title: Maternal malaria induces a procoagulant and antifibrinolytic state that is embryotoxic but responsive to anticoagulant therapy.
abstract: Low birth weight and fetal loss are commonly attributed to malaria in endemic areas, but the cellular and molecular mechanisms that underlie these poor birth outcomes are incompletely understood. Increasing evidence suggests that dysregulated hemostasis is important in malaria pathogenesis, but its role in placental malaria (PM), characterized by intervillous sequestration of Plasmodium falciparum, proinflammatory responses, and excessive fibrin deposition is not known. To address this question, markers of coagulation and fibrinolysis were assessed in placentae from malaria-exposed primigravid women. PM was associated with significantly elevated placental monocyte and proinflammatory marker levels, enhanced perivillous fibrin deposition, and increased markers of activated coagulation and suppressed fibrinolysis in placental plasma. Submicroscopic PM was not proinflammatory but tended to be procoagulant and antifibrinolytic. Birth weight trended downward in association with placental parasitemia and high fibrin score. To directly assess the importance of coagulation in malaria-induced compromise of pregnancy, Plasmodium chabaudi AS-infected pregnant C57BL/6 mice were treated with the anticoagulant, low molecular weight heparin. Treatment rescued pregnancy at midgestation, with substantially decreased rates of active abortion and reduced placental and embryonic hemorrhage and necrosis relative to untreated animals. Together, the results suggest that dysregulated hemostasis may represent a novel therapeutic target in malaria-compromised pregnancies.
authors.affiliation: Department of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Avery
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Smith
authors.forename: Simon O
authors.initials: SO
authors.lastname: Owino
authors.forename: Demba
authors.initials: D
authors.lastname: Sarr
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.forename: Stephen
authors.initials: S
authors.lastname: Mwalimu
authors.forename: James
authors.initials: J
authors.lastname: Matthias
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Kelly
authors.forename: Jayakumar S
authors.initials: JS
authors.lastname: Poovassery
authors.forename: Joab D
authors.initials: JD
authors.lastname: Middii
authors.forename: Carlos
authors.initials: C
authors.lastname: Abramowsky
authors.forename: Julie M
authors.initials: JM
authors.lastname: Moore
mesh_terms: D000818:Animals; D001724:Birth Weight; D001777:Blood Coagulation; D005260:Female; D005342:Fibrinolysis; D006487:Hemostasis; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D008288:Malaria / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D051379:Mice; D010920:Placenta / Q000098:blood supply / Q000469:parasitology; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood* / Q000188:drug therapy; D019851:Thrombophilia / Q000469:parasitology*; D016896:Treatment Outcome
chemical_list: D006495:Heparin, Low-Molecular-Weight