Von Willebrand Faktor spaltende Protease und thrombotische Mikroangiopathien. Von Willebrand factor cleaving protease and thrombotic microangiopathy

2004 ◽  
Vol 28 (6) ◽  
pp. 506-513
Author(s):  
Ulrich Budde ◽  
Reinhard Schneppenheim
Keyword(s):  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Thrombotische Mikroangiopathien ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Endothelial von Willebrand Factor Release Due to eNOS Deficiency Predisposes to Thrombotic Microangiopathy in Mouse Aging Kidney

2010 ◽  
Vol 176 (5) ◽  
pp. 2198-2208 ◽  
Author(s):  
Takahiro Nakayama ◽  
Waichi Sato ◽  
Ashio Yoshimura ◽  
Li Zhang ◽  
Tomoki Kosugi ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Aging Kidney ◽  
Factor Release

Flow Driven Self-Assembly of Von Willebrand Factor Strands and Cables in Synthetic Blood Vessels

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 261-261
Author(s):  
Junmei Chen ◽  
Ying Zheng ◽  
Jose A. Lopez
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Cleavage Site ◽  
Vessel Wall ◽  
Small Vessels ◽  
Microvascular Thrombosis ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 261 Endothelial activation and microvascular thrombosis are hallmarks of thrombotic microangiopathy—a group of life-threatening disorders that includes thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Activated endothelial cells release von Willebrand factor (VWF), which can form long strands under flow that remain attached to the endothelium until they are cleaved off by the metalloprotease ADAMTS13. Failure to remove these strands, either because of ADAMTS13 deficiency or oxidation of its cleavage site on VWF, results in microvascular thrombosis. Until now, studies of VWF strands under flow have been performed either in flow chambers with cultured endothelial cells, which does not account for either vessel caliber or geometry, or in live mice, in which it is impossible to study individually the contributions of the various blood components. Recently, we developed a technique to engineer microvessels in vitro that enables us to precisely control several vessel parameters, including lumen diameter and branching architecture, flow patterns, and applied shear stresses, in addition to being able to test individual components of the blood in a system with only human components (PNAS 2012, 109:9342–9347). In the current study, we used this system to examine the effects of a number of variables on the formation of VWF strands from the endothelium of stimulated vessels. We found that VWF fibers can extend across the vessel lumen and attach to opposite sides of the vessel wall in agonist-treated microvessels of up to 200 μm in diameter. Depending on flow conditions, smaller strands can self-associate to form longer and thicker cables. The VWF cables produced solely from VWF contributed by the vessel wall reached lengths up to 5 cm, and became so thick as to be visible, unstained, by light microscopy. When plasma or recombinant VWF was perfused over the VWF cables, the fluid-phase VWF associated with the vessel-bound cables, further thickening them and sometimes inducing web-like structures. The location and structure of the VWF fibers were dependent on vessel geometry and flow pattern; secondary flows that developed at bends or bifurcations in the vessel induced circular clumping of the VWF strands. When whole blood was perfused into the vessels, the transluminal VWF fiber webs caught flowing platelets and leukocytes to form aggregates in the middle of blood stream that sometimes occluded the vessels. The region where the vessel is most likely to occlude also depends on geometry. After this type of trapping, leukocytes were seen to transmigrate across the endothelium. The structure and size of the cables also depended on the agonist employed to stimulate VWF release from the endothelium. Phorbol myristate acetate and shiga-like toxin–2 both produced thicker cables than histamine did, and these were more resistant to ADAMTS13 cleavage. This difference is potentially a result of the former agonists stimulating an endothelial respiratory burst and oxidation of the ADAMTS13 cleavage site on VWF. In summary, our data show that VWF secreted from activated endothelial cells can form transluminal fibers and cables in small vessels. Some of the fibers or cables are resistant to ADAMTS13 cleavage, a likely consequence of their thickness and possibly, oxidation. The webs of VWF fibers or cables in the lumen of small vessels obstruct blood flow by binding to circulating platelets and leukocytes, and are also capable of shredding erythrocytes as they flow past. These findings provide insights into the mechanisms of microangiopathy, and raise the possibility that VWF cables alone, even in the absence of bound platelets, may be capable of occluding small blood vessels and produce many of the characteristic signs of thrombotic microangiopathy. Disclosures: No relevant conflicts of interest to declare.

Schistocytic anaemia, severe thrombocytopenia, and renal dysfunction: thrombotic microangiopathy due to severe acquired ADAMTS-13 deficiency

2003 ◽  
Vol 23 (03) ◽  
pp. 103-108 ◽  
Author(s):  
A. Winkler ◽  
J. A. Kremer Hovinga ◽  
V. Bianchi ◽  
J.-D. Studt ◽  
B. Lämmle
Keyword(s):  
Renal Dysfunction ◽  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Plasma Exchange Therapy ◽  
Therapeutic Measures ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe present the case of a woman (age: 64 years) with acute thrombotic microangiopathy due to severe acquired ADAMTS-13 (von Willebrand factor-cleaving protease) deficiency. She was successfully treated with plasma exchange therapy and glucocorticosteroids. She relapsed seven months later, and splenectomy led to lasting remission.Pathomechanisms of thrombotic thrombocytopenic purpura, especially the role of ADAMTS-13, are discussed and therapeutic measures outlined.

ADAMTS13 related markers and von Willebrand factor in plasma from patients with thrombotic microangiopathy (TMA)

2008 ◽  
Vol 121 (6) ◽  
pp. 849-854 ◽  
Author(s):  
Toshihiko Kobayashi ◽  
Hideo Wada ◽  
Norihiro Nishioka ◽  
Masae Yamamoto ◽  
Takeshi Matsumoto ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Von Willebrand ◽  
Willebrand Factor

Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure

2009 ◽  
Vol 101 (02) ◽  
pp. 239-247 ◽  
Author(s):  
Ulrich Budde ◽  
Karim Kentouche ◽  
Maik Sossdorf ◽  
Thomas Hilberg ◽  
Reinhart Schneppenheim ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Von Willebrand Factor ◽  
Thrombotic Microangiopathy ◽  
Therapeutic Monitoring ◽  
Healthy Controls ◽  
Combined Approach ◽  
Antigen Level ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVon Willebrand factor (VWF) and related parameters as well as the protease activity regulating its biological activity were measured in plasma of healthy controls and patients with different cause and severity of systemic inflammation to examine the efficacy of the measures to detect highly prothrombotic states including thrombotic microangiopathy (TMA), one of the sequelae of sepsis. Plasma levels of VWF increased with increasing severity of systemic inflammation, probably due to activation of the endothelium. In parallel, the proteolytic activity of VWF inactivating protease, ADAMTS13, stepwise declined with the severity of inflammation, emphasizing the role of VWF-triggered platelet aggregation on the endothelium subsequently followed by development of TMA. As a consequence, the ratio of VWF antigen level and ADAMTS13 activity was significantly higher in patients with inflammation and sepsis, suggesting that this ratio might be more useful for the diagnosis of highly prothrombotic states including TMA than VWF multimer analysis alone. These findings suggest that ADAMTS13, VWF and related parameters, even in a combined approach, might be useful for the diagnosis and the therapeutic monitoring of patients with sepsis associated thrombotic microangiopathy.

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