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.

Placental Malaria in Colombia: Histopathologic Findings in Plasmodium vivax and P. falciparum Infections

“…3 Studies conducted in populations in Africa confirmed the association between P. falciparum submicroscopic infection during pregnancy with maternal anemia and low birth weight 57 and with a pro-coagulant/anti-fibrinolytic effect, but not with inflammation. 58 Submicroscopic infection in gestational malaria and placental malaria is a common finding in northwestern Colombia. 29 Preliminary results of ongoing studies in the region indicate an association between increased apoptosis and some pro-inflammatory cytokines during placental infection by any species (Agudelo O and others, unpublished data).…”

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

“…Unstained, paraffin-embedded 5 μm mouse and human placental tissue sections (for whom the consent process and clinical and parasitological data were previously described [28]) were used for immunohistochemistry (IHC) according to previously reported methods [26] with a Polink-HRP kit for rat or rabbit antibodies (used according to manufacturer instructions; GBI, Inc. Mukilteo, WA, USA). Tissue sections were deparaffinized and rehydrated through xylene and graded alcohol series.…”

“…Like P. berghei ANKA, P. chabaudi AS -iRBCs have also been reported to accumulate in placental tissue [25]. P. chabaudi AS infection early in pregnancy leads to poor outcomes in C57BL/6J (B6) mice as well as in A/J mice, with characteristic features of human PM that lead to poor pregnancy outcomes being found in both strains [25-28]. Reduced thickness of the labyrinth, extensive hemorrhage, and coagulopathy are found in mid-gestation placentae of B6 mice infected with P. chabaudi AS during early pregnancy [26, 28].…”

“…P. chabaudi AS infection early in pregnancy leads to poor outcomes in C57BL/6J (B6) mice as well as in A/J mice, with characteristic features of human PM that lead to poor pregnancy outcomes being found in both strains [25-28]. Reduced thickness of the labyrinth, extensive hemorrhage, and coagulopathy are found in mid-gestation placentae of B6 mice infected with P. chabaudi AS during early pregnancy [26, 28]. Whereas TNF responses to malaria are observed in both strains, levels are quite high in A/J mice [25, 26]; ablation of this response with neutralizing antibodies significantly improves mid-gestational pregnancy success in B6 [26] but not in A/J mice [25], in which higher neutralizing activity may be required.…”

Excess Fibrin Deposits Decrease Fetal Weight of Pregnant Mice Infected by Plasmodium berghei

“…Placental malaria revealed a number of abnormalities to placental tissue such as excess of fibrinoid deposits and malarial pigment deposits (haemozoin) [8].…”