Abstract
BackgroundThrombotic thrombocytopenic purpura (TTP), caused by a genetic or autoimmune‐driven lack of ADAMTS‐13 activity, leads to high levels of the ultra‐large von Willebrand factor (VWF) multimers produced by endothelial cells, causing excess platelet recruitment into forming thrombi, often with mortal consequences. Treatments include plasma infusion or replacement to restore ADAMTS‐13 activity, or prevention of platelet recruitment to VWF. ObjectivesWe tested a different approach, exploiting the unique cell biology of the endothelium. Upon activation, the VWF released by exocytosis of Weibel‐Palade bodies (WPBs), transiently anchored to the cell surface, unfurls as strings into flowing plasma, recruiting platelets. Using plasma from patients with TTP increases platelet recruitment to the surface of cultured endothelial cells under flow. WPBs are uniquely plastic, and shortening WPBs dramatically reduces VWF string lengths and the recruitment of platelets. We wished to test whether the TTP plasma‐driven increase in platelet recruitment would be countered by reducing formation of the longest WPBs that release longer strings. MethodsEndothelial cells grown in flow chambers were treated with fluvastatin, one of 37 drugs shown to shorten WPBs, then activated under flow in the presence of platelets and plasma of either controls or patients with TTP. ResultWe found that the dramatic increase in platelet recruitment caused by TTP plasma is entirely countered by treatment with fluvastatin, shortening the WPBs. ConclusionsThis potential approach of ameliorating the endothelial contribution to thrombotic risk by intervening far upstream of hemostasis might prove a useful adjunct to more conventional and direct therapies. [Display omitted]
Highlights
Thrombotic thrombocytopenic purpura (TTP) is a severe disease resulting in multiorgan failure and, untreated, has a mortality of >90%
von Willebrand factor (VWF) undergoes a complex biosynthesis in endothelial cells, culminating in the formation of tubules of multiple coiled ultra-large (UL-VWF) multimers that drive the formation of the rod-shaped endothelial secretory granules, Weibel-P alade bodies (WPBs).4-6 Endothelial activation drives Weibel-Palade bodies (WPBs) exocytosis to release their content into the plasma, where flow unfurls the tubular coils of UL-VWF into long strings anchored to the endothelial surface by an unknown mechanism.[7]
We recently showed that the lengths of VWF strings change with the length of WPBs; that WPBs are formed in a range of sizes from 0.5 to 5 μm and that their size is affected by physiological cues, or by drugs that affect the modulators of WPB size (Golgi linkage, secretory trafficking rate, and VWF expression level).9-12 In TTP, the lack of functional ADAMTS-13 precludes proteolysis of the just-secreted UL-VWF multimers
Summary
Thrombotic thrombocytopenic purpura (TTP) is a severe disease resulting in multiorgan failure and, untreated, has a mortality of >90%. With UL-VWF persisting, excess platelet recruitment to strings or into thrombi occurs.13-17 We describe here a potential approach toward ameliorating congenital TTP (cTTP) that focuses on modulating endothelial cell function. We show, in these in vitro proof-of-concept experiments, that we can repurpose a representative of well-understood drugs, statins, that we previously identified as able to decrease WPB size, decreasing string lengths, to reduce the platelet recruitment under flow in vitro. Thrombotic thrombocytopenic purpura (TTP), caused by a genetic or autoimmune-driven lack of ADAMTS-13 activity, leads to high levels of the ultra- large von Willebrand factor (VWF) multimers produced by endothelial cells, causing excess platelet recruitment into forming thrombi, often with mortal consequences. Conclusions: This potential approach of ameliorating the endothelial contribution to thrombotic risk by intervening far upstream of hemostasis might prove a useful adjunct to more conventional and direct therapies
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