Calciphylaxis in a haemodialysis patient: functional protein S deficiency?

Consecutive patients with a history of thrombo-embolic disease (n = 241, 109 males, 132 females, mean age 46 y), referred to the Coagulation Laboratory during an 18 month period, were analysed for defects in their coagulation and fibrinolytic systems. The diagnosis of thrombosis had been verified with phlebography and that of pulmonary embolus with scintigraphy or angiography. Retinal venous thrombosis was found in 15 of the patients. In 15 cases the thrombotic episodes occurred postoperatively, in 15 during pregnancy, in 12 during the postpartum period and in 20 during use of oral contraceptives. In the remaining cases no clinical riskfactors were identified.The concentration of protein C zymogen was measured with an immunoradiometric assay. Functional protein C was determined with a clotting inhibition assay. Protein C deficiency was found in 8 cases. Two of these had a functional protein C deficiency with normal zymogen levels. The concentration of total, as well as free (not in complex with C4b-binding protein), protein S was determined with a radioimmunoassay. Two cases of protein S deficiency were detected. Three patients with antithrombin III deficiency and two with plasminogen deficiency were found.The fibrinolytic activity after venous occlusion was analysed in 216 patients. Decreased levels were found in 32 %. The concentration of tissue plasminogen activator inhibitor (PAI) was measured in 110 patients and found to be increased in 65 % of the cases. In 99 patients both the fibrinolytic activity and the PAI concentration were measured. A combination of decreased fibrinolytic activity and increased levels of PAI was found in 44 cases. The concentration of tissue plasminogen activator antigen was decreased in 22 % of 105 cases analysed.Thus, in this material of patients with thrombo-embolic disease, abnormalities were found in 47 %. Defects in the fibrinolytic system were the most common findings. Protein C or protein S deficiency was diagnosed in less than 5 % of the cases.

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Familial protein S deficiency with a variant protein S molecule in plasma and platelets

Blood ◽

10.1182/blood.v74.1.213.213 ◽

1989 ◽

Vol 74 (1) ◽

pp. 213-221 ◽

Cited By ~ 20

Author(s):

HP Schwarz ◽

MJ Heeb ◽

R Lottenberg ◽

H Roberts ◽

JH Griffin

Keyword(s):

Gene Expression ◽

Family Member ◽

Anticoagulant Activity ◽

Oral Anticoagulants ◽

Protein S ◽

The Other ◽

Protein S Deficiency ◽

Functional Protein ◽

S Deficiency ◽

Variant Protein

Abstract A protein S deficient family presenting a variant protein S molecule in plasma and platelets is described. The propositus, age 20, and two brothers suffered from venous thrombotic disease. The propositus, the only family member studied while taking oral anticoagulants, had a protein S antigen (ag) level of 17% and undetectable activity. As demonstrated by immunoblotting both the propositus and one clinically affected brother (42% ag, 7% activity) presented variant protein S molecules of 65,000 molecular weight (mol wt) while the other clinically affected brother (64% ag, 11% activity) had only protein S with normal electrophoretic mobility of 70,000 mol wt. The mother had normal protein S levels (93% ag, 100% activity) but had both normal and variant protein S molecules and based on her functional protein S data a normal anticoagulant activity of the variant molecule is suggested. One asymptomatic but protein S deficient sister (68% ag, 9% activity) as well as the asymptomatic protein S deficient father (59% ag, 10% activity) had only protein S molecules of 70,000 mol wt. The variant protein S bound to C4b-binding protein in plasma, and differed from normal protein S in carbohydrate content. Platelets of each family member contained the same immunoblotting pattern of normal and variant protein S forms as found in plasma, consistent with the hypothesis that protein S gene expression involves codominant expression of two alleles that is similar in cells that control the synthesis of both platelet and plasma forms of protein S.

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Acquired functional protein s deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases

The American Journal of Medicine ◽

10.1016/s0002-9343(89)80698-9 ◽

1989 ◽

Vol 87 (2) ◽

pp. 207-210 ◽

Cited By ~ 67

Author(s):

Jan Moreb ◽

Craig S. Kitchens

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Cerebral Venous Thrombosis ◽

Skin Necrosis ◽

Protein S ◽

Protein S Deficiency ◽

Functional Protein ◽

S Deficiency ◽

Syndrome Report

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Combination of APC resistance and acquired protein S deficiency in a haemodialysis patient with recurrent A-V shunt thrombosis

Nephrology Dialysis Transplantation ◽

10.1093/ndt/14.10.2474 ◽

1999 ◽

Vol 14 (10) ◽

pp. 2474-2477 ◽

Cited By ~ 3

Author(s):

Ivaylo Mitsiev ◽

Simone Reinhold ◽

Sabine Ziemer ◽

Hans-H. Neumayer ◽

Berthold Hocher

Keyword(s):

Haemodialysis Patient ◽

Protein S ◽

Protein S Deficiency ◽

Shunt Thrombosis ◽

Apc Resistance ◽

S Deficiency

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Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency

Blood ◽

10.1182/blood-2002-03-0909 ◽

2002 ◽

Vol 100 (8) ◽

pp. 2812-2819 ◽

Cited By ~ 16

Author(s):

Suely M. Rezende ◽

David A. Lane ◽

Blandine Mille-Baker ◽

Michel M. Samama ◽

Jacqueline Conard ◽

...

Keyword(s):

Molecular Model ◽

Protein S ◽

Activity Levels ◽

Missense Mutations ◽

Protein S Deficiency ◽

Functional Protein ◽

Anionic Phospholipid ◽

S Deficiency ◽

Functional Defect ◽

Gla Domain

We have identified 2 PROS1 missense mutations in the exon that encodes the vitamin K–dependent Gla domain of protein S (Gly11Asp and Thr37Met) in kindred with phenotypic protein S deficiency and thrombosis. In studies using recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor Va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (P < .001) and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (P < .0001) and decreased affinity for an antibody specific for the Ca2+-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only a modest 1.5-fold (P < .001), reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterization of natural protein S Gla-domain variants highlights the importance of the high affinity protein S–phospholipid interaction for its anticoagulant role.

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