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von Willebrand factor in experimental malaria‐associated acute respiratory distress syndrome

Published on Aug 1, 2019in Journal of Thrombosis and Haemostasis4.662
· DOI :10.1111/JTH.14485
Sirima Kraisin1
Estimated H-index: 1
(Katholieke Universiteit Leuven),
Sebastien Verhenne6
Estimated H-index: 6
(Katholieke Universiteit Leuven)
+ 7 AuthorsSimon F. De Meyer24
Estimated H-index: 24
(Katholieke Universiteit Leuven)
Abstract
BACKGROUND: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lethal complication of severe malaria, characterized by marked pulmonary inflammation. Patient studies have suggested a link between von Willebrand factor (VWF) and malaria severity. OBJECTIVES: To investigate the role of VWF in the pathogenesis of experimental MA-ARDS. METHODS: Plasmodium berghei NK65-E (PbNK65) parasites were injected in Vwf+/+ and Vwf-/- mice. Pathological parameters were assessed following infection. RESULTS: In accordance with patients with severe malaria, plasma VWF levels were increased and ADAMTS13 activity levels were reduced in experimental MA-ARDS. ADAMTS13- and plasmin-independent reductions of high molecular weight VWF multimers were observed at the end stage of disease. Thrombocytopenia was VWF-independent because it was observed in both Vwf+/+ and Vwf-/- mice. Interestingly, Vwf-/- mice had a shorter survival time compared with Vwf+/+ controls following PbNK65 infection. Lung edema could not explain this shortened survival because alveolar protein levels in Vwf-/- mice were approximately two times lower than in Vwf+/+ controls. Parasite load, on the other hand, was significantly increased in Vwf-/- mice compared with Vwf+/+ mice in both peripheral blood and lung tissue. In addition, anemia was only observed in PbNK65-infected Vwf-/- mice. Of note, Vwf-/- mice presented with two times more reticulocytes, a preferential target of the parasites. CONCLUSIONS: This study suggests that parasite load together with malarial anemia, rather than alveolar leakage, might contribute to shortened survival in PbNK65-infected Vwf-/- mice. VWF deficiency is associated with early reticulocytosis following PbNK65 infection, which potentially explains the increase in parasite load.
  • References (60)
  • Citations (3)
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References60
Newest
#1Leen Vandermosten (Rega Institute for Medical Research)H-Index: 4
#2Thao-Thy Pham (Rega Institute for Medical Research)H-Index: 5
Last. P. E. Van den Steen (Rega Institute for Medical Research)H-Index: 7
view all 11 authors...
Background Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a complication of malaria with a lethality rate of up to 80% despite anti-malarial treatment. It is characterized by a vast infiltration of leukocytes, microhaemorrhages and vasogenic oedema in the lungs. Previously, a mouse model for MA-ARDS was developed by infection of C57BL/6 mice with the Edinburgh line NK65-E of Plasmodium berghei.
7 CitationsSource
#1Claudia Tersteeg (Katholieke Universiteit Leuven)H-Index: 13
#2Bérangère S. Joly (Paris Diderot University)H-Index: 7
Last. Karen Vanhoorelbeke (Katholieke Universiteit Leuven)H-Index: 38
view all 12 authors...
Background Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening pathology, caused by occlusive von Willebrand factor (VWF)-rich microthrombi that accumulate in absence of ADAMTS13. We previously demonstrated that plasmin can cleave VWF and that plasmin is generated in patients during acute TTP. However, the exact role for plasmin in TTP remains unclear. Objectives Investigate if endogenous plasmin-mediated proteolysis of VWF can influence acute TTP episodes. Results Also in mic...
5 CitationsSource
#1Charlotte Kawecki (French Institute of Health and Medical Research)H-Index: 1
#1Charlotte Kawecki (French Institute of Health and Medical Research)H-Index: 7
Last. Cécile V. Denis (French Institute of Health and Medical Research)H-Index: 35
view all 3 authors...
Summary Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for coagulation factor VIII. In pathological settings, VWF is recognized as a risk factor for both arterial and venous thrombosis, as well as a molecular player that directly promotes the thrombotic process. Recent years have seen the emergence of t...
39 CitationsSource
#1Louis Deforche (Katholieke Universiteit Leuven)H-Index: 5
#2Claudia Tersteeg (Katholieke Universiteit Leuven)H-Index: 13
Last. Karen Vanhoorelbeke (Katholieke Universiteit Leuven)H-Index: 38
view all 11 authors...
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy linked to a deficiency in the metalloprotease ADAMTS13. In the current study, a novel mouse model for acquired TTP was generated to facilitate development and validation of new therapies for this disease. Therefore, a large panel (n = 19) of novel anti-mouse ADAMTS13 (mADAMTS13) monoclonal antibodies (mAbs) of mouse origin was generated. Inhibitory anti-mADAMTS13 mAbs were identified using the FRETS-VWF73 ...
9 CitationsSource
#2Roger J. S. Preston (Trinity College, Dublin)H-Index: 20
Last. James S. O’DonnellH-Index: 33
view all 4 authors...
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 b...
27 CitationsSource
#1Susan M. Graham (UW: University of Washington)H-Index: 27
#2Junmei ChenH-Index: 18
Last. W. Conrad Liles (UW: University of Washington)H-Index: 51
view all 10 authors...
Background Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, and poor outcomes have been associated with endothelial activation. In this study, biomarkers of endothelial activation, haemostasis, and thrombosis were measured in Ugandan children with severe malaria who participated in a clinical trial, in order to investigate associations between these processes.
10 CitationsSource
Objective—The metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) regulates the size of von Willebrand factor multimers. A deficiency in ADAMTS13 activity is associated with the life-threatening disease thrombotic thrombocytopenic purpura (TTP). The vast majority of patients have acquired TTP, where circulating anti-ADAMTS13 autoantibodies are causative for the decreased ADAMTS13 activity. Current treatment consists of plasma exchange, but...
41 CitationsSource
#1Sebastien Verhenne (Katholieke Universiteit Leuven)H-Index: 6
#2Frederik Denorme (Katholieke Universiteit Leuven)H-Index: 10
Last. Simon F. De Meyer (Katholieke Universiteit Leuven)H-Index: 13
view all 11 authors...
Abstract Von Willebrand factor (VWF) is a key hemostatic protein synthesized in both endothelial cells and megakaryocytes. Megakaryocyte-derived VWF is stored in α-granules of platelets and is enriched in hyperactive "ultra-large" VWF multimers. To elucidate the specific contribution of platelet VWF in hemostasis and thrombosis, we performed crossed bone marrow transplantations between C57BL/6J and Vwf(-/-) mice to generate chimeric mice. Chimeric mice specifically lacking platelet VWF showed no...
37 CitationsSource
#1Peter J. Lenting (French Institute of Health and Medical Research)H-Index: 53
Last. Cécile V. Denis (French Institute of Health and Medical Research)H-Index: 35
view all 3 authors...
To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra- and extracellular) that implicate a wide range of other proteins: its...
119 CitationsSource
#1E. De Cock (Katholieke Universiteit Leuven)H-Index: 1
#2Cédric HermansH-Index: 28
Last. Karen Vanhoorelbeke (Katholieke Universiteit Leuven)H-Index: 38
view all 12 authors...
Summary: Background: Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by mutations in the ADAMTS13 gene, which either impair protein secretion or influence ADAMTS13 (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type-1 motif, member 13) activity. Phenotypic consequences of these mutations have not yet been evaluated in animal models for TTP. Objectives: To identify the in vitro effect of a novel ADAMTS13 mutation and to investigate whether this mutation i...
14 CitationsSource
Cited By3
Newest
#1Isaclaudia G. de Azevedo-Quintanilha (FIOCRUZ: Oswaldo Cruz Foundation)H-Index: 1
#2Isabel Matos Medeiros-de-Moraes (FIOCRUZ: Oswaldo Cruz Foundation)H-Index: 3
Last. Hugo C. Castro-Faria-Neto (FIOCRUZ: Oswaldo Cruz Foundation)H-Index: 40
view all 10 authors...
Malaria-triggered lung injury can occur in both severe and non-severe cases. Platelets may interact with parasitized erythrocytes, leukocytes and endothelium. These interactions can lead to microvessel obstructions and induce release of inflammatory mediators. Induction of the haem oxygenase enzyme is important in the host’s response to free haem and to several other molecules generated by infectious or non-infectious diseases. In addition, an important role for the haem oxygenase-1 isotype has ...
Source
#1Thao-Thy Pham (Rega Institute for Medical Research)H-Index: 5
#2Chuchard Punsawad (WU.: Walailak University)H-Index: 9
Last. P. E. Van den Steen (Rega Institute for Medical Research)H-Index: 7
view all 6 authors...
Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an understudied complication of malaria and is characterized by pulmonary inflammation and disruption of the alveolar-capillary membrane. Its pathogenesis remains poorly understood. Since endothelial activation plays an important role in other malarial complications, the expression of two endothelial activation markers, von Willebrand factor (VWF) and angiopoietin-2 (ANG-2), was investigated in the lungs of patients with MA-ARDS...
Source
#1Jae C. Chang (UCI: University of California, Irvine)H-Index: 18
#1Jae C. Chang (UCI: University of California, Irvine)
Acute respiratory distress syndrome (ARDS) is a life-threatening noncardiogenic circulatory disorder of the lungs associated with critical illnesses such as sepsis, trauma, and immune and collagen ...
13 CitationsSource