title: Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes.
abstract: In severe falciparum malaria cytoadherence of parasitised red blood cells (PRBCs) to vascular endothelium (causing sequestration) and to uninfected red cells (causing rosette formation) contribute to microcirculatory flow obstruction in vital organs. Heparin can reverse the underlying ligand-receptor interactions, but may increase the bleeding risks. As a heparin-derived polysaccharide, sevuparin has been designed to retain anti-adhesive properties, while the antithrombin-binding domains have been eliminated, substantially diminishing its anticoagulant activity. Sevuparin has been evaluated recently in patients with uncomplicated falciparum malaria, and is currently investigated in a clinical trial for sickle cell disease. The effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum isolates from Thailand were investigated. Trophozoite stages of P. falciparum-infected RBCs (Pf-iRBCs) were cultured from 49 patients with malaria. Pf-iRBCs were treated with sevuparin at 37°C and assessed in rosetting and in cytoadhesion assays with human dermal microvascular endothelial cells (HDMECs) under static and flow conditions. The proportion of Pf-iRBCs forming rosettes ranged from 6.5% to 26.0% (median = 12.2%). Rosetting was dose dependently disrupted by sevuparin (50% disruption by 250 μg/mL). Overall 57% of P. falciparum isolates bound to HDMECs under static conditions; median (interquartile range) Pf-iRBC binding was 8.5 (3.0-38.0) Pf-iRBCs/1000 HDMECs. Sevuparin in concentrations ≥ 100 μg/mL inhibited cytoadherence. Sevuparin disrupts P. falciparum rosette formation in a dose dependent manner and inhibits cytoadherence to endothelial cells. The data support assessment of sevuparin as an adjunctive treatment to the standard therapy in severe falciparum malaria.
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Somporn
authors.initials: S
authors.lastname: Saiwaew
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Juntima
authors.initials: J
authors.lastname: Sritabal
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Nattaporn
authors.initials: N
authors.lastname: Piaraksa
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Srisuda
authors.initials: S
authors.lastname: Keayarsa
authors.affiliation: Mae Sot Hospital, Mae Sot, Tak, Thailand.
authors.forename: Ronnatrai
authors.initials: R
authors.lastname: Ruengweerayut
authors.affiliation: Mae Ramat Hospital, Mae Ramat, Tak, Thailand.
authors.forename: Chirapong
authors.initials: C
authors.lastname: Utaisin
authors.affiliation: Mae Ramat Hospital, Mae Ramat, Tak, Thailand.
authors.forename: Patima
authors.initials: P
authors.lastname: Sila
authors.affiliation: Queen Sirikit National Institute of Child Health, Bangkok, Thailand.
authors.forename: Rangsan
authors.initials: R
authors.lastname: Niramis
authors.affiliation: Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand.
authors.forename: Rachanee
authors.initials: R
authors.lastname: Udomsangpetch
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Prakaykaew
authors.initials: P
authors.lastname: Charunwatthana
authors.affiliation: Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Emsri
authors.initials: E
authors.lastname: Pongponratn
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.affiliation: Dilaforette AB, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Leitgeb
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005260:Female; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000378:metabolism*; D012397:Rosette Formation; D053058:Trophozoites / Q000378:metabolism*
chemical_list: C000619443:sevuparin; D006493:Heparin