Late-onset homozygous protein C deficiency

SummryHomozygosity for a novel D180G mutation in the protease domain of protein C, associated with plasma protein C activity and antigen levels of 8% of normal was identified in a thrombosis prone family. Transient expression of protein C in HK-293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein as compared with wild-type protein was reduced by 79% while the intracellular contents were similar. Computer analysis of the X-ray structure of activated protein C and of a theoretical model of the zymogen predicts that the mutation destabilises the molecule locally. Our results are compatible with a relatively unstable mutant molecule that could be trapped inside the cell and degraded. However, if secreted the mutant molecule could have a relatively normal catalytic activity and structure consistent with the plasma levels of protein C activity and the late onset of thrombosis.

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Problems of Oral Anticoagulation in an Adult with Homozygous Protein C Deficiency and Late Onset of Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651603 ◽

1993 ◽

Vol 69 (04) ◽

pp. 311-315 ◽

Cited By ~ 26

Author(s):

P Pescatore ◽

H M Horellou ◽

J Conard ◽

M Piffoux ◽

P Van Dreden ◽

...

Keyword(s):

Molecular Weight ◽

Oral Anticoagulation ◽

Skin Necrosis ◽

Protein C ◽

Low Molecular Weight Heparin ◽

Late Onset ◽

Low Molecular Weight ◽

Activity Levels ◽

Protein C Deficiency ◽

New Therapeutic Approaches

SummaryWe describe a 57-year-old woman with homozygous protein C deficiency and mild thrombotic manifestations consisting of three spontaneous distal deep vein thromboses occurring after the age of 45. Previous surgery and pregnancies had been uneventful. Low but detectable protein C antigen and activity levels (both 20%) were discovered on the occasion of skin necrosis induced by oral anticoagulation. This therapy was interrupted because of skin necrosis and several episodes of disseminated intravascular coagulation (DIC) at the initiation of treatment despite a cautious protocol. No recurrent thromboembolic event has occurred in our patient using prophylactic doses of low molecular weight heparin for 24 months. New therapeutic approaches might be the administration of low molecular weight heparin or oral anticoagulation associated with protein C replacement in the induction period. This case reflects the variability of expression of protein C deficiency as well as the potential hazards of antivitamin K anticoagulation in this disorder.

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Late Onset of Clinical Symptoms and Recurrent Ecchymotic Skin Lesions in a 12-Year-Old Girl With a Severe Double Heterozygous Protein C Deficiency

Journal of Pediatric Hematology/Oncology ◽

10.1097/00043426-200401000-00002 ◽

2004 ◽

Vol 26 (1) ◽

pp. 2-4 ◽

Cited By ~ 4

Author(s):

Mich??le Loop ◽

Alina Ferster ◽

Francis Corazza ◽

Martine Alhenc-Gelas ◽

Anne Demulder

Keyword(s):

Protein C ◽

Clinical Symptoms ◽

Late Onset ◽

Skin Lesions ◽

Protein C Deficiency ◽

Heterozygous Protein C Deficiency

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Homozygous protein C deficiency with late onset venous thrombosis: identification and in vitro expression study of a novel Pro275Ser mutation

Pathology ◽

10.1097/pat.0b013e328353a218 ◽

2012 ◽

Vol 44 (4) ◽

pp. 348-353 ◽

Cited By ~ 6

Author(s):

Tingting Yu ◽

Jing Dai ◽

Hongjing Liu ◽

Jian Wang ◽

Qiulan Ding ◽

...

Keyword(s):

Venous Thrombosis ◽

Protein C ◽

Late Onset ◽

Expression Study ◽

Protein C Deficiency ◽

In Vitro Expression

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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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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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