Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden

Nogami, Keiji; Shinozawa, Keiko; Ogiwara, Kenichi; Matsumoto, Tomoko; Amano, Kagehiro; Fukutake, Katsuyuki; Shima, Midori

doi:10.1182/blood-2013-10-530089

Cited by 62 publications

(69 citation statements)

References 43 publications

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“…To achieve comparable levels of FVa Nara inactivation, >50 nmol/L protein S was required. These results suggest that the reduced inactivation of FVa Nara observed in Figures C‐F is unlikely to be related to decreased phospholipid binding alone, but rather to a combination of decreased affinity of FVa Nara toward both the phospholipid membranes and protein S. Of note, Nogami and colleagues showed lack of cleavage of FVa Nara at Arg306, which is completely dependent upon phospholipids and enhancement by protein S …”

Section: Resultsmentioning

confidence: 84%

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The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex

Gierula

Salles‐Crawley

Santamaria

et al. 2019

Journal of Thrombosis and Haemostasis

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BackgroundActivated protein C (APC)‐mediated inactivation of factor (F)Va is greatly enhanced by protein S. For inactivation to occur, a trimolecular complex among FVa, APC, and protein S must form on the phospholipid membrane. However, direct demonstration of complex formation has proven elusive.ObjectivesTo elucidate the nature of the phospholipid‐dependent interactions among APC, protein S, and FVa.MethodsWe evaluated binding of active site blocked APC to phospholipid‐coated magnetic beads in the presence and absence of protein S and/or FVa. The importance of protein S and FV residues were evaluated functionally.ResultsActivated protein C alone bound weakly to phospholipids. Protein S mildly enhanced APC binding to phospholipid surfaces, whereas FVa did not. However, FVa together with protein S enhanced APC binding (>14‐fold), demonstrating formation of an APC/protein S/FVa complex. C4b binding protein‐bound protein S failed to enhance APC binding, agreeing with its reduced APC cofactor function. Protein S variants (E36A and D95A) with reduced APC cofactor function exhibited essentially normal augmentation of APC binding to phospholipids, but diminished APC/protein S/FVa complex formation, suggesting involvement in interactions dependent upon FVa. Similarly, FVaNara (W1920R), an APC‐resistant FV variant, also did not efficiently incorporate into the trimolecular complex as efficiently as wild‐type FVa. FVa inactivation assays suggested that the mutation impairs its affinity for phospholipid membranes and with protein S within the complex.ConclusionsFVa plays a central role in the formation of its inactivation complex. Furthermore, membrane proximal interactions among FVa, APC, and protein S are essential for its cofactor function.

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Section: Resultsmentioning

confidence: 84%

“…Nogami et al. recently identified the homozygous FV Nara mutation (FV W1920R) in a boy with recurrent DVT, whose phenotype was attributed to severe APC resistance of the mutant FV . The authors suggested that APC resistance may be caused by disruption of an APC interaction site.…”

Section: Discussionmentioning

confidence: 99%

The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex

Gierula

Salles‐Crawley

Santamaria

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Potential candidate mechanisms that do not involve the degradation of fVa or fVIIIa but are consistent with known functions of pS and fV include (1) the destabilization of the signaling-competent conformation of the TF complex secondary to physical interactions of B domain-containing fVa with fXa 49 and of pS with TF and fXa 50 , and/or (2) the recruitment of TF pathway inhibitor a (TFPIa) to the TF-fVIIa-fXa complex via interaction of pS with the TFPIa K3 domain or of the fV B domain with the carboxyterminal fragment of TFPIa (reviewed in Wood et al 51 ). It also remains to be clarified whether other naturally occurring fV variants such as fV Liverpool (I359T), 52 fV Nara (W1920R), 53 fV released from platelets, 54 or fV present in homozygous carriers of the fV R2 haplotype 11,[55][56][57] would exhibit similarly defective cofactor function for the inhibition of TF signaling by aPC as does fV Leiden.…”

Section: Discussionmentioning

confidence: 99%

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

Liang

Kerschen

Basu

et al. 2015

Blood

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Key Points• Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C.• The R506Q mutation (Leiden mutation) abrogates the antiinflammatory cofactor function of factor V for activated protein C.The key effector molecule of the natural protein C pathway, activated protein C (aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. Coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. In this study, using a mouse model of Staphylococcus aureus sepsis, we demonstrate marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC. aPC resistance of factor (f)V due to the R506Q Leiden mutation protected against detrimental anticoagulant effects of aPC therapy but also abrogated the anti-inflammatory and mortalityreducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. We found that procofactor V (cleaved by aPC at R506) and protein S were necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involved the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities did not involve proteolysis of activated coagulation factors Va and VIIIa. These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. (Blood. 2015;126(21):2415-2423 Introduction Natural aPC exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation (for review, see Esmon, 1 Mosnier and Griffin,2 and Dahlbäck and Villoutreix 3 ) that are predominantly mediated by 2 mechanistically discernable pathways: (1) aPC degrades activated coagulation factor (f)Va and fVIIIa to curtail the formation of thrombin by the plasma coagulation system and (2) when bound to the endothelial protein C receptor (EPCR, ProcR) or the integrin aMb2 (Mac1)(CD11b/CD18), aPC becomes competent for activating the G protein-coupled protease activated receptor (PAR) 1, 2, or 3. PAR activation and crosstalk with other receptors mediate anti-inflammatory and cytoprotective effects of aPC in innate immune cells, vascular endothelium, and other cells (for review, see Weiler,4 Mosnier et al, 5 and Dahlbäck and Villoutreix 6). In animal models of endotoxemia and sepsis, the cell signaling activity of aPC on vascular endothelium and innate immune cells is the predominant therapeutic mechanism of action, and recombinant variants of aPC that are largely devoid of anticoagulant activity but retain signaling function confer vasoprotection, inhibit inflammation, and reduce mortality. 7-9 Although the incidence of microvascular coagulopathies in p...

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“…1 Since the affected amino acid residue is located in the light chain of FV, far from the known APC-cleavage sites, this discovery may afford new insights into the molecular mechanisms of APC resistance.…”

Section: Elisabetta Castoldi 1 1 Maastricht Universitymentioning

confidence: 99%

“…The interesting study by Nogami et al describes a 13-year-old Japanese boy who developed recurrent venous thrombosis during oral anticoagulant treatment. 1 The patient had reduced FV levels (40 IU/dL antigen, 10 IU/dL activity) and pronounced APC resistance (see figure), prompting FV gene sequencing. This revealed a novel homozygous missense mutation (Trp1920→Arg, FV Nara ) in the C1 domain of FV, which was not found in 50 healthy Japanese people.…”

Section: Elisabetta Castoldi 1 1 Maastricht Universitymentioning

confidence: 99%

FV and APC resistance: the plot thickens

Castoldi

2014

Blood

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Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden

Abstract: Key Points FVNara (W1920R), associated with serious deep vein thrombosis, is more resistant to APC relative to FVLeiden (R506Q). This mechanism results from significant decreases in FVa susceptibility to APC and FV cofactor activity for APC.

Cited by 62 publications

References 43 publications

The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex

The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

FV and APC resistance: the plot thickens

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