thromboplastin and Malaria--Falciparum

Malaria remains a highly prevalent disease in more than 90 countries and accounts for at least 1 million deaths every year. Plasmodium falciparum infection is often associated with a procoagulant tonus characterized by thrombocytopenia and activation of the coagulation cascade and fibrinolytic system; however, bleeding and hemorrhage are uncommon events, suggesting that a compensated state of blood coagulation activation occurs in malaria. This article (i) reviews the literature related to blood coagulation and malaria in a historic perspective, (ii) describes basic mechanisms of coagulation, anticoagulation, and fibrinolysis, (iii) explains the laboratory changes in acute and compensated disseminated intravascular coagulation (DIC), (iv) discusses the implications of tissue factor (TF) expression in the endothelium of P. falciparum infected patients, and (v) emphasizes the procoagulant role of parasitized red blood cells (RBCs) and activated platelets in the pathogenesis of malaria. This article also presents the Tissue Factor Model (TFM) for malaria pathogenesis, which places TF as the interface between sequestration, endothelial cell (EC) activation, blood coagulation disorder, and inflammation often associated with the disease. The relevance of the coagulation-inflammation cycle for the multiorgan dysfunction and coma is discussed in the context of malaria pathogenesis.

Topics: Animals; Blood Platelets; Coma; Disseminated Intravascular Coagulation; Endothelium, Vascular; Erythrocytes; Fibrinolysis; Humans; Inflammation; Malaria, Falciparum; Plasmodium falciparum; Platelet Activation; Thrombocytopenia; Thromboplastin

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

Serum from patients with P. falciparum malaria at day 1 (pretherapy) induces tissue factor (TF) in cultured endothelial cells. TF induction depends on de novo transcription as shown in Nuclear Run On assays. Electrophoretic mobility shift assays demonstrated binding of AP-1 and NF-kappa B/Rel proteins to their recognition sites in the TF promotor. After therapy (day 28), stimulation of TF antigen by patient serum is reduced by 70%. When serum obtained before and after therapy was compared, a decrease of NF-kappa B activation was evident. Activation of NF-kappa B-like proteins was in part dependent on TNF alpha in patient serum, since a TNF alpha neutralizing antibody reduced induction of TF transcription and translation and induction of NF-kappa B-like proteins. Induction of TF activity was suppressed by pDTC, an inhibitor of NF-kappa B activation. When different promotor constructs of the TF gene were tested, induction was dependent upon the presence of the intact NF-kappa B-like binding site in the TF promotor. A mutant with deleted NF-kappa B, but intact AP-1 sites was not inducible. Mutation of the AP-1 sites did not prevent induction, but reduced inducibility by pretherapy serum. Therefore, NF-kappa B/Rel proteins are responsible for induction of TF transcription by pretherapy serum, but AP-1 is needed for highest inducibility. The effect of antiparasitic therapy on the induction of TF by serum from patients with complicated P. falciparum malaria is dependent on a therapy-mediated loss of activation of NF-kappa B-like proteins in post-treatment patient serum.

Topics: Antimalarials; Base Sequence; Binding Sites; Cells, Cultured; Endothelium, Vascular; Gene Expression Regulation; Genes, Reporter; Humans; Malaria, Falciparum; Molecular Sequence Data; Mutagenesis; NF-kappa B; Promoter Regions, Genetic; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; Thromboplastin; Transcription Factor AP-1; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha; Umbilical Veins

Monocytes are active elements of the host response against Plasmodium falciparum. They are able to express tissue factor and trigger the extrinsic pathway of blood coagulation the activation of which remained unclear in malaria. Our aim was to assess the tissue factor expression of purified blood monocytes stimulated by cultured Plasmodium falciparum-infected erythrocytes. Malaria parasite induced an early generation of tissue factor with a peak between 8 and 12 h of stimulation. Maximum expression was observed for parasitemia ranging from 1 to 2%. Plasmodium falciparum culture supernatants had the same effect showing the existence of a soluble factor able to induce the tissue factor expression. These data, demonstrating an activation of the tissue factor pathway by the malaria parasite, emphasize thrombin generation. Therefore, thrombin could participate in malaria pathology either in the microcirculatory blockade via platelet and fibrinogen activation or as a mitotic.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Erythrocytes; Humans; In Vitro Techniques; Malaria, Falciparum; Monocytes; Plasmodium falciparum; Thromboplastin