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

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.

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Protein S mRNA in Patients with Protein S Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653862 ◽

1995 ◽

Vol 73 (05) ◽

pp. 746-749 ◽

Cited By ~ 5

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.

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Characterization of a large chromosomal deletion in the PROS1 gene of a patient with protein S deficiency type I using long PCR

British Journal of Haematology ◽

10.1046/j.1365-2141.1996.403943.x ◽

1996 ◽

Vol 92 (4) ◽

pp. 986-991 ◽

Cited By ~ 7

Author(s):

Zandra R. Holmes ◽

Rogier M. Bertina ◽

Pieter H. Reitsma

Keyword(s):

Protein S ◽

Type I ◽

Chromosomal Deletion ◽

Protein S Deficiency ◽

Long Pcr ◽

S Deficiency ◽

Deficiency Type

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Protein S deficiency type I: identification of point mutations in 9 of 10 families

Blood ◽

10.1182/blood.v86.9.3444.bloodjournal8693444 ◽

1995 ◽

Vol 86 (9) ◽

pp. 3444-3451 ◽

Cited By ~ 25

Author(s):

S Mustafa ◽

I Pabinger ◽

C Mannhalter

Keyword(s):

Stop Codon ◽

Direct Sequencing ◽

Protein S ◽

Type I ◽

Missense Mutations ◽

Protein S Deficiency ◽

Site Mutation ◽

Frame Shift ◽

S Deficiency ◽

Deficiency Type

We identified potentially causative mutations in the active protein S gene (PROS 1) by direct sequencing of PROS 1-specific polymerase chain reaction (PRC) products of all 15 exons, including exon-intron boundaries in 10 families with hereditary protein S deficiency type I. Seven different mutations were found in 9 of 10 families, including one frame shift mutation, a previously published splice site mutation (both occurring in two unrelated families), four missense mutations, and a stop codon at the beginning of exon 12. In family studies, cosegregation of the mutation with the disease could be demonstrated for five mutations; for two missense mutations, this was not possible due to limited family data. All seven mutations were the only abnormalities identified in the respective index patients and were absent in 44 to 62 normal individuals. Therefore, they most likely represent the causal gene defects. For five mutations, analysis of ectopic RNA could be performed. Mutant transcripts were present in the case of the frame shift and three of the missense mutations, while no mutant RNA could be detected in the case of the stop codon.

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Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I.

Journal of Clinical Investigation ◽

10.1172/jci116997 ◽

1994 ◽

Vol 93 (2) ◽

pp. 486-492 ◽

Cited By ~ 34

Author(s):

P H Reitsma ◽

H K Ploos van Amstel ◽

R M Bertina

Keyword(s):

Protein S ◽

Type I ◽

Protein S Deficiency ◽

Novel Mutations ◽

S Deficiency ◽

Deficiency Type

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Identification of Eight Point Mutations in Protein S Deficiency Type I – Analysis of 15 Pedigrees

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653863 ◽

1995 ◽

Vol 73 (05) ◽

pp. 750-755 ◽

Cited By ~ 16

Author(s):

P H Reitsma ◽

E Gómez ◽

S R Poort ◽

R M Bertina

Keyword(s):

Direct Sequencing ◽

Molecular Genetic ◽

Point Mutations ◽

Protein S ◽

Type I ◽

Protein S Deficiency ◽

Genetic Abnormality ◽

Genetic Studies ◽

S Deficiency ◽

Deficiency Type

SummaryWe describe molecular genetic studies of 15 patients with protein S deficiency type I (i. e. reduced total protein S antigen). All the exons of the PROS 1 gene were analyzed both by PCR and direct sequencing in all 15 probands. This analysis led to the identification of point mutations affecting eight individuals. One of these mutations (codon -25, insertion of T) has been described previously in a Dutch pedigree. The other mutations are novel and all are located in exons that code for the protein S domain that is homologous to the steroid hormone binding globulins. They include two amino acid replacements (one individual with 340 Gly → Val, and two individuals with 467 → Val Gly), and four frameshift mutations due to either one bp deletions (in codon 261 deletion of T and in codon 267 deletion of G) or insertions (in codon 565 insertion T and after codon 578 insertion of C). Studies performed in six families (totalling 43 subjects) showed cosegregation of the genetic abnormality with reduced plasma protein S levels, and provided genetic evidence for a heterozygous protein S deficiency in 25 of them. The yield of mutations in this study (53%) confirms that the percentage of protein S deficient cases in which a point mutation is found remains low.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642558 ◽

1988 ◽

Vol 59 (01) ◽

pp. 018-022 ◽

Cited By ~ 139

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.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646544 ◽

1989 ◽

Vol 61 (01) ◽

pp. 144-147 ◽

Cited By ~ 47

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.

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Arterial Thrombosis and Protein S Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651049 ◽

1989 ◽

Vol 62 (03) ◽

pp. 1040-1040 ◽

Cited By ~ 26

Author(s):

P Sié ◽

B Boneu ◽

R Biermé ◽

M L Wiesel ◽

L Grunebaum ◽

...

Keyword(s):

Arterial Thrombosis ◽

Protein S ◽

Protein S Deficiency ◽

S Deficiency

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Isolated Protein S Deficiency - Cause of Recurrent Stent Thrombosis - A Case Report

Cardiovascular Journal ◽

10.3329/cardio.v6i2.18364 ◽

2014 ◽

Vol 6 (2) ◽

pp. 175-179

Author(s):

AK Choudhury ◽

M Khalequzzaman ◽

S Hasem ◽

M Akhtaruzzaman ◽

S Jannat

Keyword(s):

Case Report ◽

Stent Thrombosis ◽

Arterial Thrombosis ◽

Protein C ◽

Protein S ◽

Antiplatelet Agents ◽

Percutaneous Coronary Interventions ◽

Protein S Deficiency ◽

S Deficiency ◽

Percutaneous Coronary

Stent thrombosis (ST) is one of the major complications that occur in percutaneous coronary interventions (PCIs) with stents. Various factors have been attributed to the development of ST, and several strategies have been recommended for its management. Protein C or protein S deficiencies may uncommonly be responsible for coronary arterial thrombosis. We report a young woman with recurrent stent thrombosis due to the deficiency of protein S. After coronary stenting, stent thrombosis occurred two times despite aggressive medical therapy. This report suggests that the deficiency of protein C or S should be born in mind in a young patient with recurrent thrombotic events, and that anticoagulants in addition to antiplatelet agents considered in the presence of their deficiency DOI: http://dx.doi.org/10.3329/cardio.v6i2.18364 Cardiovasc. j. 2014; 6(2): 175-179

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