Plasma protein S deficiency in familial thrombotic disease

Schwarz, HP; Fischer, M; Hopmeier, P; Batard, MA; Griffin, JH

doi:10.1182/blood.v64.6.1297.bloodjournal6461297

Cited by 45 publications

(51 citation statements)

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“…The protein C/S pathway is therefore a potent source of naturally occurring anticoagulant activity. Inherited deficiency states of protein C and protein S are associated with an increased risk of venous thromboembolism (Griffin et al, 1981;Schwartz et al, 1984). In SS disease, protein C 73 .…”

Section: Discussionmentioning

confidence: 99%

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

et al. 1997

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Summary. The aim of this study was to confirm reports of low protein C (PC) and S (PS) concentrations in steady-state patients with homozygous sickle cell (SS) disease when compared to a racially matched normal haemoglobin (AA) control group and to examine the mechanisms of this reduction with respect to hepatic function, coagulation activation and haematological indices.In 36 SS patients and 35 AA race-matched controls PC (functional and immunoreactive), PS (free and total) were measured. C4B binding protein (C4B) was assessed by immunoelectrophoresis and D-dimer by ELISA. Hepatic function was assessed by prothrombin (PT) time (49 SS, 64 AA), factor V (34 SS, 36 AA) and factor VII concentrations (28 SS, 29 AA). Proteins induced in vitamin K absence or antagonism (PIVKA) were sought in 12 SS's. The relationship between PC, PS and total bilirubin, haemoglobin (Hb) F and reticulocyte count was also assessed.PC, PS and C4B were lower in SS disease. SS patients had longer PT times, and lower factor V and VII concentrations in comparison to AA controls. PC (functional and immunoreactive) and free PS correlated with PT. Within SS genotype PT correlated negatively with factor V and factor VII. Factor V and VII were positively correlated. PIVKAs were not detected. There was no correlation between PC, PS and Ddimer, haemolytic rate or Hb F concentration.Prolongation of PT time, low factor V and VII suggest that hepatic dysfunction, rather than coagulation activation or haemolytic rate, accounts for the reduced concentrations of PC and PS in steady-state SS disease. The absence of PIVKAs suggests a hepatocellular problem.

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Section: Discussionmentioning

confidence: 99%

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

et al. 1997

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“…type I and type III [25]. Similarly, the ratio of total PS and FII [33] or FX [5] has been proposed to detect PS deficiency in subjects receiving vitamin K-antagonist treatment, provided they have a stable level of anticoagulation.…”

Section: Laboratorymentioning

confidence: 99%

“…In 1984, the first clinical report on PS deficiency as a risk factor for venous thromboembolism (VTE) was published. Schwarz et al [5] described a family with VTE caused by hereditary PS deficiency. Now, 30 years after the first publication, still new functions are attributed to PS.…”

Section: Introductionmentioning

confidence: 99%

Protein S deficiency: a clinical perspective

2008

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Summary. Protein S (PS) is an extensively studied protein with an important function in the downregulation of thrombin generation. Because of the presence of a pseudogene and two different forms of PS in plasma, a bound and a free form, it is one of the most difficult thrombophilias to study. A deficiency of PS predisposes subjects to (recurrent) venous thromboembolism (VTE) and foetal loss. However, the conundrum of diagnosing PS deficiency has led to conflicting reports of PS as a risk factor for VTE. In this review, we aim to present a clinical perspective of PS deficiency.

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“…Vitamin K-dependent protein S (PS) is an anticoagulant plasma glycoprotein whose heterozygous deficiency is associated with increased risk of venous thrombosis and stroke (1,2), and whose homozygous deficiency can lead to life-threatening purpura fulminans at birth (3). PS is best known as a cofactor for activated protein C (APC) during proteolytic inactivation of procoagulant factor (F) Va and FVIIIa (4).…”

mentioning

confidence: 99%

Plasma protein S contains zinc essential for efficient activated protein C‐independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor

Heeb¹,

Prashun

Griffin³

et al. 2009

FASEB j.

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Protein S (PS) is a cofactor for activated protein C (APC), which inactivates coagulation factors (F) Va and VIIIa. Deficiency of protein C or PS is associated with risk of thrombosis. We found that PS also has APC-independent anticoagulant activity (PS-direct) and directly inhibits thrombin generated by FXa/FVa (prothrombinase complex). Here we report that PS contains Zn(2+) that is required for PS-direct and that is lost during certain purification procedures. Immunoaffinity-purified PS contained 1.4 +/- 0.6 Zn(2+)/mol, whereas MonoQ-purified and commercial PS contained 0.15 +/- 0.15 Zn(2+)/mol. This may explain the controversy regarding the validity of PS-direct. Zn(2+) content correlated positively with PS-direct in prothrombinase assays and clotting assays, but APC-cofactor activity of PS was independent of Zn(2+) content. PS-direct and Zn(2+) were restored to inactive PS under mildly denaturing conditions. Conversely, o-phenanthroline reversibly impaired the PS-direct of active PS. Zn(2+)-containing PS bound FXa more efficiently (K(d)(app)=9.3 nM) than Zn(2+)-deficient PS (K(d)(app)=110 nM). PS bound TFPI efficiently, independently of Zn(2+) content (K(d)(app)=21 nM). Antibodies that block PS-direct preferentially recognized Zn(2+)-containing PS, suggesting conformation differences at or near the interface of 2 laminin G-like domains near the PS C terminus. Thus, Zn(2+) is required for PS-direct and efficient FXa binding and may play a role in stabilizing PS conformation.

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Plasma protein S deficiency in familial thrombotic disease

Cited by 45 publications

References 0 publications

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

Protein S deficiency: a clinical perspective

Plasma protein S contains zinc essential for efficient activated protein C‐independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor

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