Impaired nitric oxide bioavailability and <scp>l</scp>-arginine–reversible endothelial dysfunction in adults with falciparum malaria

Yeo, Tsin Wen; Lampah, Daniel A.; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; McNeil, Yvette R.; Darcy, Christabelle J.; Granger, Donald L.; Weinberg, J. Brice; Lopansri, Bert K.; Price, Ric N.; Duffull, Stephen B.; Celermajer, David S.; Anstey, Nicholas M.

doi:10.1084/jem.20070819

Cited by 273 publications

(468 citation statements)

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“…Accordingly, an apoptosis-coagulation-inflammation imbalance could occur in falciparum malaria, and it is plausible that the vicious cycle of coagulation and inflammation [27][28][29][30][31][32]51 operate and contribute to organ dysfunction, particularly in severe P. falciparum infections. It is important to recognize that nitric oxide (NO) availability may be impaired by hemolysis and hypoargininemia in both human 47 and mice 48 infected with Plasmodium sp. ; it has also been reported that carbon monoxide (CO) suppresses the pathogenesis of experimental cerebral malaria 45 .…”

Section: Discussionmentioning

confidence: 99%

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Francischetti

2008

Trends in Parasitology

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Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor (TF) in the brain endothelium of patients who died from cerebral malaria casts new light in our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells (pRBC) support assembly of multimolecular coagulation complexes. In this article, the role of TF expression by the endothelium and amplification of the coagulation cascade by pRBC and/or activated platelets-particularly at sequestration sitesis discussed as crucial events in mounting and sustaining a coagulation-inflammation cycle that contributes to organ dysfunction and coma in P. falciparum malaria. Blood coagulation and malariaMalaria caused by P. falciparum remains a highly endemic disease; it has been estimated that at least one million deaths occur every year. Children are at high risk, and often severe malaria (severe anemia or cerebral malaria [CM]) is the cause of death in this population 1-4. P. falciparum infection is associated with sequestration 5 -8 , endothelial cell (EC) activation 8-10, increase in inflammatory cytokines 3 , 11, and activation of the coagulation cascade 12 -20. Despite several papers devoted to the coagulation disorder in malaria-many of them published during the 1970s and 1980s (reviewed in Ref. 20)-the mechanism that triggers and propagates the coagulation activation in P. falciparum infection has remained elusive. These studies, however, demonstrated that bleeding and/or hemorrhage are typically not present, although laboratory tests indicate a certain degree of in vivo blood coagulation activation 12 -20 . Accordingly, prothrombin time (PT) and partial thromboplastin time (PTT) are close to normal values or prolonged, whereas thrombin-antithrombin complex (TAT) (which indicates in vivo thrombin formation) and D-dimers (which are a marker of in vivo fibrinolysis) are often elevated, and thrombocytopenia is a usual finding 12 -21 . This laboratory profile is compatible with disseminated intravascular coagulation (DIC), which is diagnosed according to a score defined by the International Society of Thrombosis and Haemostasis (ISTH) 22 . The scoring system takes into account i) platelet count, ii) elevated fibrin related markers, iii) prolonged prothrombin time, and iv) fibrinogen level 22 23 . Depending on the score punctuation, levels < 5 are suggestive of non-overt (compensated) DIC while scores > or = 5 are compatible with overt (decompensated) DIC. Bleeding is more common in overt DIC, but it is not needed for the formal diagnosis 22 23. In other words, absence of bleeding in P. falciparum-infected patients does not exclude the presence of DIC in this same population; actually, most of these patients meet the criteria for DIC as defined above 22 . Unfortunately, absence of bleeding is often mistakenly regarded as the reason why DIC is supposedly not present in malaria. Further, some reports do not support the view that coa...

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Section: Discussionmentioning

confidence: 99%

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Francischetti

2008

Trends in Parasitology

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“…Clinical studies on lung function in adult and pediatric patients support the presence of capillary dysfunction manifested as impaired gas exchange and reduced peripheral reactive hyperemic index. 34,35 However, despite evidence of acute lung injury, the presence of overt pulmonary edema in severe malaria varies from 5 to 25% in adults and less than 10% in children. 32 In the latter group, respiratory distress is believed to be mainly central nervous system (CNS)-driven as a response to systemic metabolic acidosis.…”

Section: Clinical Evidence Of Barrier Dysfunction In Severe Malariamentioning

confidence: 99%

“…87 In patients with both P. falciparum and P. vivax malaria, an inverse relationship between the severity of the infection and nitric oxide production/nitric oxide synthase expression has been demonstrated by several studies. 35,88 The decreased NO production and its precursor L-arginine were attributed to a deficiency of arginine and increased arginase activity. These derangements are compounded by the increased cell-free hemoglobin circulating in malaria patients secondary to hemolysis, leading to increased NO scavenging and plasma L-arginine catabolism, and an overall reduction in NO bioavailability as seen in sickle cell disease.…”

Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

“…The readouts were reactive hyperemiaperipheral arterial tonometry, which is more a measure of vascular tone, and gaseous exchange that could be affected by perfusion. Clinical trials of L-arginine in patients with severe falciparum malaria have led to some improvement in vascular tone, 35 but larger randomized trials will be needed to assess effects on disease severity or mortality. A clinical trial in pediatric malaria showed that inhaled nitric oxide did not affect biomarkers of severe disease.…”

Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

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Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

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“…La arginina es el sustrato para la síntesis de óxido nítrico; los pacientes con malaria presentan bajos niveles de este aminoácido en sangre que se asocian con malaria grave y muerte (70,71). Durante la hemólisis de los glóbulos rojos parasitados se libera arginasa eritrocitaria y hemoglobina, que reducen la disponibilidad del óxido nítrico, la primera, por degradar la arginina y la segunda, por secuestrar el óxido nítrico disponible.…”

Section: Hipótesis De La Biodisponibilidad Del óXido Nítricounclassified

Pathogenic mechanisms in Plasmodium falciparum malaria

Vásquez

Tobón

2012

biomedica

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Se presentan los mecanismos patogénicos más conocidos en la infección por Plasmodium falciparum durante la fase eritrocitaria y extraeritrocitaria. La obstrucción vascular, explicada por los fenómenos de secuestro de glóbulos rojos parasitados y la formación de rosetas, mediados por diversos ligandos y receptores endoteliales, además de los procesos inflamatorios instaurados ante la presencia del parásito, son aspectos centrales en la patogenia de la malaria que permiten explicar los procesos de disfunción, daño y muerte celular en diferentes órganos. A partir de eventos como la lesión y la destrucción de eritrocitos, hepatocitos y células endoteliales, la pérdida de integridad del endotelio y la activación de promotores de daño celular y de apoptosis, se explican alteraciones como el aumento de la permeabilidad vascular, la hipoxia y el metabolismo anaerobio, que conducen tanto a lesiones localizadas en órganos como cerebro y pulmón, como a un estado de acidosis generalizada y falla multisistémica.Palabras clave: malaria/etiología, Plasmodium falciparum, inflamación. Pathogenic mechanisms in Plasmodium falciparum malariaThe most recognized pathogenic mechanisms of the infection with Plasmodium falciparum, during both the erythrocytic and exo-erithrocytic stages are presented. Vascular obstruction explained by the sequestration of parasitized red blood cells and erythrocyte rosetting, mediated by different endothelial ligands and receptors, in addition to the inflammatory processes induced by the presence of the parasite, are central aspects in the pathogenesis of malaria that explain the processes of damage, dysfunction and cell death in various organs. Alterations such as increased vascular permeability, hypoxia and anaerobic metabolism leading to localized lesions in organs such as brain and lung, as well as to a generalized acidotic state with multisystem failure can be explained by events such as the injury and destruction of erythrocytes, hepatocytes and endothelial cells, the loss of endothelial integrity, and the activation of cell damage and apoptosis promoters.Key words: Malaria/ethiology, Plasmodium falciparum, inflamation.Los signos y síntomas clínicos en la malaria, o paludismo, expresión del daño ocasionado en diversos órganos y sistemas, se exacerban durante el período de multiplicación del parásito en el eritrocito, mientras que el estadio hepático y la presencia de gametocitos tradicionalmente no se han asociado con la sintomatología. La malaria causa lesiones estructurales y alteraciones funcionales y metabólicas, cuya presentación clínica está en función de la edad, el estado inmunitario y las características genéticas del huésped, y por la especie, el genotipo y la virulencia del parásito. Puede conducir a un cuadro clínico grave el cual casi siempre se observa en las infecciones causadas por Plasmodium falciparum. Las complicaciones informadas con mayor frecuencia incluyen anemia grave, malaria cerebral, síndrome de dificultad respiratoria aguda y falla renal (1); en los últimos años se vien...

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Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria

Cited by 273 publications

References 54 publications

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Pathogenic mechanisms in Plasmodium falciparum malaria

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