fibrin and Malaria--Falciparum

A procoagulant state is implicated in cerebral malaria (CM) pathogenesis, but whether disseminated intravascular coagulation (DIC) is present or associated with a fatal outcome is unclear.. To determine the frequency of overt DIC, according to ISTH criteria, in children with fatal and non-fatal CM.. Malawian children were recruited into a prospective cohort study in the following diagnostic groups: retinopathy-positive CM (n = 140), retinopathy-negative CM (n = 36), non-malarial coma (n = 14), uncomplicated malaria (UM), (n = 91), mild non-malarial febrile illness (n = 85), and healthy controls (n = 36). Assays in the ISTH DIC criteria were performed, and three fibrin-related markers, i.e. protein C, antithrombin, and soluble thrombomodulin, were measured.. Data enabling assignment of the presence or absence of 'overt DIC' were available for 98 of 140 children with retinopathy-positive CM. Overt DIC was present in 19 (19%), and was associated with a fatal outcome (odds ratio [OR] 3.068; 95% confidence interval [CI] 1.085-8.609; P = 0.035]. The levels of the three fibrin-related markers and soluble thrombomodulin were higher in CM patients than in UM patients (all P < 0.001). The mean fibrin degradation product level was higher in fatal CM patients (71.3 μg mL(-1) [95% CI 49.0-93.6]) than in non-fatal CM patients (48.0 μg mL(-1) [95% CI 37.7-58.2]; P = 0.032), but, in multivariate logistic regression, thrombomodulin was the only coagulation-related marker that was independently associated with a fatal outcome (OR 1.084 for each ng mL(-1) increase [95% CI 1.017-1.156]; P = 0.014). Despite these laboratory derangements, no child in the study had clinically evident bleeding or thrombosis. An overt DIC score and high thrombomodulin levels are associated with a fatal outcome in CM, but infrequently indicate a consumptive coagulopathy.

Topics: Biomarkers; Blood Glucose; Child; Child, Preschool; Coma; Disseminated Intravascular Coagulation; Female; Fever; Fibrin; Hematologic Tests; Humans; Infant; Lactates; Malaria, Cerebral; Malaria, Falciparum; Malawi; Male; Parasitemia; Prospective Studies; Retinal Hemorrhage; Risk Factors; Thrombomodulin

Inflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, 'parasite-derived' uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.. We measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5-17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.. Elevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084).

Topics: E-Selectin; Endothelium; Erythrocytes; Fibrin; Humans; Inflammation; Intercellular Adhesion Molecule-1; Malaria, Falciparum; Microvessels; Plasmodium falciparum; Platelet Aggregation; Thrombomodulin; Uric Acid; Vascular Cell Adhesion Molecule-1

Maternal anemia and low birth weight (LBW) may complicate malaria in pregnancy, and placental monocyte infiltrates have been associated with LBW, and anecdotally with anemia. We examined placental pathology from 357 Malawian women. Intervillous monocyte infiltrates were frequent in placental malaria and were not seen in uninfected placentas. Histology was grouped according to a 5-point scale. Dense monocyte infiltrates and presence of intramonocytic malaria pigment were associated with anemia and LBW. Of factors associated with LBW and/or anemia in univariate analysis, gravidity (P = 0.002), number of antenatal clinic (ANC) visits (P < 0.001), malaria pigment in fibrin (P = 0.03), and monocyte malaria pigment (P = 0.0001) remained associated with lower birth weight by multivariate analysis. Associated with maternal anemia were HIV infection (P < 0.0001), intervillous monocyte numbers (P < 0.0001), number of ANC visits (P = 0.002), and recent febrile symptoms (P = 0.0001). Pigment-containing placental monocytes are associated with anemia and LBW due to malaria, and may have a causative role in their development.

Topics: Adolescent; Adult; Anemia; Animals; Birth Weight; Female; Fibrin; Hemoglobins; Humans; Infant, Low Birth Weight; Infant, Newborn; Malaria, Falciparum; Middle Aged; Monocytes; Pigments, Biological; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Prospective Studies; Risk Factors

The expression of tissue factor (TF), the initiator of the clotting system, was investigated by immunohistochemical staining for its role in clotting mechanisms of Plasmodium falciparum-infected placenta. Most mononuclear cells in the intervillous space of infected placentas stained with an anti-TF monoclonal antibody (MAb) and were positive for antimacrophage MAb. The intervillous space of infected placentas had significant fibrin deposition. In contrast, only small amounts of leukocytes, TF-positive cells, and fibrin were seen in the intervillous space in noninfected placentas. These results indicate that macrophages accumulated in infected placentas express TF and that subsequent perivillous fibrin clot formation leads to a narrowing and plugging of the intervillous space and disturbance of the blood supply. Macrophage TF expression in placentas could be associated with retarded placental growth and low birth weight in malaria infection and should be further investigated.

Topics: Animals; Female; Fibrin; Gene Expression Regulation; Humans; Immunohistochemistry; Infant, Newborn; Macrophages; Malaria, Falciparum; Placenta; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Thromboplastin

Maternal malaria is associated with reduced birth weight, which is thought to be effected through placental insufficiency, which leads to intrauterine growth retardation (IUGR). The impact of malaria on preterm delivery is unclear. The effects of placental malaria-related changes on birth weight and gestational age were studied in 1177 mothers (and their newborns) from Tanzania. Evidence of malaria infection was found in 75.5% of placental samples. Only massive mononuclear intervillous inflammatory infiltration (MMI) was associated with increased risk of low birth weight (odds ratio ¿OR, 4.0). Maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of premature delivery (OR, 3.2; OR, 2.1, respectively). MMI is an important mechanism in the pathogenesis of IUGR in malaria-infected placentas. This study also shows that placental malaria causes prematurity even in high-transmission areas. The impact of maternal malaria on infant mortality may be greater than was thought previously.

Topics: Birth Weight; Chorionic Villi Sampling; Female; Fetal Growth Retardation; Fibrin; Gestational Age; Humans; Infant, Low Birth Weight; Infant, Newborn; Infectious Disease Transmission, Vertical; Malaria, Falciparum; Odds Ratio; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Tanzania

Pregnant women are more likely to contract malaria than their non-pregnant counterparts. The aim of this study was to develop a simple classification system for the histopathological diagnosis of placental malaria infection applicable to placentas collected in field conditions. The placentas were classified into four groups depending on the presence and distribution of parasites and malaria pigment: active infection, active-chronic infection, past-chronic infection, not infected. The frequency of parasitized placentas (26.4%) was in keeping with the prevalence of placental parasitaemia documented in epidemiological studies. An additional 29.8% placentas showed pigment in fibrin only, indicating past-chronic infection. Chronic placental malaria infection was most common in primigravidae, possibly reflecting ineffective clearance of parasites from the placenta. Seasonal fluctuations between infection categories support progression of placental infection with delayed clearance of pigment from fibrin. The proposed classification system has allowed diagnosis of different categories of placental malaria infection by two independent observers. A standardized method of diagnosis may enhance understanding of placental pathology and reduced birth weight in malaria infection during pregnancy.

Topics: Adolescent; Adult; Africa, Western; Animals; Antibodies, Protozoan; Birth Weight; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Humans; Immunoglobulin G; Immunoglobulin M; Incidence; Malaria, Falciparum; Parity; Placenta; Placenta Diseases; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Seasons

Malaria in pregnancy is associated with reduced birth weight. Most pathological studies of placental malaria infection have focused on severe Plasmodium falciparum infection. In the present study of 121 placentas delivered in a rural area of The Gambia, malaria infection was diagnosed in tissue sections using a simple classification system and severity of pathology was ranked semiquantitatively. Deposition of malaria pigment in circulating cells was associated with active infections whereas pigment in fibrin was a feature of active-chronic infections. Primigravidae had higher levels of pigment at all sites, although these observations were not always significant. Thickening of the trophoblast basement membrane occurred in all infection categories but fibrinoid necrosis of chorionic villi was a feature of active and active-chronic infection. Both birth weight and placental weight were increased in infected placentas but widespread trophoblast basement membrane thickening was associated with decreased birth weight. Both birth weight and placental weight decreased with increased fibrinoid necrosis and cytotrophoblast prominence but the results were not significant. By this approach it has been possible to correlate placental pathology with different infection categories and to analyse the pathological features associated with decreased birth weight.

Topics: Adolescent; Adult; Basement Membrane; Birth Weight; Female; Fibrin; Humans; Malaria, Falciparum; Organ Size; Parity; Pigmentation Disorders; Placenta; Placenta Diseases; Pregnancy; Severity of Illness Index