Diffuse skin necrosis in a patient with an anti‐endothelial cell protein C receptor autoantibody which blocks protein C activation

Lavigne-Lissalde, Géraldine; Cochery-Nouvellon, Éva; Granier, Guillaume; Quéré, I.; Gris, Jean‐Christophe

doi:10.1111/j.1538-7836.2005.01152.x

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…We and others have detected the presence of blocking anti-EPCR autoantibodies in patients with thrombosis, which, once purified, were able to reduce the activation of protein C on endothelial cells in vitro (9,10). We now provide direct evidence that blocking anti-EPCR antibodies exacerbates thrombosis in animal models, thus strongly suggesting that autoantibodies may play an active role in human thrombotic pathology.…”

Section: Discussionsupporting

confidence: 55%

“…Recently, we and others have demonstrated that blocking anti-EPCR autoantibodies can be detected in some patients with thrombosis (9,10). However, somewhat surprisingly, transgenic animals expressing low amounts of EPCR did not display a higher thrombogenic phenotype than their wild-type littermates when their susceptibility to carotid artery thrombosis was examined (11).…”

Section: Introductionmentioning

confidence: 99%

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Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Centelles¹,

Puy²,

López‐Sagaseta³

et al. 2010

Thromb Haemost

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SummaryThe endothelial protein C receptor (EPCR) plays an anticoagulant role by improving protein C activation. Although low levels of activated protein C (APC) constitute a thrombosis risk factor, the relationship between modulating EPCR function and thrombosis has not been addressed so far. Monoclonal antibodies (mAb) against murine EPCR were raised, and their ability to block protein C/APC binding was tested. The ferric chloride carotid artery injury model in mice was chosen to test the effect of anti-EPCR mAb on thrombus formation. The time to total occlusion of the vessel was analysed in three groups, given an isotype control mAb (IC), a blocking (RCR-16) or a non-blocking (RCR-20) anti-EPCR mAb. RCR-16 prevented the interaction between protein C/APC and EPCR as demonstrated by surface plasmon resonance and flow cytometry, and inhibited the activation of protein C on the endothelium. IC and RCR-20 were unable to induce such effects. In vivo, RCR-16 shortened the time to total vessel occlusion with respect to IC [13.4 ± 1.0 (mean ± SD) and 17.8 ± 3.2 minutes, respectively, p<0.001]. Occlusive thrombi lasting for more than one hour were observed in all RCR-16-treated animals, but only in 43% of IC-treated ones. Results with RCR-20 were indistinguishable from those observed with IC. For the first time, a direct relationship between blocking EPCR and thrombosis is demonstrated. Blocking anti-EPCR autoantibodies can predispose to thrombosis episodes and may constitute a new therapeutic target.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Centelles¹,

Puy²,

López‐Sagaseta³

et al. 2010

Thromb Haemost

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“…Anti‐EPCR autoantibodies can reasonably be thought to play a causative role in thrombosis. Firstly, as has previously been demonstrated [10,14], the anti‐EPCR autoantibodies may impair the APC generation, which may lead to increased thrombin generation. Indeed, low levels of circulating APC are associated with an increased risk of venous and arterial thrombosis [12,13].…”

Section: Discussionmentioning

confidence: 92%

“…The effect of the anti‐EPCR autoantibodies is possibly via impaired protein C activation on cell surfaces as low levels of circulating APC were reported to be associated with an increased risk of thrombosis [12,13]. In fact, inhibitory anti‐EPCR autoantibodies have been described in two patients with combined venous and arterial thrombosis [10,14]. It is also plausible that antibodies against EPCR lead to an increased risk of thrombophilic complications as a result of an endothelial injury.…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis

Vlieg

Montes

Rosendaal

et al. 2007

Journal of Thrombosis and Haemostasis

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Summary. Background: The endothelial protein C receptor (EPCR) binds protein C and enhances its activation. Anti‐EPCR autoantibodies are found in patients with antiphospholipid syndrome and may explain the increased risk of thrombosis in these patients. Anti‐EPCR autoantibodies have been associated with fetal death and myocardial infarction in young women. Objectives: To determine whether anti‐EPCR autoantibodies are associated with deep vein thrombosis (DVT). Patients/methods: We measured plasma anti‐EPCR autoantibody levels in the Leiden Thrombophilia Study (LETS), a population‐based case–control study consisting of 474 patients with a first DVT and 474 control subjects. Results: The estimated risk of DVT was increased approximately 2‐fold in the presence of elevated IgA, IgG or IgM anti‐EPCR autoantibodies (i.e. levels above the 90th percentile as measured in the control subjects). The risk conferred by anti‐EPCR increased in a dose‐dependent manner for IgA and IgG. When anti‐EPCR autoantibodies were considered in the co‐presence of lupus anticoagulant (LAC) the odds ratio (OR) was 6.1 [95% CI 1.3–27.9]. Anti‐EPCR without LAC remained associated with DVT (OR 1.6; 95% CI 1.2–2.1). Anti‐EPCR autoantibodies were associated with high levels of D‐dimer and soluble EPCR in controls, suggestive of a prothrombotic status induced by the autoantibodies. Conclusions: This study demonstrates that the presence of anti‐EPCR autoantibodies is a moderate risk factor for DVT in the general population.

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“…IgM fractions isolated from these patients potently inhibited PC activation on endothelial cells. These autoantibodies that block PC activation might lead to skin necrosis 37 by reducing APC levels. Low APC levels are a risk factor for thrombosis, and this might explain the multiple episodes of venous thrombosis experienced by APS patients with PC-activation-blocking antibodies.…”

Section: Circumstances Leading To Inhibition Of Apc-membrane Interactmentioning

confidence: 99%

Endothelial cell protein C receptor and the risk of venous thrombosis

Gandrille¹

2008

Haematologica

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Diffuse skin necrosis in a patient with an anti‐endothelial cell protein C receptor autoantibody which blocks protein C activation

Cited by 6 publications

References 17 publications

Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis

Endothelial cell protein C receptor and the risk of venous thrombosis

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