Systemic antithrombotic effects of ADAMTS13

Chauhan, Anil K.; Motto, David G.; Lamb, Colin B.; Bergmeier, Wolfgang; Dockal, Michael; Plaimauer, Barbara; Scheiflinger, Friedrich; Ginsburg, David; Wagner, Denisa D.

doi:10.1084/jem.20051732

Cited by 197 publications

(212 citation statements)

References 52 publications

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“…In vitro and in vivo studies have observed that some VWF molecules may be anchored to endothelial surface upon secretion from endothelial cells [31][32][33]. This anchoring appears fragile but may be sufficient to allow conformational unfolding of VWF by shear stress.…”

Section: Adamts13 Prevents Microvascular Platelet Thrombosismentioning

confidence: 99%

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Tsai

2007

Hematology/Oncology Clinics of North America

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Section: Adamts13 Prevents Microvascular Platelet Thrombosismentioning

confidence: 99%

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Tsai

2007

Hematology/Oncology Clinics of North America

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“…Our results showed that in TTP patients their plasma levels of HNP1-3 correlated with plasma levels of Bb (rho=0.48, P<0.001) ( Figure 3A) and serum LDH (rho=0. 28 Figure 3B), but not with the inhibitor titer (P>0.05) ( Figure 3C) and serum creatinine (P>0.05) ( Figure 3D). …”

Section: Correlations Between Hnp1-3 or Bb And Other Key Clinical Andmentioning

confidence: 99%

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

et al. 2016

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A cquired thrombotic thrombocytopenic purpura is primarily caused by the deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease, but the underlying mechanisms are not fully understood. Herein, 52 patients with acquired autoimmune thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study. The plasma levels of human neutrophil peptides 1-3 and complement activation fragments (i.e. Bb, iC3b, C4d, and sC5b-9) were determined by enzyme-linked immunosorbent assays. Univariate analyses were performed to determine the correlation between each biomarker and clinical outcomes. We found that the plasma levels of human neutrophil peptides 1-3 and Bb in patients with acute thrombotic thrombocytopenic purpura were significantly higher than those in the control (P<0.0001). The plasma levels of HNP1-3 correlated with the levels of plasma complement fragment Bb (rho=0.48, P=0.0004) and serum lactate dehydrogenase (rho=0.28, P=0.04); in addition, the plasma levels of Bb correlated with iC3b (rho=0.55, P<0.0001), sC5b-9 (rho=0.63, P<0.0001), serum creatinine (rho=0.42, p=0.0011), and lactate dehydrogenase (rho=0.40, P=0.0034), respectively. Moreover, the plasma levels of iC3b and sC5b-9 were correlated (rho=0.72, P<0.0001), despite no statistically significant difference of the two markers between thrombotic thrombocytopenic purpura patients and the control. We conclude that innate immunity, i.e. neutrophil and complement activation via the alternative pathway, may play a role in the pathogenesis of acute autoimmune thrombotic thrombocytopenic purpura, and a therapy targeted at these pathways may be considered in a subset of these patients.

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“…19 Briefly, mice were anesthetized and an incision was made through the abdominal wall to expose the mesenteric venules of 200-to 300-m in diameter. The shear rate was calculated using an optical Doppler velocimeter (Microcirculation Research Institute, Texas A&M College of Medicine, College Station, TX).…”

Section: Intravital Microscopymentioning

confidence: 99%

“…We have demonstrated earlier an important role for VWF in promoting platelet endothelial interaction in vivo under venous conditions 23 that was accentuated in mice lacking ADAMTS13, the enzyme cleaving VWF multimers. 19,24 But the role of VWF-GPIb␣ in platelet adhesion to subendothelium and aggregation at low venous Fluorescently-labeled platelets representing approximately 2.5% of total platelets were observed in mesenteric venules of live mice after ferric-chloride injury. Representative photographs of the injured venules are shown.…”

mentioning

confidence: 99%

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Chauhan

Kisucka

Lamb

et al. 2006

Blood

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von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using genetargeted mice, we show that in ferric chloride-injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF ؊/؊ mice when compared with wild type (WT). We also observed increased embolization in the VWF ؊/؊ mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF ؊/؊ venules did not occlude. Introductionvon Willebrand factor (VWF) is a large adhesive glycoprotein synthesized in megakaryocytes and endothelial cells and stored in platelet ␣-granules and Weibel-Palade bodies, respectively. VWF circulates in plasma as a series of multimers ranging from 500 to 20 000 kDa. The size of the multimers is regulated through proteolysis 1,2 by a specific protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13). [3][4][5] There are 3 pools of VWF: (1) soluble plasma VWF, (2) subendothelial (ECM) VWF, and (3) cellular VWF in storage granules. 6 VWF is a carrier for factor VIII (FVIII) and protects it from inactivation. 7 The formation of a thrombus on an injured vessel wall is a complex process that involves multiple adhesion molecules (VWF, collagen, fibrinogen, and fibronectin) and their respective receptors on the platelet surface (GPIb␣, GPVI, ␤1 and ␤3 integrins). VWF has 2 main receptors, GPIb␣ in the GPIb-IX-V complex and the integrin ␣IIb␤3. 8 Pathological thrombosis can occur in arteries and veins. Arterial thrombosis is often linked to inappropriate platelet activation and can result in myocardial infarction and ischemic stroke, while venous thrombosis (eg, deep vein thrombosis) is commonly linked to high procoagulant activity, which produces fibrin-rich thrombi. In the clinical setting, elevated levels of FVIII and VWF are associated with an increased risk of venous thrombosis. The Leiden Thrombophilia Study suggested that the effect of elevated VWF on the risk of venous thrombosis was due to increased FVIII levels. 9 In contrast, the Longitudinal Investigation of Thromboembolism Etiology (LITE) Study showed FVIII and VWF were independently associated with venous thromboembolism. 10 Under high shear, the VWF-GPIb␣ interaction is necessary for initial platelet contact with the subendothelium, while irreversible platelet aggregation also requires interaction between the VWF and integrin ␣IIb␤3. 8,[11][12][13] Although an important role for VWF in platelet-platelet cohesion and thrombus formation at arterial shear rates was demonstrated both in vitro 13,14 and in vivo, 15,...

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Systemic antithrombotic effects of ADAMTS13

Cited by 197 publications

References 52 publications

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

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