polymorphism, detectable by restriction analysis (BstXI) of amplified exonic sequences (exon 15), was studied in seven Italian families with protein S deficiency. In the 17 individuals heterozygous for the polymorphism the study was extended to platelet mRNA through reverse transcription, amplification and densitometric analysis. mRNA produced by the putative defective protein S genes was absent in three families and reduced to a different extent (as expressed by altered allelic ratios) in four families. The allelic ratios helped to distinguish total protein S deficiency (type I) from free protein S deficiency (type IIa) in families with equivocal phenotypes. This study indicates that the study of platelet mRNA, in association with phenotypic analysis based upon protein S assays in plasma, helps to classify patients with protein S deficiency.

The APC-independent anticoagulant activity of protein S in plasma is decreased by elevated prothrombin levels due to the prothrombin G20210A mutation

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1686-1692 ◽  
Author(s):  
Rory R. Koenen ◽  
Guido Tans ◽  
René van Oerle ◽  
Karly Hamulyák ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Healthy Population ◽  
Factor V ◽  
Thrombotic Risk ◽  
G20210a Mutation

AbstractProtein S exhibits anticoagulant activity independent of activated protein C (APC). An automated factor Xa–based one-stage clotting assay was developed that enables quantification of the APC-independent activity of protein S in plasma from the ratio of clotting times (protein S ratio [pSR]) determined in the absence and presence of neutralizing antibodies against protein S. The pSR was 1.62 ± 0.16 (mean ± SD) in a healthy population (n = 60), independent of plasma levels of factors V, VIII, IX, and X; protein C; and antithrombin, and not affected by the presence of factor V Leiden. The pSR strongly correlates with the plasma level of protein S and is modulated by the plasma prothrombin concentration. In a group of 16 heterozygous protein S–deficient patients, the observed mean pSR (1.31 ± 0.09) was significantly lower than the mean pSR of the healthy population, as was the pSR of plasma from carriers of the prothrombin G20210A mutation (1.47 ± 0.21; n = 46). We propose that the decreased APC-independent anticoagulant activity of protein S in plasma with elevated prothrombin levels may contribute to the thrombotic risk associated with the prothrombin G20210A mutation.

scholarly journals Protein C deficiency resulting from possible double heterozygosity and its response to danazol

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 370-374
Author(s):  
RA Gruppo ◽  
P Leimer ◽  
RB Francis ◽  
RA Marlar ◽  
E Silberstein
Keyword(s):  
Functional Activity ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Anticoagulation Therapy ◽  
Renal Vein Thrombosis ◽  
Type I ◽  
Amidolytic Activity ◽  
Protein C Deficiency ◽  
Protein Levels ◽  
Anticoagulant Function

A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function.

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

2012 ◽  
Vol 107 (03) ◽  
pp. 468-476 ◽  
Author(s):  
Ilze Dienava-Verdoold ◽  
Marina R. Marchetti ◽  
Liane C. J. te Boome ◽  
Laura Russo ◽  
Anna Falanga ◽  
...  
Keyword(s):  
Protein C ◽  
Normal Values ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Intact Protein ◽  
The Impact ◽  
Independent Protein

SummaryThe natural anticoagulant protein S contains a so-called thrombin-sensitive region (TSR), which is susceptible to proteolytic cleavage. We have previously shown that a platelet-associated protease is able to cleave protein S under physiological plasma conditions in vitro. The aim of the present study was to investigate the relation between platelet-associated protein S cleaving activity and in vivo protein S cleavage, and to evaluate the impact of in vivo protein S cleavage on its anticoagulant activity. Protein S cleavage in healthy subjects and in thrombocytopenic and thrombocythaemic patients was evaluated by immunological techniques. Concentration of cleaved and intact protein S was correlated to levels of activated protein C (APC)-dependent and APC-independent protein S anticoagulant activity. In plasma from healthy volunteers 25% of protein S is cleaved in the TSR. While in plasma there was a clear positive correlation between levels of intact protein S and both APC-dependent and APC-independent protein S anticoagulant activities, these correlations were absent for cleaved protein S. Protein S cleavage was significantly increased in patients with essential thrombocythaemia (ET) and significantly reduced in patients with chemotherapy-induced thrombocytopenia. In ET patients on cytoreductive therapy, both platelet count and protein S cleavage returned to normal values. Accordingly, platelet transfusion restored cleavage of protein S to normal values in patients with chemotherapy-induced thrombocytopenia. In conclusion, proteases from platelets seem to contribute to the presence of cleaved protein S in the circulation and may enhance the coagulation response in vivo by down regulating the anticoagulant activity of protein S.

Sign in / Sign up

Export Citation Format

Share Document