Protein S as Cofactor for TFPI

Abstract

Abstract-In the last decades evidence was obtained that protein S not only acts as cofactor of activated protein C (APC) in the downregulation of coagulation, but also expresses anticoagulant activity in the absence of APC. The search for the mechanism(s) underlying the APC-independent anticoagulant activity of protein S was hampered by the fact that protein S exhibited 2 seemingly identical anticoagulant activities in model systems and in plasma. Later it was shown that the anticoagulant activity of purified protein S in model systems was dependent on the concentration of phospholipid vesicles and was explained by low amounts of protein S multimers generated during purification that effectively inhibited phospholipid-dependent coagulation reactions via competition for phospholipid binding sites. Plasma does not contain multimers, and the anticoagulant activity of protein S in plasma was not affected by the phospholipid concentration but was dependent on the amount of tissue factor (TF) used for initiation of thrombin generation. This led to the discovery that protein S acts as cofactor of tissue factor pathway inhibitor (TFPI) which stimulates the inhibition of factor Xa by TFPI Ϸ10-fold. The current review describes the background of the TFPI-cofactor activity of protein S as well as the rationale for the observation that the TFPI/protein S system particularly inhibits the TF pathway at low procoagulant stimuli. . It is well known that protein S acts as a cofactor of activated protein C (APC) in the proteolytic inactivation of blood coagulation factors Va and VIIIa, thus providing a negative feedback on coagulation and making the APC/protein S pathway essential for normal hemostasis. [2][3][4][5] Homozygous deficiencies in either protein C or protein S result in severe neonatal procoagulant phenotypes, whereas heterozygous deficiencies are associated with a 10-fold increased risk of venous thrombosis. 6 -8 More recently it has been shown that protein S also effectively inhibits thrombin generation in plasma in the absence of APC. 9 This anticoagulant property of protein S was especially observed at low TF concentrations (Ϸ1 pmol/L) leading to the concept that protein S took part in regulating the initiation phase of coagulation and effectively counteracts ongoing procoagulant processes in the circulation. 10 Interestingly, protein S had no effect on thrombin generation when coagulation was initiated through the intrinsic route, regardless of the amount of trigger used. 5 Because of the dependence of the anticoagulant activity of protein S on the TF concentration, a new role of protein S was identified as a cofactor for TFPI in the inhibition of FXa. 11 In contrast to investigations in plasma, many studies were performed in model systems using purified protein S preparations that also led to reports about APC-independent anticoagulant properties of protein S. [12][13][14][15][16] Although the anticoagulant activities in plasma and in model systems containing purified proteins initially looked mechanistic...

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

“…Protein S is a cofactor to TFPIα in the inactivation of FXa on the surface of negatively charged phospholipid vesicles and as TFPIα/FXa efficiently inhibits TF/FVIIa, protein S indirectly stimulates inhibition of TF/FVIIa 15, 18, 20, 34, 35. There is no consensus regarding the question whether protein S directly stimulates inhibition of TF/FVIIa.…”

Molecular basis of protein S deficiency in China

“…The physiological requirement for ProS became evident from the clinical association between partial ProS deficiency (PSD) and venous thrombosis in patients with a familial history of thrombosis [6], and the observation that homozygous protein S-deficient mice were incompatible with life due to a vasculopathy associated with embryonic lethality [7,8]. In recent decades, evidence has been presented that suggests that ProS can act specifically as a cofactor for tissue factor pathway inhibitor (TFPI) to inhibit tissue factor (TF) activity by facilitating the interaction between full-length TFPI and FXa [9]. More recently, studies have shown that ProS also inhibits extrinsic and intrinsic FXase complexes independently of TFPI and APC [10,11].…”

Novel Insights into Genetics of Arterial Thrombosis

“…The detailed discussion of these systems is beyond the scope of this chapter. 14,15 The fibrinolytic system plays an important role in breaking down cross-linked fibrin clots. The main enzyme responsible for the dissolution of fibrin is plasmin.…”