Biomedical subjects

Kristin M Seré

Publications and source records attributed to Kristin M Seré.

4 recordsLinked to original sources

PubMed2006

Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor.

Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer. In this article we uncover a mechanism in which protein S, which is well known as the cofactor of activated protein C, specifically inhibits TF activity by promoting the interaction between full-length TF pathway inhibitor (TFPI) and factor Xa (FXa). The stimulatory effect of protein S on FXa inhibition by TFPI is caused by a 10-fold reduction of the K(i) of the FXa/TFPI complex, which decreased from 4.4 nM in the absence of protein S to 0.5 nM in the presence of protein S. This decrease in K(i) not only results in an acceleration of the feedback inhibition of the TF-mediated coagulation pathway, but it also brings the TFPI concentration necessary for effective FXa inhibition well within range of the concentration of TFPI in plasma. This mechanism changes the concept of regulation of TF-induced thrombin formation in plasma and demonstrates that protein S and TFPI act in concert in the inhibition of TF activity. Our data suggest that protein S deficiency not only increases the risk of thrombosis by impairing the protein C system but also by reducing the ability of TFPI to down-regulate the extrinsic coagulation pathway.

Factor VIIa↗

PubMed2006

Protein S multimers are generated in vitro and affect protein S structure-function analyses.

Purified human protein S preparations contain small amounts of multimeric protein S. Protein S multimers are absent in plasma, suggesting that multimerization results from purification. Protein S multimers effectively inhibit phospholipid-dependent reactions at low phospholipid concentrations, and may therefore interfere during functional analysis of protein S. We have demonstrated that anion-exchange chromatography, as well as high ionic strength or low pH elution conditions used in immunoaffinity purification of protein S, induce protein S multimer formation. When protein S multimers were removed from protein S preparations by size-exclusion chromatography, multimers spontaneously reappeared in the protein S monomer fraction. In model systems, high phospholipid concentrations (>50 micromol/L) completely abrogate the inhibitory effect of protein S multimers on prothrombinase complex activity. In addition, C4BP does not bind to protein S multimers. Thus, at low phospholipid concentrations, addition of C4BP to purified protein S will not affect the inhibitory activity of protein S multimers. In conclusion, to avoid misinterpretations during protein S structure-function analysis due to multimers present in purified protein S preparations, we recommend studying the anticoagulant activities of protein S either in plasma, where protein S is in its unmodified natural form, or at high phospholipid concentrations in model systems with purified proteins.

Complement C4b-Binding Protein↗

PubMed2004

Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the hemostatic balance.

The activated protein C (APC)-independent anticoagulant activity of protein S on tissue factor-induced thrombin generation was quantified in plasma. In absence of APC, protein S significantly decreased the endogenous thrombin potential (ETP) in a concentration-dependent manner. The APC-independent anticoagulant activity of protein S in plasma was not affected by phospholipid concentrations but strongly depended on tissue factor concentrations: protein S inhibited the ETP from 6% at 140 pM tissue factor to 74% at 1.4 pM tissue factor. Plasma with both 60% protein S and 140% prothrombin showed an ETP of 240% compared to normal plasma, suggesting an APC-independent protective role of protein S in the development of thrombosis as a result of protein S deficiency and the prothrombin-G20210A mutation. At high tissue-factor concentrations, protein S hardly expressed APC-independent anticoagulant activity but exerted potent APC-cofactor activity when thrombomodulin or APC were added to plasma. Neutralization of protein S under these conditions resulted in a 20-fold reduction of the anticoagulant activity of APC. The present study shows that protein S effectively regulates coagulation at 2 levels: at low procoagulant stimuli, protein S maintains the hemostatic balance by directly inhibiting thrombin formation, and at high procoagulant stimuli, protein S restores the hemostatic balance via its APC-cofactor activity.

Adult↗

PubMed2003

Basic mechanisms of hemostasis.

Hemostasis governs two essential processes of human life in that it maintains the fluidity of blood under physiological conditions and prevents excessive blood loss after injury. Hemostasis is regulated by components of the vessel wall and blood cells and by humoral coagulation factors. Under normal conditions, these components are involved in an active equilibrium through activation, propagation, and termination of the hemostatic pathways. This equilibrium is disturbed upon vascular injury, leading to a procoagulant response when needed. Unfortunately, pathological disturbances can occur as a result of inherited or acquired coagulation factor deficiencies that may lead to bleeding or thrombotic disorders.

Anticoagulants↗