scholarly journals The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis

Blood ◽  
2018 ◽  
Vol 132 (9) ◽  
pp. 903-910 ◽  
Author(s):  
Camila Masias ◽  
Spero R. Cataland
Keyword(s):  
Thrombotic Microangiopathies ◽  
Acute Setting ◽  
Artery Disease ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Deficient Activity

Abstract ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP.

scholarly journals Assessment of the Dual Role of Clumping Factor A in S. Aureus Adhesion to Endothelium in Absence and Presence of Plasma

2018 ◽  
Vol 118 (07) ◽  
pp. 1230-1241 ◽  
Author(s):  
Jorien Claes ◽  
Bartosz Ditkowski ◽  
Laurens Liesenborghs ◽  
Tiago Veloso ◽  
Jose Entenza ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Binding Protein ◽  
Protein A ◽  
Bacterial Proteins ◽  
Fibronectin Binding Protein ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractAdhesion of Staphylococcus aureus to endothelial cells (ECs) is paramount in infective endocarditis. Bacterial proteins such as clumping factor A (ClfA) and fibronectin binding protein A (FnbpA) mediate adhesion to EC surface molecules and (sub)endothelial matrix proteins including fibrinogen (Fg), fibrin, fibronectin (Fn) and von Willebrand factor (vWF). We studied the influence of shear flow and plasma on the binding of ClfA and FnbpA (including its sub-domains A, A16+, ABC, CD) to coverslip-coated vWF, Fg/fibrin, Fn or confluent ECs, making use of Lactococcus lactis, expressing these adhesins heterologously. Global adherence profiles were similar in static and flow conditions. In the absence of plasma, L. lactis-clfA binding to Fg increased with shear forces, whereas binding to fibrin did not. The degree of adhesion of L. lactis-fnbpA to EC-bound Fn and of L. lactis-clfA to EC-bound Fg, furthermore, was similar to that of L. lactis-clfA to coated vWF domain A1, in the presence of vWF-binding protein (vWbp). Yet, in plasma, L. lactis-clfA adherence to activated EC-vWF/vWbp dropped over 10 minutes by 80% due to vWF-hydrolysis by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 and that of L. lactis-fnbpA likewise by > 70% compared to the adhesion in absence of plasma. In contrast, plasma Fg supported high L. lactis-clfA binding to resting and activated ECs. Or, in plasma S. aureus adhesion to active endothelium occurs mainly via two complementary pathways: a rapid but short-lived vWF/vWbp pathway and a stable integrin-coupled Fg-pathway. Hence, the pharmacological inhibition of ClfA-Fg interactions may constitute a valuable additive treatment in infective endocarditis.

scholarly journals Regulation of plasma von Willebrand factor

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 96 ◽  
Author(s):  
Karl C Desch
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Vascular Wall ◽  
Healthy Human ◽  
Venous Thromboembolic ◽  
Artery Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study.

scholarly journals Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

2020 ◽  
Vol 11 ◽  
Author(s):  
Junxian Yang ◽  
Zhiwei Wu ◽  
Quan Long ◽  
Jiaqi Huang ◽  
Tiantian Hong ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Therapeutic Strategy ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Neutrophil Extracellular Trap ◽  
Activated Neutrophils ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

scholarly journals How I treat refractory thrombotic thrombocytopenic purpura

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3860-3867 ◽  
Author(s):  
Farzana A. Sayani ◽  
Charles S. Abrams
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Symptoms ◽  
Thrombocytopenic Purpura ◽  
New Therapeutic Approaches ◽  
Number Of Patients ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.

scholarly journals The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

2021 ◽  
Vol 8 (9) ◽  
pp. 115
Author(s):  
Benjamin Reardon ◽  
Leonardo Pasalic ◽  
Emmanuel J. Favaloro
Keyword(s):  
Von Willebrand Factor ◽  
Cardiac Disease ◽  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Primary Hemostasis ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Relationship Of ◽  
Willebrand Factor

von Willebrand factor (VWF) is an adhesive protein involved in primary hemostasis and facilitates platelet adhesion to sites of vascular injury, thereby promoting thrombus formation. VWF exists in plasma as multimers of increasing size, with the largest (high molecular weight; HMW) expressing the greatest functional activity. A deficiency of VWF is associated with a bleeding disorder called von Willebrand disease (VWD), whereas an excess of VWF, in particular the HMW forms, is associated with thrombosis. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif-13), also known as VWF-cleaving protease, functions to moderate the activity of VWF by cleaving multimers of VWF and limiting the expression of the largest multimers of VWF. A deficiency of ADAMTS13 is therefore associated with an excess of (HMW forms of) VWF, and thus thrombosis. Indeed, any disturbance of the VWF/ADAMTS13 ratio or ‘axis’ may be associated with pathophysiological processes, including prothrombotic tendency. However, both thrombosis or bleeding may be associated with such disturbances, depending on the presenting events. This review evaluates the relationship of VWF and ADAMTS13 with cardiac disease, including cardiac failure, and associated pathophysiology.

ADAMTS13 turns 3

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Gallia G. Levy ◽  
David G. Motto ◽  
David Ginsburg
Keyword(s):  
Research Effort ◽  
Adamts13 Activity ◽  
Hematologic Disease ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Normal Hemostasis ◽  
Von Willebrand ◽  
Willebrand Factor

It has now been 3 years since the von Willebrand factor (VWF)–cleaving protease implicated in thrombocytopenic purpura (TTP) pathogenesis was identified as ADAMTS13 (adisintegrin-like and metalloprotease with thrombospondin type 1 motif 13). More than 50 ADAMTS13 mutations resulting in familial TTP have been reported. Considerable progress has also been realized toward understanding the role of ADAMTS13 in normal hemostasis, as well as the mechanisms by which ADAMTS13 deficiency contributes to TTP pathogenesis. Measurement of ADAMTS13 activity in TTP and other pathologic conditions also remains a focus of a substantial clinical research effort. Building on these studies, continued investigation of ADAMTS13 and VWF holds considerable promise for advancing the understanding of TTP pathogenesis and should lead to improved diagnosis and treatment for this important hematologic disease.

Development of novel treatment options for patients with haemophilia

2013 ◽  
Vol 33 (S 01) ◽  
pp. S36-S38 ◽  
Author(s):  
H. J. Ehrlich ◽  
W. Y. Wong ◽  
B. M. Ewenstein ◽  
M. Dockal ◽  
P. L. Turecek ◽  
...  
Keyword(s):  
Treatment Options ◽  
New Products ◽  
Factor Ix ◽  
Added Value ◽  
Recombinant Factor Ix ◽  
A Disintegrin And Metalloproteinase ◽  
Recombinant Fviii ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryTreatment of haemophilia has vastly improved over the last years, but many needs are still unmet. Baxter is continuously pursuing the aim to provide new therapeutic options to patients with haemophilia and to their treating physicians. In fact, there are several opportunities to improve existing therapies, e.g., by new indications for existing products, the introduction of new products, and by novel therapeutic approaches other than factor replacement. Among these, Baxter is working on a number of innovations, such as pharmacokinetics-tailored factor VIII prophylaxis, bypassing agent prophylaxis with FEIBA in inhibitor patients, development of a longer acting pegylated recombinant FVIII, a new recombinant factor IX, a new recombinant factor FVIIa, the first recombinant von Willebrand factor, recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as well as gene therapy to cure haemophilia B. Conclusion: Baxter is truly committed to the benefit for the patient, and therefore engaged in providing a more and more individualized treatment, in increasing efficiency of current products, in developing new products and new approaches with added value.

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