Activation of the host response in human plasmodium falciparum malaria: Relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels

Hemmer, Christoph Josef; Kern, Peter; Holst, Friedrich Georg Ernst; Radtke, Klaus-Peter; Egbring, R; Bierhaus, Angelika; Nawroth, Peter P.; Dietrich, M.

doi:10.1016/0002-9343(91)90071-5

Cited by 64 publications

(83 citation statements)

References 27 publications

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“…: tissue factor pathway inhibitor, thrombomodulin/ protein C, and antithrombin), and antiplatelet substances produced by the endothelium (e.g., prostacyclin) may determine the procoagulantinflammatory tonus in vessels of patients with malaria. Likewise, bioavailability of vasodilator nitric oxide (NO), which may be impaired in human and in experimental malaria, could potentially aggravate inflammation-related events through enhanced expression of adhesion molecules and the exarcebation of cytoadherence and [13][14][15][16] . In support of a decompensated state in severe malaria are findings of EC apoptosis 42 , identification of circulating microparticles 21,46 , and accumulation of platelets and monocytes in the vessels of the brain 39 from CM cases but not from uncomplicated malaria.…”

Section: The Tissue Factor Model For Malaria Pathogenesismentioning

confidence: 99%

“…The main argument that supports this notion is the fact that the vast majority, perhaps all patients with mild and severe malaria, present elevated levels of D-dimers20, a specific marker of plasmin-mediated fibrin proteolysis in vivo 23 . Finally, it has been reported that hemostatic alterations correlate with parasitemia, thrombocytopenia, and/or severity of P. falciparum infection in a number of studies; in addition, antiparasitic treatment halts the coagulation disorder and improves clinical outcome [12][13][14][15][16][17][18][19][20] .Therefore, it is plausible that hemostatic alterations play a role in the disease progression and organ failure observed in malaria 16,20 .More recently, it has been demonstrated that P. falciparum-parasitized RBC (pRBC) induce tissue factor (TF) expression in the microvascular EC in vitro, and support the assembly of multimolecular coagulation complexes 10 . TF is the clotting initiator 24-26 and a structural member of the cytokine receptor family, which signifies the expansion of the adaptive immune system in vertebrates, indicating a close connection of the coagulation pathways with the host response to infection 27 .…”

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confidence: 99%

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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: The Tissue Factor Model For Malaria Pathogenesismentioning

confidence: 99%

mentioning

confidence: 99%

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

Francischetti

2008

Trends in Parasitology

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“…74 Consequently, analogous to the previous discussion regarding a putative role for VWF in malaria, it remains unclear whether coagulation cascade activation is directly involved in modulating the pathogenesis of P falciparum malaria, or whether instead this coagulation activation merely represents a secondary epiphenomenon. Although previous studies demonstrated no beneficial effect with heparin anticoagulation in patients with severe malaria, 88 further studies will be necessary to determine whether other targeted coagulation cascade inhibition (eg, specific FXa or FIIa inhibition with direct oral anticoagulant agents) may have a role to play.…”

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confidence: 96%

Emerging roles for hemostatic dysfunction in malaria pathogenesis

O’Sullivan

Preston

O’Regan

et al. 2016

Blood

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Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum–infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

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“…20,21 For patients who received antimalarial drugs, which induce a non-natural state during treatment, the rare finding of thrombin and fibrin formation might result from a return to normal condition from a hypercoagulable state after administration of antimalarial drugs. 17,22 In contrast with P. falciparum infection, altered thrombostasis and intravascular coagulation have not yet been characterized in P. vivax infection. 4,23 However, a study of acute kidney injury that developed with P. vivax infection found that the characteristics of renal biopsies were thrombotic microangiopathy, arterioles filled with an intraluminal fibrin thrombus or platelets, and endothelial injury.…”

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confidence: 99%

“…Elevation of cytokines such as tumor necrosis factor (TNF)-α and interferon (INF)-γ, in conjunction with the cytoadhesion of malaria-iRBCs to endothelial cells, can cause endothelial injury and activation, followed by expression of tissue factors and hypercoagulability. 22,26,27 Microvascular endothelial adhesion of P. falciparum-iRBCs appears to develop throughout the body, and distribution of iRBCs and extent of sequestration varies by organ system and is not even uniform within the same organ. 20,21,[28][29][30][31][32] Elevation of TNF-α and IFN-γ/IL-10 and increase in endothelial activation markers such as thrombomodulin, intracellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, and E-selectin are also observed in P. vivax infection.…”

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confidence: 99%

Malaria-Induced Splenic Infarction

Hwang

Lee

2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Splenic infarction is a rare complication of malaria. We report two recent cases of splenic infarction after Plasmodium vivax infection. No systematic review of malaria-induced splenic infarction was available, therefore we conducted a systematic review of the English, French, and Spanish literature in PubMed and KoreaMed for reports of malaria-associated splenic infarction from 1960 to 2012. Of the 40 cases collected on splenic infarction by Plasmodium species, 23 involved P. vivax, 11 Plasmodium falciparum, one Plasmodium ovale, and five a mixed infection of P. vivax and P. falciparum. Of the 40 cases, 2 (5.0%) involved splenectomy and 5 (12.5%) were accompanied by splenic rupture. The median time from symptom onset to diagnosis was 8.5 days (range, 3-90 days). Improved findings after treatment were observed in 8 (88.9%) of 9 patients with splenic infarction on follow-up by computed tomography or ultrasonography. All patients survived after treatment with the exception of one patient with cerebral malaria. Clinicians should consider the possibility of splenic infarction when malaria-infected patients have left upper quadrant pain.

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Activation of the host response in human plasmodium falciparum malaria: Relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels

Cited by 64 publications

References 27 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?

Emerging roles for hemostatic dysfunction in malaria pathogenesis

Malaria-Induced Splenic Infarction

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