scholarly journals Plasma protein S deficiency in familial thrombotic disease

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1297-1300 ◽  
Author(s):  
HP Schwarz ◽  
M Fischer ◽  
P Hopmeier ◽  
MA Batard ◽  
JH Griffin
Keyword(s):  
Plasma Protein ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulant Therapy ◽  
Activated Protein C ◽  
Protein S ◽  
Factor X ◽  
Protein C Deficiency ◽  
Thrombotic Disease ◽  
Disease Protein

Abstract A family with a history of severe recurrent venous thromboembolic disease was studied to determine if a plasma protein deficiency could account for observed disease. Protein S levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his mother, his aunt, and his cousin who were clinically affected had 17% to 65% of the control levels of protein S antigen (normal range, 71% to 147%). Since three of these patients were receiving oral anticoagulant therapy, the ratios of protein S to prothrombin, factor X, and protein C in these patients were compared with values for a group of orally anticoagulated controls. These results suggested that protein S is half-normal in all family members with thrombotic disease. Other proteins known to be associated with familial thrombotic disease, including antithrombin III, plasminogen, fibrinogen, and protein C, were normal. Because plasma protein S serves as a cofactor for the anticoagulant activity of activated protein C and because protein C deficiency is associated with recurrent thrombotic disease, it is suggested that recurrent thrombotic disease in this family is the result of an inherited deficiency of protein S.

scholarly journals Plasma protein S deficiency in familial thrombotic disease

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1297-1300 ◽  
Author(s):  
HP Schwarz ◽  
M Fischer ◽  
P Hopmeier ◽  
MA Batard ◽  
JH Griffin
Keyword(s):  
Plasma Protein ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulant Therapy ◽  
Activated Protein C ◽  
Protein S ◽  
Factor X ◽  
Protein C Deficiency ◽  
Thrombotic Disease ◽  
Disease Protein

A family with a history of severe recurrent venous thromboembolic disease was studied to determine if a plasma protein deficiency could account for observed disease. Protein S levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his mother, his aunt, and his cousin who were clinically affected had 17% to 65% of the control levels of protein S antigen (normal range, 71% to 147%). Since three of these patients were receiving oral anticoagulant therapy, the ratios of protein S to prothrombin, factor X, and protein C in these patients were compared with values for a group of orally anticoagulated controls. These results suggested that protein S is half-normal in all family members with thrombotic disease. Other proteins known to be associated with familial thrombotic disease, including antithrombin III, plasminogen, fibrinogen, and protein C, were normal. Because plasma protein S serves as a cofactor for the anticoagulant activity of activated protein C and because protein C deficiency is associated with recurrent thrombotic disease, it is suggested that recurrent thrombotic disease in this family is the result of an inherited deficiency of protein S.

Protein S Released From Stimulated Platelets Has Anticoagulant Activity Independent of Activated Protein C and Tissue Factor Pathway Inhibitor (TFPI).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1137-1137
Author(s):  
Mary J. Heeb ◽  
Erning Duan
Keyword(s):  
Plasma Protein ◽  
Neutralizing Antibodies ◽  
Protein C ◽  
Thrombin Generation ◽  
Conflicts Of Interest ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Platelet Protein ◽  
Presence And Absence

Abstract Abstract 1137 Background: Platelets contain in their alpha granules ∼2.5% of the protein S in blood. It has been suggested that this protein S supports the anticoagulant activity of exogenous activated protein C (APC), but it is not known whether protein S that is released from stimulated platelets can exert anticoagulant activity that is independent of APC and TFPI. We recently showed that at least some of the anticoagulant activity of plasma protein S is independent of APC and TFPI, although data suggested that plasma protein S may also have TFPI-dependent activity. Objective and methods: To determine if platelet protein S has anticoagulant activity that is independent of APC and TFPI, prothrombinase and extrinsic FXase reactions were initiated on the surface of fresh stimulated or unstimulated washed platelets in the presence and absence of blocking antibodies against APC, TFPI, and/or protein S, or in the presence and absence of purified plasma-derived protein S. Platelets were adjusted to a concentration of 0.7 to 2 × 10e8/ml, which contained 2.3–6.5 nM total platelet protein S. The last platelet wash contained negligible amounts of plasma protein S. Results: Neutralizing anti-protein S antibodies allowed up to 5.7-fold (mean: 2.1 ± 1.5 –fold, n=13) more thrombin generation on calcium ionophore-stimulated platelets following supplementation with 50–500 pM FXa and 600 nM prothrombin, and allowed up to 2.5-fold (mean: 1.7 ± 0.7 –fold, n=11) more thrombin generation on platelets that were not ionophore-stimulated but were gradually stimulated following FXa and prothrombin supplementation. Anti-protein S antibodies had no effect on thrombin generation on platelets that were treated with prostaglandin E1 (PGE1) to suppress platelet activation and then supplemented with procoagulants. This implies that platelet protein S is released from stimulated platelets and downregulates thrombin generation on platelets, and that neutralizing anti-protein S antibodies block this activity of protein S. Anti-protein S antibodies allowed up to 1.8-fold (mean 1.5 ± 0.2 –fold, n=8) more FXa generation on the surface of stimulated platelets supplemented with 5 pM TF, 100 pM FVIIa, and 160 nM FX, but anti-protein S antibodies had no effect on FXa generation on platelets treated with PGE1. Most of these experiments were performed in the presence of neutralizing antibodies against TFPI and APC, but thrombin and FXa generation on platelets under the varying conditions described were unaffected by the presence of these neutralizing antibodies. Purified plasma-derived zinc-containing protein S downregulated thrombin and FXa generation on platelets (IC50 = 6–18 nM PS) and in plasma >10-fold more potently than zinc-deficient protein S. We could not demonstrate a synergistic anticoagulant effect when TFPI was combined with zinc-deficient protein S in the presence of stimulated platelets and procoagulant proteins. Conclusion: Protein S that is released from stimulated platelets exerts anticoagulant activity that is independent of TFPI and APC. Disclosures: No relevant conflicts of interest to declare.

Defects in the protein C pathway

1987 ◽  
Author(s):  
P C Comp ◽  
C T Esmon
Keyword(s):  
Plasminogen Activator ◽  
Plasma Protein ◽  
Skin Necrosis ◽  
Protein C ◽  
Binding Protein ◽  
Active Form ◽  
Activated Protein C ◽  
Protein S ◽  
Receptor Protein ◽  
Protein C Deficiency

Activated protein C functions as an anticoagulant by enzymatically degrading factors Va and Villa in the clotting cascade. Protein C may be converted to its enzymatically active form bythrombin. The rate at which thrombin cleavage of the zymogen occurs is greatly enhanced when thrombin is bound to an endothelial cell receptor protein, thrombomodulin. Activated proteinC has a relatively long half-life in vivo and the formation of activated protein C in response to low level thrombin infusion suggests that the protein C system may provide a feedback mechanism to limit blood clotting. Clinical support for such a physiologic role for activated protein C includes an increased incidence of thrombophlebitis and pulmonary emboli in heterozygous deficient individuals, and severe, often fatal, cutaneous thrombosis in homozygous deficient newborns. A third thrombotic condition associated with protein C deficiency is coumarin induced skin (tissue) necrosis. This localized skin necrosis occurs shortly after the initiation of coumarin therapy and is hypothesized to bedue to the rapid disappearance of protein C activity in the plasma beforean adequate intensity of anticoagulation is achieved. Recent estimates of heterozygous protein C deficiency range as high as 1 in 300 individuals in the general population. Since coumarin compounds are in routine clinical use throughout the world and skin necrosis remains a relatively rare clinical finding, this suggests that factors other than protein C deficiency alone may be involved in the pathogenesis of the skin necrosis.The anticoagulant properties of activated protein C are greatly enhanced by another vitamin K-dependent plasma protein, protein S. Protein S functions by increasing the affinity of activated protein C for cell surfaces.Protein S is found in two forms in plasma: free and in complex with C4b-binding protein, "an inhibitor of the complement system. Free protein S is functionally active and the complexed protein S is not active. Individuals congenitally deficient in protein S ae subject to recurrent thromboembolicevents. At least two classes of protin S deficiency occur.Some patienshavedecreased levels of protein S antigen and reduced protein S functional activity. A second group of deficient individuals have normal levels of protein S antigen but most or all their protein S is complexed to C4b-binding protein and they have little or no functional protein S activity. Such a protein S distribution could result from abnormal forms of protein S or C4b-binding protein or some other abnormal plasma or cellular component. Patients with functionally inactive forms of protein S have yet to be identified. Identification of protein S deficient individuals is complicated by thepossible effect of sex hormones on plasma protein S levels. Total protein S antigen is reduced during pregnancyand during oral contraceptive administration. This finding is of practicalclinical importance since the decrease in protein S which occurs during pregnancy may be an added risk factor for congenitally protein S deficient women and may explain why some proteinS deficient women experience their first episode of thrombosis during pregnancy.In addition to having anticoagulant properties, activated protein C enhances fibrinolysis, at least in part,by inhibiting the inhibitor of tissueplasminogen activator. This profibrinolytic effect is enhanced by protein S and cell surfaces. This protection of plasminogen activator activity suggests that the combination of tissue plasminogen activator and activated protein C may be useful in the treatment of coronary artery thrombi. Tissueplasminogen activator would promote clot lysis while activated protein C protected the plasminogen activatorfrom inhibition and also prevented further clot deposition. There is no evidence at present that fibrinolytic activity is reduced in protein C deficient individuals. The possible clinical relevance of this aspect of protein Cfunction in the predisposition of protein C deficient individuals to thrombosis remains to be defined.

Treatment of Hereditary Protein C Deficiency with Stanozolol

1987 ◽  
Vol 57 (01) ◽  
pp. 020-024 ◽  
Author(s):  
A W Broekmans ◽  
J Conard ◽  
R G van Weyenberg ◽  
M H Horellou ◽  
C Kluft ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Protein C ◽  
Protein S ◽  
Fold Increase ◽  
Factor Ix ◽  
Factor Vii ◽  
Type I ◽  
Factor V ◽  
Factor X ◽  
Protein C Deficiency

SummaryFive type I protein C deficient male patients received 5 mg stanozolol b.i.d. during 4 weeks. After four weeks of treatment plasma protein C activity increased from 0.42 to 0.74 U/ml and protein C antigen from 0.49 to 0.75 U/ml. This approximately 1.6 fold increase in plasma protein C was accompanied by an increase in factor II antigen (1.5 fold), factor V activity (1.6 fold), factor X antigen (1.1 fold), antithrombin III antigen (1.3 fold) and heparin cofactor II antigen (1.5 fold), while the concentration of factor VII, factor VIII, and factor IX activity, and of protein S antigen remained unchanged. Prothrombin fragment F1+2, measured in two patients, increased 1.3 fold. In addition to its effect on procoagulant and anticoagulant factors stanozolol had profibrinolytic effects, reflected in an increase in tPA activity and in the concentration of plasminogen. These data indicate that in type I protein C deficient patients stanozolol increases the concentrations of both procoagulant and anticoagulant factors and favours fibrinolysis. The efficacy of stanozolol in preventing thrombotic disease in type I protein C deficient patients, however, remains to be established. During the four weeks of stanozolol treatment no thrombotic manifestations were observed in the protein C deficient patients.

Severe Protein S Deficiency in a Newborn

PEDIATRICS ◽  
1992 ◽  
Vol 89 (4) ◽  
pp. 674-676
Author(s):  
CHARLES H. PEGELOW ◽  
MARUIES LEDFORD ◽  
JONELL YOUNG ◽  
GASTON ZILLERUELO
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Purpura Fulminans ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Newborn Period ◽  
Thrombotic Disease ◽  
S Deficiency

Protein S is a vitamin K-dependent glycoprotein which acts as a cofactor for the anticoagulant activity of protein C.1,2 With production under autosomal control, heterozygotes produce half-normal levels and thrombotic disease may develop.3-6 Although thromboses occur primarily in adults, there are isolated reports of their occurrence in affected children.7-13 Severe protein C deficiency results in a syndrome in which affected children develop multiple thromboses in the newborn period.14 A recent report described a child with homozygous protein S deficiency who presented with neonatal purpura fulminans and other thromboses similar to those found in protein C deficiency.15,16 In this report, we

A Plasma Coagulation Assay for an Activated Protein C-independent Anticoagulant Activity of Protein S

1998 ◽  
Vol 80 (12) ◽  
pp. 930-935 ◽  
Author(s):  
Cornelis van ’t Veer ◽  
Joost Meijers ◽  
Rogier Bertina ◽  
Merel van Wijnen ◽  
Bonno Bouma
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulant Therapy ◽  
Activated Protein C ◽  
Protein S ◽  
Laboratory Diagnosis ◽  
Clotting Time ◽  
Functional Protein ◽  
Physiological Importance ◽  
The Mean

SummaryTo study the physiological importance of the activated protein C (APC)-independent anticoagulant activity of protein S, we developed an assay specific for this activity. The ability of protein S to prolong the clotting time in an APC-independent way was expressed as the ratio of the clotting time in a plasma sample divided by the clotting time in the presence of a polyclonal antibody against human protein S (both after 1:1 dilution in protein S-C4BP deficient plasma). The mean protein S-dependent anticoagulant ratio (PSdAR) was 1.53 ± 0.18 in 34 healthy controls, and was significantly lower in 16 heterozygous protein S deficient patients (PSdAR = 1.15 ± 0.09). In plasmas from patients under oral anticoagulant therapy the mean PSdAR was within the range of the control population (1.50 ± 0.18). The mean total protein S antigen level in these plasmas was 58%, suggesting a higher specific APC-independent anticoagulant activity of protein S in these patients than in normals.This functional protein S assay can be used for the laboratory diagnosis of protein S deficiency, and to study the mechanism of the APC-independent anticoagulant activity in plasma.

Oral anticoagulation reduces activated protein C less than protein C and other vitamin K–dependent clotting factors

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4232-4233 ◽  
Author(s):  
Marleen J. A. Simmelink ◽  
Philip G. de Groot ◽  
Ronald H. W. M. Derksen ◽  
José A. Fernández ◽  
John H. Griffin
Keyword(s):  
Anticoagulant Therapy ◽  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulant Therapy ◽  
Activated Protein C ◽  
Clotting Factor ◽  
Factor X ◽  
Clotting Factors

Oral anticoagulant therapy, which is used for prophylaxis and management of thrombotic disorders, causes similar reductions in plasma levels of vitamin K–dependent procoagulant and anticoagulant clotting factor zymogens. When we measured levels of circulating activated protein C, a physiologically important anticoagulant and anti-inflammatory agent, in patients on oral anticoagulant therapy, the results unexpectedly showed that such therapy decreases levels of activated protein C substantially less than levels of protein C, prothrombin, and factor X, especially at lower levels of prothrombin and factor X. Thus, we suggest that oral anticoagulant therapy results in a relatively increased expression of the protein C pathway compared with procoagulant pathways not only because there is less prothrombin to inhibit activated protein C anticoagulant activity, but also because there is a disproportionately higher level of circulating activated protein C.

The Anticoagulant Properties of a Modified Form of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 298-304 ◽  
Author(s):  
C A Mitchell ◽  
S M Kelemen ◽  
H H Salem
Keyword(s):  
Monoclonal Antibody ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Factor Xa ◽  
Protein S ◽  
Human Neutrophil Elastase ◽  
Factor X ◽  
Sds Page

SummaryProtein S (PS) is a vitamin K-dependent anticoagulant that acts as a cofactor to activated protein C (APC). To date PS has not been shown to possess anticoagulant activity in the absence of APC.In this study, we have developed monoclonal antibody to protein S and used to purify the protein to homogeneity from plasma. Affinity purified protein S (PSM), although identical to the conventionally purified protein as judged by SDS-PAGE, had significant anticoagulant activity in the absence of APC when measured in a factor Xa recalcification time. Using SDS-PAGE we have demonstrated that prothrombin cleavage by factor X awas inhibited in the presence of PSM. Kinetic analysis of the reaction revealed that PSM competitively inhibited factor X amediated cleavage of prothrombin. PS preincubated with the monoclonal antibody, acquired similar anticoagulant properties. These results suggest that the interaction of the monoclonal antibody with PS results in an alteration in the protein exposing sites that mediate the observed anticoagulant effect. Support that the protein was altered was derived from the observation that PSM was eight fold more sensitive to cleavage by thrombin and human neutrophil elastase than conventionally purified protein S.These observations suggest that PS can be modified in vitro to a protein with APC-independent anticoagulant activity and raise the possibility that a similar alteration could occur in vivo through the binding protein S to a cellular or plasma protein.

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.

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