Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell‐induced vaso‐occlusion

Telen, Marilyn J.; Batchvarova, Milena; Shan, Siqing; Bovée-Geurts, Petra H. M.; Zennadi, Rahima; Leitgeb, Anna M.; Brock, Roland; Lindgren, Maria

doi:10.1111/bjh.14303

Cited by 45 publications

(28 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Facilitating rapid de-sequestration has also been suggested as a therapeutic mode of action for severe malaria, with recent clinical testing of the anti-rosetting compound sevuparin [90]. One could hypothesize that a compound that blocks sequestration keeps parasites in the vasculature and thus increases the ability of both the spleen and the immune system to clear these.…”

Section: Severe Malariamentioning

confidence: 99%

New developments in anti-malarial target candidate and product profiles

Burrows

Duparc

Gutteridge

et al. 2017

Malar J

408

480

View full text Add to dashboard Cite

A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

show abstract

Section: Severe Malariamentioning

confidence: 99%

New developments in anti-malarial target candidate and product profiles

Burrows

Duparc

Gutteridge

et al. 2017

Malar J

408

480

View full text Add to dashboard Cite

show abstract

“…Sevuparin is a low-anticoagulant heparin analog from which the high-affinity antithrombin III-binding pentasaccharide has been removed, resulting in a lack of direct effect on factor Xa and thrombin. Sevuparin was developed to prevent vaso-occlusion in patients with malaria and sickle cell disease, in which the mode of action is to inhibit aggregation of erythrocytes (13,14). Here, we show that sevuparin attenuates neutrophil-induced hyperpermeability and lung edema without inhibiting neutrophil accumulation in lung tissue.…”

mentioning

confidence: 73%

Heparinoid sevuparin inhibitsStreptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins

et al. 2019

View full text Add to dashboard Cite

Acute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A Streptococcus (GAS). In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil‐induced lung plasma leakage in a murine model of systemic inflammation evoked by heat‐killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS‐induced endothelial barrier disruption by neutralizing the activity of neutrophil‐derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil‐derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.—Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. FASEB J. 33, 10443–10452 (2019). http://www.fasebj.org

show abstract

“…However, well-designed placebo-controlled studies with different LMWH, and enrolling participants with different genotypes of sickle cell disease are lacking 50. Telen et al51 demonstrated that sevuparin, a heparin-derived polysaccharide, reduced sickle cell related VOC’s. The efficacy of sevuparin is believed to be due to its anti-adhesive properties, as it binds to P-and L-selectins, TSP, fibronectin, and VWF, all of which are involved in the sickle cell VOC’s.…”

Section: Discussionmentioning

confidence: 99%

Increased Vasoocclusive Crisis in “O” Blood Group Sickle Cell Disease Patients: Association With Underlying Thrombospondin Levels.

Huneini

Alkindi

Panjwani

et al. 2017

Mediterr J Hematol Infect Dis

View full text Add to dashboard Cite

ObjectivesTo explore the incidence of vaso-occlusive crisis (VOC) in Blood Group “O” sickle cell disease (SCD) patients, and correlate it with the blood group and thrombospondin (TSP) levels.MethodsIn 89 consecutive SCD patients, blood samples were obtained for von Williebrand factor (vWF:Ag) antigen, collagen binding activity (CBA), ristocetin binding activity (RCo), blood group typing, C-reactive protein (CRP), high performance liquid chromatography (HPLC), Serum TSP 1 and TSP 2 levels, complete blood counts (CBC), lactic dehydrogenase (LDH) levels, liver function (LFT) and renal function tests (RFT) during VOC episodes and in steady state conditions.ResultsIn steady state SCD patients (n=72), “O” blood group patients (n=37) showed a significantly higher median serum TSP 1 and TSP 2 levels as compared to non-O blood group patients [n=35] [p <0.05, Mann-Whitney test]; with an inverse relation between vWF:Ag, Factor VIII:C and TSP levels. Furthermore, the serum TSP 1 and TSP 2 levels were significantly higher in patients presenting with acute VOC [n=17], as well as in those with repeated VOC’s (group 1, n=16), especially amongst blood group “O” patients [p, <0.05, Mann-Whitney test].ConclusionsThe study demonstrates an inverse relation between TSP and vWF levels, in blood group “O” SCD patients, with an upregulation of the TSP levels. Expectedly, during active VOC crisis, the TSP 1 and TSP 2 levels were significantly elevated.

show abstract

Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell‐induced vaso‐occlusion

Cited by 45 publications

References 84 publications

New developments in anti-malarial target candidate and product profiles

New developments in anti-malarial target candidate and product profiles

Heparinoid sevuparin inhibitsStreptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins

Increased Vasoocclusive Crisis in “O” Blood Group Sickle Cell Disease Patients: Association With Underlying Thrombospondin Levels.

Contact Info

Product

Resources

About