Acute intestinal infarction caused by initially unexplained splanchnic venous thromboses in a patient with protein C deficiency: A thought-provoking emergency case

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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Application of Two Neutral Mspl DNA Polymorphisms in the Analysis of Hereditary Protein C Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647293 ◽

1990 ◽

Vol 64 (02) ◽

pp. 239-244 ◽

Cited By ~ 8

Author(s):

P H Reitsma ◽

W te Lintel Hekkert ◽

E Koenhen ◽

P A van der Velden ◽

C F Allaart ◽

...

Keyword(s):

Protein C ◽

Stop Codon ◽

Normal Population ◽

Amino Acid Position ◽

Rare Allele ◽

Dna Polymorphisms ◽

Type I ◽

Protein C Deficiency ◽

Gene Deletions ◽

Allelic Frequencies

SummaryScreening of restriction erzyme digested DNA from normal and protein C deficient individuals with a variety of probes derived from the protein C locus has revealed the existence of two neutral MspI polymorphism. One polymorphism (MI), which is located ≈7 kb upstream of the protein C gene, has allelic frequencies of 69 and 31%, and was used to exclude extensive gene deletions as a likely cause of type I protein C deficiency in 50% of cases in a panel of 22 families. Furtherrnore, the same polymorphism has been used in 5 doubly affected individuals establishing compound heterozygosity in 3 of these.The second, intragenic, polymorphism (MII) has allelic frequencies of 99 and 1% in the normal population. The frequency of the rare allele of this RFLP was with 7% much higher in a panel of 22 Dutch families with protein C deficiency. Interestingly, in all three probands that were heterozygous for MII the rare allele of MII coincided with a point mutation that leads to a stop codon in amino acid position 306 of the protein C coding sequence. This mutation may account for 14% of the protein C deficient individuals in The Netherlands.

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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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Ectopic Transcript Analysis Indicates that Allelic Exclusion is an Important Cause of Type I Protein C Deficiency in Patients with Nonsense and Frameshift Mutations in the PROC Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650386 ◽

1996 ◽

Vol 75 (06) ◽

pp. 870-876 ◽

Cited By ~ 4

Author(s):

José Manuel Soria ◽

Lutz-Peter Berg ◽

Jordi Fontcuberta ◽

Vijay V Kakkar ◽

Xavier Estivill ◽

...

Keyword(s):

Splice Site ◽

Protein C ◽

Stop Codon ◽

Premature Stop Codon ◽

Allelic Exclusion ◽

Polymorphism Analysis ◽

Type I ◽

Protein C Deficiency ◽

Nonsense Mutations ◽

Stop Codons

SummaryNonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons

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Severe Homozygous Protein C Deficiency: Identification of a Splice Site Missense Mutation (184, Q → H) in Exon 7 of the Protein C Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648812 ◽

1994 ◽

Vol 72 (01) ◽

pp. 065-069 ◽

Cited By ~ 2

Author(s):

J M Soria ◽

D Brito ◽

J Barceló ◽

J Fontcuberta ◽

L Botero ◽

...

Keyword(s):

Missense Mutation ◽

Gene Product ◽

Splice Site ◽

Protein C ◽

Purpura Fulminans ◽

Single Strand Conformation Polymorphism ◽

Donor Splice Site ◽

Protein C Deficiency ◽

Donor Splice ◽

Newborn Child

SummarySingle strand conformation polymorphism (SSCP) analysis of exon 7 of the protein C gene has identified a novel splice site missense mutation (184, Q → H), in a newborn child with purpura fulminans and undetectable protein C levels. The mutation, seen in the homozygous state in the child and in the heterozygous state in her mother, was characterized and found to be a G to C nucleotide substitution at the -1 position of the donor splice site of intron 7 of the protein C gene, which changes histidine 184 for glutamine (184, Q → H). According to analysis of the normal and mutated sequences, this mutation should also abolish the function of the donor splice site of intron 7 of the protein C gene. Since such a mutation is compatible with the absence of gene product in plasma and since DNA sequencing of all protein C gene exons in this patient did not reveal any other mutation, we postulate that mutation 184, Q → H results in the absence of protein C gene product in plasma, which could be the cause of the severe phenotype observed in this patient.

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