• 1.

    World Health Organization, 2008. World Malaria Report. Geneva, Switzerland: World Health Organization.

  • 2.

    Udomsangpetch R, Wåhlin B, Carlson J, Berzins K, Torii M, Aikawa M, Perlmann P, Wahlgren M, 1989. Plasmodium falciparum-infected erythrocytes form spontaneous erythrocyte rosettes. J Exp Med 169: 18351840.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kaul DK, Roth EF Jr, Nagel RL, Howard RJ, Handunnetti SM, 1991. Rosetting of Plasmodium falciparum-infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions. Blood 78: 812819.

    • Search Google Scholar
    • Export Citation
  • 4.

    MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA, 1985. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol 119: 385401.

    • Search Google Scholar
    • Export Citation
  • 5.

    Treutiger CJ, Hedlund I, Helmby H, Carlson J, Jepson A, Twumasi P, Kwiatkowski D, Greenwood BM, Wahlgren M, 1992. Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria. Am J Trop Med Hyg 46: 503510.

    • Search Google Scholar
    • Export Citation
  • 6.

    Heddini A, Pettersson F, Kai O, Shafi J, Obiero J, Chen Q, Barragan A, Wahlgren M, Marsh K, 2001. Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors. Infect Immun 69: 58495856.

    • Search Google Scholar
    • Export Citation
  • 7.

    Roberts DJ, Pain A, Kai O, Kortok M, Marsh K, 2000. Autoagglutination of malaria-infected red blood cells and malaria severity. Lancet 355: 14271428.

    • Search Google Scholar
    • Export Citation
  • 8.

    Rowe A, Obeiro J, Newbold CI, Marsh K, 1995. Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Infect Immun 63: 23232326.

    • Search Google Scholar
    • Export Citation
  • 9.

    Carlson J, Helmby H, Hill AV, Brewster D, Greenwood BM, Wahlgren M, 1990. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet 336: 14571460.

    • Search Google Scholar
    • Export Citation
  • 10.

    Carlson J, Nash GB, Gabutti V, al-Yaman F, Wahlgren M, 1994. Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation. Blood 84: 39093914.

    • Search Google Scholar
    • Export Citation
  • 11.

    Rowe JA, Obiero J, Marsh K, Raza A, 2002. Short report: positive correlation between rosetting and parasitemia in Plasmodium falciparum clinical isolates. Am J Trop Med Hyg 66: 458460.

    • Search Google Scholar
    • Export Citation
  • 12.

    Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, Taraschi TF, Howard RJ, 1995. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82: 7787.

    • Search Google Scholar
    • Export Citation
  • 13.

    Chen Q, Barragan A, Fernandez V, Sundstrom A, Schlichtherle M, Sahlen A, Carlson J, Datta S, Wahlgren M, 1998. Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum. J Exp Med 187: 1523.

    • Search Google Scholar
    • Export Citation
  • 14.

    Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, Pinches R, Newbold CI, Miller LH, 1995. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82: 101110.

    • Search Google Scholar
    • Export Citation
  • 15.

    Su XZ, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JA, Peterson DS, Ravetch JA, Wellems TE, 1995. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82: 89100.

    • Search Google Scholar
    • Export Citation
  • 16.

    Vogt AM, Barragan A, Chen Q, Kironde F, Spillmann D, Wahlgren M, 2003. Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1. Blood 101: 24052411.

    • Search Google Scholar
    • Export Citation
  • 17.

    Vogt AM, Winter G, Wahlgren M, Spillmann D, 2004. Heparan sulphate identified on human erythrocytes: a Plasmodium falciparum receptor. Biochem J 381: 593597.

    • Search Google Scholar
    • Export Citation
  • 18.

    Carlson J, Wahlgren M, 1992. Plasmodium falciparum erythrocyte rosetting is mediated by promiscuous lectin-like interactions. J Exp Med 176: 13111317.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rowe A, Berendt AR, Marsh K, Newbold CI, 1994. Plasmodium falciparum: a family of sulphated glycoconjugates disrupts erythrocyte rosettes. Exp Parasitol 79: 506516.

    • Search Google Scholar
    • Export Citation
  • 20.

    Moll K, Pettersson F, Vogt AM, Jonsson C, Rasti N, Ahuja S, Spangberg M, Mercereau-Puijalon O, Arnot DE, Wahlgren M, Chen Q, 2007. Generation of cross-protective antibodies against Plasmodium falciparum sequestration by immunization with an erythrocyte membrane protein 1-duffy binding-like 1 alpha domain. Infect Immun 75: 211219.

    • Search Google Scholar
    • Export Citation
  • 21.

    Barragan A, Fernandez V, Chen Q, von Euler A, Wahlgren M, Spillmann D, 2000. The duffy-binding-like domain 1 of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a heparan sulfate ligand that requires 12 mers for binding. Blood 95: 35943599.

    • Search Google Scholar
    • Export Citation
  • 22.

    Barragan A, Spillmann D, Kremsner PG, Wahlgren M, Carlson J, 1999. Plasmodium falciparum: molecular background to strain-specific rosette disruption by glycosaminoglycans and sulfated glycoconjugates. Exp Parasitol 91: 133143.

    • Search Google Scholar
    • Export Citation
  • 23.

    Vogt AM, Pettersson F, Moll K, Jonsson C, Normark J, Ribacke U, Egwang TG, Ekre HP, Spillmann D, Chen Q, Wahlgren M, 2006. Release of sequestered malaria parasites upon injection of a glycosaminoglycan. PLoS Pathog 2: e100.

    • Search Google Scholar
    • Export Citation
  • 24.

    Carlson J, Ekre HP, Helmby H, Gysin J, Greenwood BM, Wahlgren M, 1992. Disruption of Plasmodium falciparum erythrocyte rosettes by standard heparin and heparin devoid of anticoagulant activity. Am J Trop Med Hyg 46: 595602.

    • Search Google Scholar
    • Export Citation
  • 25.

    Jaroonvesama N, 1972. Intravascular coagulation in falciparum malaria. Lancet 1: 221223.

  • 26.

    Munir M, Tjandra H, Rampengan TH, Mustadjab I, Wulur FH, 1980. Heparin in the treatment of cerebral malaria. Paediatr Indones 20: 4750.

  • 27.

    Rampengan TH, 1991. Cerebral malaria in children. Comparative study between heparin, dexamethasone and placebo. Paediatr Indones 31: 5966.

    • Search Google Scholar
    • Export Citation
  • 28.

    Sheehy TW, Reba RC, 1967. Complications of falciparum malaria and their treatment. Ann Intern Med 66: 807809.

  • 29.

    Smitskamp H, Wolthuis FH, 1971. New concepts in treatment of malignant tertian malaria with cerebral involvement. BMJ 1: 714716.

  • 30.

    World Health Organization, 1986. Severe and complicated malaria. World Health Organization Malaria Action Programme. Trans R Soc Trop Med Hyg 80 (Suppl): 350.

    • Search Google Scholar
    • Export Citation
  • 31.

    Lindahl U, Backstrom G, Hook M, Thunberg L, Fransson LA, Linker A, 1979. Structure of the antithrombin-binding site in heparin. Proc Natl Acad Sci USA 76: 31983202.

    • Search Google Scholar
    • Export Citation
  • 32.

    Petitou M, Lormeau JC, Choay J, 1988. Interaction of heparin and antithrombin III. The role of O-sulfate groups. Eur J Biochem 176: 637640.

  • 33.

    Fransson LA, 1978. Periodate oxidation of D-glucuronic acid residues in heparan sulfate and heparin. Carbohydr Res 62: 235244.

  • 34.

    Skidmore MA, Dumax-Vorzet AF, Guimond SE, Rudd TR, Edwards EA, Turnbull JE, Craig AG, Yates EA, 2008. Disruption of rosetting in Plasmodium falciparum malaria with chemically modified heparin and low molecular weight derivatives possessing reduced anticoagulant and other serine protease inhibition activities. J Med Chem 51: 14531458.

    • Search Google Scholar
    • Export Citation
  • 35.

    Pettersson F, Vogt AM, Jonsson C, Mok BW, Shamaei-Tousi A, Bergstrom S, Chen Q, Wahlgren M, 2005. Whole-body imaging of sequestration of Plasmodium falciparum in the rat. Infect Immun 73: 77367746.

    • Search Google Scholar
    • Export Citation
  • 36.

    Blomqvist K, Normark J, Nilsson D, Ribacke U, Orikiriza J, Trillkott P, Byarugaba J, Egwang TG, Kironde F, Andersson B, Wahlgren M, 2010. var gene transcription dynamics in Plasmodium falciparum patient isolates. Mol Biochem Parasitol 170: 7483.

    • Search Google Scholar
    • Export Citation
  • 37.

    Peters J, Fowler E, Gatton M, Chen N, Saul A, Cheng Q, 2002. High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Proc Natl Acad Sci USA 99: 1068910694.

    • Search Google Scholar
    • Export Citation
  • 38.

    Peters JM, Fowler EV, Krause DR, Cheng Q, Gatton ML, 2007. Differential changes in Plasmodium falciparum var transcription during adaptation to culture. J Infect Dis 195: 748755.

    • Search Google Scholar
    • Export Citation
  • 39.

    Kimbi HK, Tetteh KK, Polley SD, Conway DJ, 2004. Cross-sectional study of specific antibodies to a polymorphic Plasmodium falciparum antigen and of parasite antigen genotypes in school children on the slope of Mount Cameroon. Trans R Soc Trop Med Hyg 98: 284289.

    • Search Google Scholar
    • Export Citation
  • 40.

    Wanji S, Tanke T, Atanga SN, Ajonina C, Nicholas T, Fontenille D, 2003. Anopheles species of the mount Cameroon region: biting habits, feeding behaviour and entomological inoculation rates. Trop Med Int Health 8: 643649.

    • Search Google Scholar
    • Export Citation
  • 41.

    Moll K, Ljungström I, Perlmann H, Scherf A, Wahlgren M, 2008. Methods in Malaria Research. MR4/ATCC, Manassas, Virginia. Paris, France: BioMalPar.

  • 42.

    Trager W, Jensen JB, 1976. Human malaria parasites in continuous culture. Science 193: 673675.

  • 43.

    European Pharmacopoeia, 2003. Heparins Low-Molecular-Mass, Monograph 0828. Strasbourg, France: European Directorate for the Quality of Medicines and Health Care.

    • Search Google Scholar
    • Export Citation
  • 44.

    Kyriacou HM, Steen KE, Raza A, Arman M, Warimwe G, Bull PC, Havlik I, Rowe JA, 2007. In vitro inhibition of Plasmodium falciparum rosette formation by Curdlan sulfate. Antimicrob Agents Chemother 51: 13211326.

    • Search Google Scholar
    • Export Citation
  • 45.

    Billa RF, Biwole MS, Juimo AG, Bejanga BI, Blackett K, 1991. Gall stone disease in African patients with sickle cell anaemia: a preliminary report from Yaounde, Cameroon. Gut 32: 539541.

    • Search Google Scholar
    • Export Citation
  • 46.

    Havlik I, Rovelli S, Kaneko Y, 1994. The effect of curdlan sulphate on in vitro growth of Plasmodium falciparum. Trans R Soc Trop Med Hyg 88: 686687.

    • Search Google Scholar
    • Export Citation
  • 47.

    Havlik I, Looareesuwan S, Vannaphan S, Wilairatana P, Krudsood S, Thuma PE, Kozbor D, Watanabe N, Kaneko Y, 2005. Curdlan sulphate in human severe/cerebral Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 99: 333340.

    • Search Google Scholar
    • Export Citation
 
 
 

 

 
 
 

 

 

 

 

 

 

Low Anticoagulant Heparin Disrupts Plasmodium falciparum Rosettes in Fresh Clinical Isolates

View More View Less
  • Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Dilafor AB, Solna, Sweden; Biotechnology Unit, Faculty of Science, University of Buea, Buea, Cameroon

The binding of Plasmodium falciparum parasitized erythrocytes to uninfected erythrocytes (rosetting) is associated with severe malaria. The glycosaminoglycan heparan sulfate is an important receptor for rosetting. The related glycosaminoglycan heparin was previously used in treatment of severe malaria, although abandoned because of the occurrence of severe bleedings. Instead, low anticoagulant heparin (LAH) has been suggested for treatment. LAH has successfully been evaluated in safety studies and found to disrupt rosettes and cytoadherence in vitro and in vivo in animal models, but the effect of LAH on fresh parasite isolates has not been studied. Herein, we report that two different LAHs (DFX232 and Sevuparin) disrupt rosettes in the majority of fresh isolates from Cameroonian children with malaria. The rosette disruption effect was more pronounced in isolates from complicated cases than from mild cases. The data support LAH as adjunct therapy in severe malaria.

Author Notes

*Address correspondence to Mats Wahlgren, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, PO Box 280, SE-171 77 Stockholm, Sweden. E-mail: mats.wahlgren@ki.se†These authors contributed equally.

Authors' addresses: Anna M. Leitgeb, Dilafor AB, Solna, Sweden, E-mail: anna.leitgeb@dilafor.com. Karin Blomqvist and Mats Wahlgren, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet (MTC), Stockholm, Sweden, E-mails: karin.blomqvist@ki.se and mats.wahlgren@ki.se. Fidelis Cho-Ngwa, Moses Samje, Peter Nde, and Vincent Titanji, University of Buea, Biotechnology Unit, Faculty of Science, Buea, Cameroon, E-mails: chongwa_ub@yahoo.co.uk, msamje@yahoo.com, ndepf@yahoo.com, and vpk.titanji@yahoo.com.

Save