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 factoractivated 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. (Blood. 2010;115:1472-1474) IntroductionPlasmodium falciparum malaria remains a scourge in many developing tropical regions of the world where it claims the lives of hundreds of thousands of children every year. A defining feature of one of the most severe forms of the disease, cerebral malaria (CM), is the sequestration of infected erythrocytes to endothelium in brain postcapillary venules. Adhesion is mediated by P falciparum erythrocyte membrane protein 1 (PfEMP1) to various host receptors, such as CD36, 1 to which almost all pediatric isolates bind. 2 With little or no CD36 being expressed on brain endothelium, it had been assumed that CD36 adhesion was not involved in CM. Several observations have challenged this assumption. First, analysis of human postmortem brain sections from fatal CM, severe malarial anemia, and nonmalarial cases showed a strong correlation between platelet accumulation, which generally colocalized with malaria pigment, and disease severity. 3 The possible mechanism underlying this association was further developed in vitro, where it was shown that platelets could act as a bridge between activated brain endothelium not expressing CD36 and infected erythrocytes (IEs) that only bind to CD36. 4 Endothelial activation is classically achieved using cytokines, such as tumor necrosis factor, which induce the relatively slow process (hours) of de novo protein synthesis. We proposed a mechanism for rapid adhesion via the multimeric protein von Willebrand factor (VWF) 5 that mediates platelet adhesion to sites of vascular injury. The mature ultra-large, and physiologically most active, form of VWF is stored in specialized secretory vesicles in endothelial cells (ECs) called Weibel-Palade bodies. 6 When released, these large VWF multimers unravel under flow to form platelet-decorated strings that are cleaved and regulated by the endogenous plasma protease ADAMTS-13 (a disintegrin a...

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

“…It is tempting to speculate that this mechanism could be relevant for other pathophysiological conditions, such as autoinflammatory diseases and sepsis, known to support the formation of ULVWF fibers and attenuate ADAMTS13 activity. 31,33,[62][63][64] Thus, our data provide essential information delineating thrombotic mechanisms and highlight EC activation or microthrombi formation as new therapeutic targets in cancer treatment ( Figure 7H). …”

N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice

“…If NAC proves useful in TTP, its use could be extended to other syndromes in which hyperactive vWF might also have a role, such as sickle cell anemia (6, 37), myocardial infarction (38), cerebral malaria (39,40), and stroke (41). We therefore expect that the result of this study may stimulate investigation of NAC as a therapy for several other disorders in which excessive vWF-mediated cell adhesion plays a causative role.…”

Platelet profile is associated with clinical complications in patients with vivax and falciparum malaria in Colombia

“…Specifi cally, the median PCs were signifi cantly lower in the patients with hepatic complications (90,500 vs. 129,000; p≤0.001), renal complications (80,000 vs. 114,000; p=0.017), neurologic complications (42,000 vs. 122,000; p≤0.001), pulmonary complications (55,000 vs. 122,000; p=0.001) and severe hypoglycemia (40,500 vs. 119,000; p=0.004). The low PC may result from the adhesion of platelets to the sites of vascular injuries and the mediation of malaria-parasitized red blood cells (pRBC) sequestration to the endothelium through von Willebrand-factor strings 53 .…”