Red blood cells from patients with homozygous sickle cell disease provide a catalytic surface for factor Va inactivation by activated protein C

Bezeaud, Annie; Vénisse, Laurence; Helley, Dominique; Trichet, Catherine; Girot, Robert; Guillin, Marie‐Claude

doi:10.1046/j.1365-2141.2002.03445.x

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…We found a relation of total protein S to hemoglobin levels in our HbSS patients. Both protein S and protein C can exert their anticoagulant effects on phosphatidylserine expressing sickle red blood cell membranes [7,8,10]. In patients with lower hemoglobin levels, there are more dense cells and membrane-shed vesicles, as well as reticulocytes (which all have high phosphatidylserine exposure) [44][45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

“…Large-vessel thrombosis causes and/or contributes to SCD-related cerebral and pulmonary complications, and some studies have suggested that reduced levels of protein S and C are associated with an increased stroke risk in patients with SCD [15][16][17][18]. Membrane-bound activated protein C, in conjunction with cofactor protein S, inactivates activated factors V and VIII, thereby blocking thrombin generation [8]. The etiology of reduced levels of NOAC in SCD is not firmly established but may involve increased consumption, decreased synthesis, or both [15,[17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…Many laboratory studies have consistently reported increased thrombin generation and increased fibrinolytic activity as well as reduced levels of naturally occurring anticoagulants (NOAC) such as protein C and S [4][5][6][7]. Multiple etiological factors have been identified for the hypercoagulability observed in SCD, varying from phosphatidylserine exposure as a result of continuous erythrocyte sickling with membrane vesiculation and endothelial tissue factor expression to cytokine-induced clotting activation [8][9][10][11][12][13][14]. Large-vessel thrombosis causes and/or contributes to SCD-related cerebral and pulmonary complications, and some studies have suggested that reduced levels of protein S and C are associated with an increased stroke risk in patients with SCD [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Protein C and S and inflammation in sickle cell disease

et al. 2004

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Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels. Am.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein C and S and inflammation in sickle cell disease

et al. 2004

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“…However, there are few studies of the anticoagulant APC-system in relation to eryMPs. It has been shown that irreversibly sickled red blood cells and eryMPs can bind protein S [18] and that the red blood cells from sickle cell disease patients support APC-mediated degradation FVa [19]. In addition, platelet-derived MPs were recently shown to stimulate APC-mediated regulation of coagulation in a protein S dependent manner through degradation of both FVa and FVIIIa [20].…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte-Derived Microparticles Supporting Activated Protein C-Mediated Regulation of Blood Coagulation

et al. 2014

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Elevated levels of erythrocyte-derived microparticles are present in the circulation in medical conditions affecting the red blood cells. Erythrocyte-derived microparticles expose phosphatidylserine thus providing a suitable surface for procoagulant reactions leading to thrombin formation via the tenase and prothrombinase complexes. Patients with elevated levels of circulating erythrocyte-derived microparticles have increased thrombin generation in vivo. The aim of the present study was to investigate whether erythrocyte-derived microparticles are able to support the anticoagulant reactions of the protein C system. Erythrocyte-derived microparticles were isolated using ultracentrifugation after incubation of freshly prepared erythrocytes with the ionophore A23187 or from outdated erythrocyte concentrates, the different microparticles preparations yielding similar results. According to flow cytometry analysis, the microparticles exposed phoshatidylserine and bound lactadherin, annexin V, and protein S, which is a cofactor to activated protein C. The microparticles were able to assemble the tenase and prothrombinase complexes and to stimulate the formation of thrombin in plasma-based thrombin generation assay both in presence and absence of added tissue factor. The addition of activated protein C in the thrombin generation assay inhibited thrombin generation in a dose-dependent fashion. The anticoagulant effect of activated protein C in the thrombin generation assay was inhibited by a monoclonal antibody that prevents binding of protein S to microparticles and also attenuated by anti-TFPI antibodies. In the presence of erythrocyte-derived microparticles, activated protein C inhibited tenase and prothrombinase by degrading the cofactors FVIIIa and FVa, respectively. Protein S stimulated the Arg306-cleavage in FVa, whereas efficient inhibition of FVIIIa depended on the synergistic cofactor activity of protein S and FV. In summary, the erythrocyte-derived microparticle surface is suitable for the anticoagulant reactions of the protein C system, which may be important to balance the initiation and propagation of coagulation in vivo.

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“…14,15,28,45 Foremost among the many cerebrovascular manifestations is ischemic disease, the complex pathophysiology of which is thought to result from a combination of small and large vessel changes, coupled with abnormal red cell rheology and a hypercoagulable state. 2,4,5,18,29,47 Cerebral aneurysms, which tend to occur in multiples and have a predilection for the posterior circulation, have also been widely described in association with SCD. 3,7,8,10,23,34,35 Based on a review of the literature, however, the description of a cerebral AVM in a patient with SCD has not yet been reported.…”

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confidence: 98%

Development of a de novo cerebral arteriovenous malformation in a child with sickle cell disease and moyamoya arteriopathy

OʼShaughnessy¹,

DiPatri²,

Parkinson³

et al. 2005

Journal of Neurosurgery

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The authors report the unique case of a 6-year-old African-American girl with sickle cell disease (SCD) and an associated moyamoya arteriopathy who developed a de novo arteriovenous malformation (AVM) of the cerebral circulation. Based on preoperative cerebral angiography, computerized tomography angiography, and magnetic resonance imaging, the incidentally discovered lesion was originally thought to be a direct arteriovenous fistula with an associated varix. At surgery, however, a 1.5-cm AVM was identified adjacent to the deep surface of the varix, and it was successfully resected. The diagnosis of cerebral AVM was then confirmed histopathologically. Based on a review of the literature, no published correlation between cerebral AVMs and SCD exists. In addition to reporting this case, the authors provide a description of AVM pathogenesis, with particular emphasis on acquired AVMs of the cerebral circulation.

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Red blood cells from patients with homozygous sickle cell disease provide a catalytic surface for factor Va inactivation by activated protein C

Cited by 11 publications

References 34 publications

Protein C and S and inflammation in sickle cell disease

Protein C and S and inflammation in sickle cell disease

Erythrocyte-Derived Microparticles Supporting Activated Protein C-Mediated Regulation of Blood Coagulation

Development of a de novo cerebral arteriovenous malformation in a child with sickle cell disease and moyamoya arteriopathy

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