scholarly journals Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1062-1071 ◽  
Author(s):  
SJ Koppelman ◽  
TM Hackeng ◽  
JJ Sixma ◽  
BN Bouma
Keyword(s):  
Factor Viii ◽  
Protein C ◽  
Intrinsic Factor ◽  
Activated Protein C ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor X ◽  
Ic50 Values ◽  
Factor X Activation ◽  
Factor X Activating Complex

Protein S is a vitamin K-dependent nonenzymatic anticoagulant protein that acts as a cofactor to activated protein C. Recently it was shown that protein S inhibits the prothrombinase reaction independent of activated protein C. In this study, we show that protein S can also inhibit the intrinsic factor X activation via a specific interaction with factor VIII. In the presence of endothelial cells, the intrinsic activation of factor X was inhibited by protein S with an IC50 value of 0.28 +/- 0.04 mumol/L corresponding to the plasma concentration of protein S. This inhibitory effect was even more pronounced when the intrinsic factor X activation was studied in the presence of activated platelets (IC50 = 0.15 +/- 0.02 mumol/L). When a nonlimiting concentration of phospholipid vesicles was used, the plasma concentration of protein S (300 nmol/L) inhibited the intrinsic factor X activation by 40%. Thrombin-cleaved protein S inhibited the endothelial cell-mediated factor X activation with an IC50 similar to that of native protein S (0.26 +/- 0.02 mumol/L). Protein S in complex with C4b-binding protein inhibited the endothelial cell-mediated factor X activation more potently than protein S alone (IC50 = 0.19 +/- 0.03 mumol/L). Using thrombin activated factor VIII, IC50 values of 0.53 +/- 0.09 mumol/L and 0.46 +/- 0.10 mumol/L were found for native protein S and thrombin-cleaved protein S, respectively. The possible interactions of protein S with factor IXa, phospholipids, and factor VIII were investigated. The enzymatic activity of factor IXa was not affected by protein S, and interaction of protein S with the phospholipid surface could not fully explain the inhibitory effect of protein S on the factor X activation. Using a solid-phase binding assay, we showed a specific, saturable, and reversible binding of protein S to factor VIII with a high affinity. The concentration of protein S where half-maximal binding was reached (B1/2max) was 0.41 +/- 0.06 mumol/L. A similar affinity was found for the interaction of thrombin-cleaved protein S with factor VIII (B1/2max = 0.40 +/- 0.04 mumol/L). The affinity of the complex protein S with C4B-binding protein appeared to be five times higher (B1/2max = 0.07 +/- 0.03 mumol/L). Because the affinities of the interaction of the different forms of protein S with factor VIII correspond to the IC50 values observed for the intrinsic factor X activating complex, the interaction of protein S with factor VIII may explain the inhibitory effect of protein S on the intrinsic factor X activating complex.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1062-1071 ◽  
Author(s):  
SJ Koppelman ◽  
TM Hackeng ◽  
JJ Sixma ◽  
BN Bouma
Keyword(s):  
Factor Viii ◽  
Protein C ◽  
Intrinsic Factor ◽  
Activated Protein C ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor X ◽  
Ic50 Values ◽  
Factor X Activation ◽  
Factor X Activating Complex

Abstract Protein S is a vitamin K-dependent nonenzymatic anticoagulant protein that acts as a cofactor to activated protein C. Recently it was shown that protein S inhibits the prothrombinase reaction independent of activated protein C. In this study, we show that protein S can also inhibit the intrinsic factor X activation via a specific interaction with factor VIII. In the presence of endothelial cells, the intrinsic activation of factor X was inhibited by protein S with an IC50 value of 0.28 +/- 0.04 mumol/L corresponding to the plasma concentration of protein S. This inhibitory effect was even more pronounced when the intrinsic factor X activation was studied in the presence of activated platelets (IC50 = 0.15 +/- 0.02 mumol/L). When a nonlimiting concentration of phospholipid vesicles was used, the plasma concentration of protein S (300 nmol/L) inhibited the intrinsic factor X activation by 40%. Thrombin-cleaved protein S inhibited the endothelial cell-mediated factor X activation with an IC50 similar to that of native protein S (0.26 +/- 0.02 mumol/L). Protein S in complex with C4b-binding protein inhibited the endothelial cell-mediated factor X activation more potently than protein S alone (IC50 = 0.19 +/- 0.03 mumol/L). Using thrombin activated factor VIII, IC50 values of 0.53 +/- 0.09 mumol/L and 0.46 +/- 0.10 mumol/L were found for native protein S and thrombin-cleaved protein S, respectively. The possible interactions of protein S with factor IXa, phospholipids, and factor VIII were investigated. The enzymatic activity of factor IXa was not affected by protein S, and interaction of protein S with the phospholipid surface could not fully explain the inhibitory effect of protein S on the factor X activation. Using a solid-phase binding assay, we showed a specific, saturable, and reversible binding of protein S to factor VIII with a high affinity. The concentration of protein S where half-maximal binding was reached (B1/2max) was 0.41 +/- 0.06 mumol/L. A similar affinity was found for the interaction of thrombin-cleaved protein S with factor VIII (B1/2max = 0.40 +/- 0.04 mumol/L). The affinity of the complex protein S with C4B-binding protein appeared to be five times higher (B1/2max = 0.07 +/- 0.03 mumol/L). Because the affinities of the interaction of the different forms of protein S with factor VIII correspond to the IC50 values observed for the intrinsic factor X activating complex, the interaction of protein S with factor VIII may explain the inhibitory effect of protein S on the intrinsic factor X activating complex.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Synergistic inhibition of the intrinsic factor X activation by protein S and C4b-binding protein

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2653-2660 ◽  
Author(s):  
SJ Koppelman ◽  
C van't Veer ◽  
JJ Sixma ◽  
BN Bouma
Keyword(s):  
Monoclonal Antibodies ◽  
Factor Viii ◽  
Protein C ◽  
Binding Protein ◽  
Intrinsic Factor ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor X ◽  
Beta Chain ◽  
Factor X Activation

Abstract The complement protein C4b-binding protein plays an important role in the regulation of the protein C anticoagulant pathway. C4b-binding protein can bind to protein S, thereby inhibiting the cofactor activity of protein S for activated protein C. In this report, we describe a new role for C4b-binding protein in coagulation. We observed inhibition of the intrinsic factor X activating reaction by the complex of C4b-binding protein and protein S. At the plasma concentration of protein S, the factor X activation was inhibited for 50% and addition of C4b-binding protein led to a potentiation of the inhibition to almost 90%. Because C4b-binding protein alone had no effect on the activation of factor X, we hypothesized that binding of C4b-binding protein to protein S was a prerequisite for optimal inhibition of factor X activation. C4b-binding protein lacking the beta-chain, which is unable to bind to protein S, did not potentiate the inhibitory effect of protein S. In an earlier study, we observed that C4b-binding protein increased the binding affinity of protein S for factor VIII. Therefore, a possible interaction of C4b-binding protein with factor VIII was investigated. C4b-binding protein bound to factor VIII and to thrombin activated factor VIII in a saturable and specific way. Also, factor VIII in complex with von Willebrand factor was able to bind C4b-binding protein. The beta-chain of C4b-binding protein was not required for the interaction with factor VIII because C4b-binding protein lacking the beta-chain also bound to factor VIII. Monoclonal antibodies directed against the alpha-chain of C4b-binding protein inhibited the binding to factor VIII, whereas monoclonal antibodies directed against the beta-chain had no effect on the binding to factor VIII. This finding indicates that the binding site for factor VIII on C4b-binding protein is localized on the alpha-chains of C4b-binding protein. The potentiation by C4b-binding protein of the inhibition of the factor X activation by protein S was blocked by a monoclonal antibody directed against the alpha-chain of C4b-binding protein. This finding indicates that the potentiation of the inhibitory effect of protein S was mediated via an interaction of C4b-binding protein with factor VIII. C4b-binding protein did not bind to factor V and was not able to potentiate the inhibitory effect of protein S on prothrombinase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Synergistic inhibition of the intrinsic factor X activation by protein S and C4b-binding protein

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2653-2660
Author(s):  
SJ Koppelman ◽  
C van't Veer ◽  
JJ Sixma ◽  
BN Bouma
Keyword(s):  
Monoclonal Antibodies ◽  
Factor Viii ◽  
Protein C ◽  
Binding Protein ◽  
Intrinsic Factor ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor X ◽  
Beta Chain ◽  
Factor X Activation

The complement protein C4b-binding protein plays an important role in the regulation of the protein C anticoagulant pathway. C4b-binding protein can bind to protein S, thereby inhibiting the cofactor activity of protein S for activated protein C. In this report, we describe a new role for C4b-binding protein in coagulation. We observed inhibition of the intrinsic factor X activating reaction by the complex of C4b-binding protein and protein S. At the plasma concentration of protein S, the factor X activation was inhibited for 50% and addition of C4b-binding protein led to a potentiation of the inhibition to almost 90%. Because C4b-binding protein alone had no effect on the activation of factor X, we hypothesized that binding of C4b-binding protein to protein S was a prerequisite for optimal inhibition of factor X activation. C4b-binding protein lacking the beta-chain, which is unable to bind to protein S, did not potentiate the inhibitory effect of protein S. In an earlier study, we observed that C4b-binding protein increased the binding affinity of protein S for factor VIII. Therefore, a possible interaction of C4b-binding protein with factor VIII was investigated. C4b-binding protein bound to factor VIII and to thrombin activated factor VIII in a saturable and specific way. Also, factor VIII in complex with von Willebrand factor was able to bind C4b-binding protein. The beta-chain of C4b-binding protein was not required for the interaction with factor VIII because C4b-binding protein lacking the beta-chain also bound to factor VIII. Monoclonal antibodies directed against the alpha-chain of C4b-binding protein inhibited the binding to factor VIII, whereas monoclonal antibodies directed against the beta-chain had no effect on the binding to factor VIII. This finding indicates that the binding site for factor VIII on C4b-binding protein is localized on the alpha-chains of C4b-binding protein. The potentiation by C4b-binding protein of the inhibition of the factor X activation by protein S was blocked by a monoclonal antibody directed against the alpha-chain of C4b-binding protein. This finding indicates that the potentiation of the inhibitory effect of protein S was mediated via an interaction of C4b-binding protein with factor VIII. C4b-binding protein did not bind to factor V and was not able to potentiate the inhibitory effect of protein S on prothrombinase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

The Mechanism of Protein S as An Anticoagulant Independent of Activated Protein C.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3186-3186
Author(s):  
Rinku Majumder
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Factor X ◽  
Protein S Deficiency ◽  
Factor Ixa ◽  
S Deficiency ◽  
Factor X Activation

Abstract 3186 Poster Board III-123 Thrombosis is a serious problem in the United States. The overall estimated incidence (annual occurrence) of deep venous thrombosis is 1 episode for every 1000 persons. Protein S, a vitamin K-dependent protein, is one of the natural anticoagulants found in the blood. Deficiency of protein S is most common protein deficiencies associated with familial venous thrombosis There are studies that suggest an association between arterial thrombosis (stroke, heart attack) in patients with protein S deficiency. At this time, the exact role of protein S deficiency and its relative importance in arterial disease is still being explored by physicians and scientists. Protein S is known as a non-enzymatic cofactor of activated Protein C in the inactivation of factors Va and VIIIa, as part of a negative feedback loop to regulate blood coagulation. Plasma coagulation assays in the absence of activated protein C suggest that Protein S may have other anticoagulant role(s). For example, it has been suggested that Protein S down-regulates thrombin generation by stimulating FXa inhibition by the tissue factor pathway inhibitor (Rosing, J., et al., Thromb Res, 2008. 122 Suppl 1: p. S60-3). It has also been proposed that protein S can directly inhibit the intrinsic Xase complex (Takeyama, M., et al.. Br J Haematol, 2008. 143(3): p. 409-20). But the exact mechanism of how Protein S exerts its anticoagulant effect on factor IXa/VIIIa complex is still unclear. In order to determine the role of Protein S as an anticoagulant in the intrinsic Xase Complex, we have used C6PS (a small six carbon chain synthetic Phosphatidylserine (PS) molecule) that does not occur in vivo, but has been used as a powerful tool in demonstrating the regulation of both factors Xa and Va by binding of molecular PS. Soluble lipid binding can offer invaluable insights into events that would be next to impossible to document on a membrane surface which is complicated as it has surface condensation effect and allosteric effects of different factors. We focus here on the conformation changes of the proteins by using C6PS as a tool. We have determined the binding of Protein S with C6PS by using tryptophan fluorescence and observed a stoichiometric Kd of ∼180 μM.We checked for micelles formation under each experimental condition. We have also determined the direct binding of factor IXa with Protein S by using DEGR-IXa ((5-(dimethylamino)1-naphthalenesulfonyl]-glutamylglycylarginyl chloromethyl ketone) in the presence and absence of C6PS. Our results show that the affinity of binding of DEGR-IXa to Protein S in the presence of C6PS is ∼22 fold tighter (Kd ∼15 nM compared to 324 nM) than without C6PS. We also measured the rate of factor X activation by factor IXa with the addition of increasing concentration of C6PS in the presence and absence of Protein S. We observed that Protein S decreased factor IXa mediated factor X activation by 14 fold. We had previously shown that apparent Kd of factor IXa binding to C6PS during factor X activation was ∼125 μM. But addition of Protein S had an effect on the apparent Kd as it increased to 700 μM indicating the affinity of factor IXa towards C6PS was decreased with the addition of Protein S during factor X activation. From these data we can speculate that Protein S induces a conformational change in factor IXa in the presence of C6PS which may affect the interaction of factor IXa with factor VIIIa, thus affecting the intrinsic Xase complex. Using this useful tool (C6PS), we will characterize the anticoagulant role of Protein S in the intrinsic Xase complex which in turn will give us some insights into this important protein which is a crucial target for therapeutic drugs for venous thrombosis. Disclosures No relevant conflicts of interest to declare.

Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1714-1720 ◽  
Author(s):  
Lynn M. O'Brien ◽  
Maria Mastri ◽  
Philip J. Fay
Keyword(s):  
Protein C ◽  
Intrinsic Factor ◽  
Activated Protein C ◽  
Protein S ◽  
Similar Rate ◽  
Factor X ◽  
Preferential Cleavage ◽  
Factor Ixa ◽  
Factor Viiia ◽  
Reduced Rate

Factor VIIIa is a trimer of A1, A2, and A3-C1-C2 subunits. Inactivation of the cofactor by human activated protein C (APC) results from preferential cleavage at Arg336 within the A1 subunit, followed by cleavage at Arg562 bisecting the A2 subunit. In the presence of human protein S, the rate of APC-dependent factor VIIIa inactivation increased several-fold and correlated with an increased rate of cleavage at Arg562. (Active site-modified) factor IXa, blocked cleavage at the A2 site. However, APC-catalyzed inactivation of factor VIIIa proceeded at a similar rate independent of factor IXa, consistent with the location of the preferential cleavage site within the A1 subunit. Addition of protein S failed to increase the rate of cleavage at the A2 site when factor IXa was present. In the presence of factor X, cofactor inactivation was inhibited, due to a reduced rate of cleavage at Arg336. However, inclusion of protein S restored near original rates of factor VIIIa inactivation and cleavage at the A1 site, thus overcoming the factor X-dependent protective effect. These results suggest that in the human system, protein S stimulates APC-catalyzed factor VIIIa inactivation by facilitating cleavage of A2 subunit (an effect retarded in the presence of factor IXa), as well as abrogating protective interactions of the cofactor with factor X.

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

1999 ◽  
Vol 81 (04) ◽  
pp. 527-531 ◽  
Author(s):  
U. Kjellberg ◽  
N.-E. Andersson ◽  
S. Rosén ◽  
L. Tengborn ◽  
M. Hellgren
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Reference Level ◽  
Soluble Fibrin ◽  
Prothrombin Fragment ◽  
D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

Characterization of an Anti-Factor VIII Monoclonal Antibody with A1 and A3 Epitopes Which Increases Factor VIII Activity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1702-1702
Author(s):  
Masahiro Takeyama ◽  
Keiji Nogami ◽  
Tetsuhiro Soeda ◽  
Tsukasa Suzuki ◽  
Kunihiro Hattori ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Factor Viii ◽  
Neutralizing Antibodies ◽  
Active Form ◽  
Activated Protein C ◽  
Factor Xa ◽  
Inhibitory Effect ◽  
Heat Denaturation ◽  
Factor X ◽  
Fviii Activity

Abstract Epitopes of anti-factor VIII (FVIII) neutralizing antibodies distribute all of the FVIII domains. They inhibit FVIII for instance by blocking the FVIII interaction with factor IXa, factor X/factor Xa (FX/FXa), phospholipid, von Willebrand factor, or thrombin. Therefore, localization of such FVIII inhibitory effect gives us useful information for understanding of FVIII structure and function. We expect FVIII enhancing antibody also may be a useful tool. In this study, we found an anti-FVIII monoclonal antibody (named by moAb216) that increased the FVIII cofactor activity. The addition of moAb216 increased FVIII activity by ~1.6-fold dose-dependently in one-stage clotting assay. The increase of FVIII activity in the presence of moAb216 correlated with that of generated thrombin or factor Xa in thrombin or FXa generation based-assay. Blotting analysis revealed that this antibody reacted with only intact FVIII molecule, whilst failed to react with either SDS-treated FVIII, FVIIIa (active-form), or isolated each A1, A2, and A3-C1-C2 subunit. Individual monoclonal antibody, with an epitope of the A1 or A3 acidic region in FVIII, competitively inhibited FVIII binding to moAb216 as well as the increase of FVIII activity by its antibody. However, anti-A2 or anti-C2 monoclonal antibody did not affect. These results supported that this unique antibody, with a discontinuous epitope spanning both acidic regions in the A1 and A3 domains, recognized the native conformation of FVIII. To examine the mechanism(s) of increasing effect by moAb216, we focused on the activation and/or inactivation of FVIII. Rate constants on thrombin- and FXa-catalyzed activation of FVIII in the presence of moAb216 were ~2 and 3-fold greater, respectively, in dose-dependent manners compared with that of FVIII in its absence. On the other hand, the antibody inhibited the activated protein C (APC)-catalyzed FVIII inactivation with ~10-fold lower of inactivation rate constant. SDS-PAGE analysis revealed that moAb216 accelerated the cleavage at Arg372 in the A1-A2 junction by thrombin and FXa, whilst decelerated the cleavage at Arg336 within the A1 domain by APC. In addition, FVIII activity in the presence of moAb216 was more stable following heat denaturation analysis than that in its absence. We demonstrated that the increasing effect of FVIII activity by moAb216 was attributed to the change of cleavage at Arg372 and/or Arg336 in the heavy chain caused by interaction with the A1/A3 domains. Furthermore, moAb216 would be useful as a new replacement therapy for hemophilia A patients, since this increases and stabilizes FVIII activity, and can function even in the presence of anti-FVIII (A2 and C2) inhibitors.

scholarly journals Procoagulant activities of skeletal and cardiac muscle myosin depend on contaminating phospholipid

Blood ◽  
2020 ◽  
Vol 136 (21) ◽  
pp. 2469-2472 ◽  
Author(s):  
Valerie A. Novakovic ◽  
Gary E. Gilbert
Keyword(s):  
Protein C ◽  
Factor Viia ◽  
Activated Protein C ◽  
Factor X ◽  
Cardiac Myosin ◽  
Prothrombinase Complex ◽  
Skeletal Myosin ◽  
Factor X Activation ◽  
Muscle Myosin ◽  
Prothrombinase Activity

Abstract Recent reports indicate that suspended skeletal and cardiac myosin, such as might be released during injury, can act as procoagulants by providing membrane-like support for factors Xa and Va in the prothrombinase complex. Further, skeletal myosin provides membrane-like support for activated protein C. This raises the question of whether purified muscle myosins retain procoagulant phospholipid through purification. We found that lactadherin, a phosphatidyl-l-serine–binding protein, blocked >99% of prothrombinase activity supported by rabbit skeletal and by bovine cardiac myosin. Similarly, annexin A5 and phospholipase A2 blocked >95% of myosin-supported activity, confirming that contaminating phospholipid is required to support myosin-related prothrombinase activity. We asked whether contaminating phospholipid in myosin preparations may also contain tissue factor (TF). Skeletal myosin supported factor VIIa cleavage of factor X equivalent to contamination by ∼1:100 000 TF/myosin, whereas cardiac myosin had TF-like activity >10-fold higher. TF pathway inhibitor inhibited the TF-like activity similar to control TF. These results indicate that purified skeletal muscle and cardiac myosins support the prothrombinase complex indirectly through contaminating phospholipid and also support factor X activation through TF-like activity. Our findings suggest a previously unstudied affinity of skeletal and cardiac myosin for phospholipid membranes.

β2-Glycoprotein I Modulates the Anticoagulant Activity of Activated Protein C on the Phospholipid Surface

1996 ◽  
Vol 75 (01) ◽  
pp. 049-055 ◽  
Author(s):  
Tatsuyuki Mori ◽  
Hiroyuki Takeya ◽  
Junji Nishioka ◽  
Esteban C Gabazza ◽  
Koji Suzuki
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor V ◽  
Clotting Time ◽  
Factor Va ◽  
Glycoprotein I ◽  
Prothrombinase Activity

SummaryThe objective of this study was to determine whether (β2-glycoprotein I (β2GPI) has procoagulant activity by inhibiting the anticoagulant activity of activated protein C (APC). β2GPI inhibited significantly the APC-catalyzed inactivation of factor Va in an assay using factor V-deficient plasma and physiological levels of protein S and factor Va. This inhibitory effect was diminished by the addition of increasing concentrations of phospholipids, suggesting that β2GPI competitively inhibits the binding of APC to the phospholipid surface. β2GPI inhibited weakly factor Va- and phospholipid-dependent prothrombinase activity at concentrations similar to those to inhibit APC activity. The depletion of β2GPI from plasma led to only a slight shortening of the diluted Russell’s viper venom-dependent clotting time, but to a strong and significant potentiation of the anticoagulant activity of APC. These results suggest that under certain physiological conditions β2GPI has procoagulant property by inhibiting the phospholipid-dependent APC anticoagulant activity.

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