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Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.

ABSTRACT: During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.

SUBMITTER: Bridges DJ

PROVIDER: S-EPMC2840836 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.

Bridges Daniel J DJ Bunn James J van Mourik Jan A JA Grau Georges G Preston Roger J S RJ Molyneux Malcolm M Combes Valery V O'Donnell James S JS de Laat Bas B Craig Alister A

Blood 20091106 7

During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adher ...[more]

PMID: 19897581

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Project description:BACKGROUND:Complete mechanistic understanding of impaired microvascular reflow after myocardial infarction will likely lead to new therapies for reducing infarct size. Myocardial contrast echocardiography perfusion imaging and molecular imaging were used to evaluate the contribution of microvascular endothelial-associated VWF (von Willebrand factor) and platelet adhesion to microvascular no-reflow. METHODS AND RESULTS:Myocardial infarction was produced by transient LAD ligation in WT (wild type) mice, WT mice treated with the VWF proteolytic enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and ADAMTS13-deficient (ADAMTS13-/-) mice. Myocardial contrast echocardiography perfusion imaging and molecular imaging of VWF and platelet GP (glycoprotein) Ib? were performed 30 minutes after ischemia-reperfusion. Infarct size was measured at 3 days. Mortality during ischemia-reperfusion incrementally increased in WT+ADAMTS13, WT, and ADAMTS13-/- mice (14%, 43%, and 63%, respectively; P<0.05). For WT mice, molecular imaging signal for platelets and VWF in the postischemic risk area was 4- to 5-fold higher ( P<0.05) compared with both the remote nonischemic regions or to sham-treated mice. Signal enhancement in the risk area was completely abolished by ADAMTS13 treatment for both platelets (12.8±3.3 versus -1.0±4.4 IU; P<0.05) and VWF (13.9±4.0 versus -1.0±3.0 IU; P<0.05). ADAMTS13-/- compared with WT mice had 2- to 3-fold higher risk area signal for platelets (33.1±8.5 IU) and VWF (30.9±1.9 IU). Microvascular reflow in the risk area incrementally decreased for WT+ADAMTS13, WT, and ADAMTS13-/- mice ( P<0.05), whereas infarct size incrementally increased ( P<0.05). CONCLUSIONS:Mechanistic information on microvascular no-reflow is possible by combining perfusion and molecular imaging. In reperfused myocardial infarction, excess endothelial-associated VWF and secondary platelet adhesion in the risk area microcirculation contribute to impaired reflow and are modifiable.

Project description:Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding. SUMMARY:Background A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.

Dataset Information

Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.

Publications

Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.

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