Impact of the von Willebrand factor-ADAMTS-13 axis on the risk of future venous thromboembolism

Edvardsen, Magnus S.; Hansen, Ellen-Sofie; Ueland, Thor; Aukrust, Pål; Brækkan, Sigrid Kufaas; Morelli, Vânia M.; Hansen, John‐Bjarne

doi:10.1016/j.jtha.2023.01.024

Cited by 5 publications

(4 citation statements)

References 58 publications

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“…Insufficient VWF modulation is also a recognized contributor to more common macrovascular thrombotic events, like acute ischemic stroke and venous thromboembolism. 17 , 18 …”

Section: Discussionmentioning

confidence: 99%

Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

El Otmani,

Frunt,

Smits

et al. 2024

Blood

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Von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. We here describe the development of a VHH-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in TTP patients during acute attacks of thrombotic microangiopathy, but not in remission. Finally, we show that therapeutic plasminogen activation in a mouse model for TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion.

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“…Insufficient VWF modulation is also a recognized contributor to more common macrovascular thrombotic events, like acute ischemic stroke and venous thromboembolism. 17 , 18 …”

Section: Discussionmentioning

confidence: 99%

Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

El Otmani,

Frunt,

Smits

et al. 2024

Blood

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“…von Willebrand factor (VWF) is a plasma glycoprotein that mediates platelet adhesion at sites of vascular injury and contributes to the process of hemostasis [1,2]. The interaction between VWF and platelets under high shear stress has been shown to be critical in arterial thrombosis [3][4][5] and recent evidence suggests that VWF also plays a role in venous thrombosis [6,7].…”

Section: Introductionmentioning

confidence: 99%

The impact of von Willebrand factor on fibrin formation and structure unveiled with type 3 von Willebrand disease plasma

Martinez-Vargas,

Courson,

Gardea

et al. 2024

Blood Coagulation &Amp; Fibrinolysis

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Normally, von Willebrand factor (VWF) remains inactive unless its A1A2 domains undergo a shear stress-triggered conformational change. We demonstrated the capacity of a recombinant A2 domain of VWF to bind and to affect fibrin formation, altering the fibrin clot structure. The data indicated that VWF contains an additional binding site for fibrin in the A2 domain that plays a role in the incorporation of VWF to the polymerizing fibrin. This study is to examine the hypothesis that active plasma VWF directly influence fibrin polymerization and the structure of fibrin clots. The study used healthy and type 3 von Willebrand disease (VWD) plasma, purified plasma VWF, fibrin polymerization assays, confocal microscopy and scanning electron microscopy. The exposed A2 domain in active VWF harbors additional binding sites for fibrinogen, and significantly potentiates fibrin formation (P < 0.02). Antibody against the A2 domain of VWF significantly decreased the initial rate of change of fibrin formation (P < 0.002). Clot analyses revealed a significant difference in porosity between normal and type 3 VWD plasma (P < 0.008), further supported by scanning electron microscopy, which demonstrated thicker fibrin fibers in the presence of plasma VWF (P < 0.0003). Confocal immunofluorescence microscopy showed punctate VWF staining along fibrin fibrils, providing visual evidence of the integration of plasma VWF into the fibrin matrix. The study with type 3 VWD plasma supports the hypothesis that plasma VWF directly influences fibrin polymerization and clot structure. In addition, a conformational change in the A1A2 domains exposes a hidden fibrin(ogen) binding site, indicating that plasma VWF determines the fibrin clot structure.

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“…Nevertheless, in both cases, the reduced proteolysis of VWF high molecular weight multimers triggers severe thrombotic events on activated or injured endothelium [21]. In addition, high plasmatic levels of VWF contribute to hemostatic imbalance and ultimately to thrombosis [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

A Long-Term Follow-Up Study in Immune-Mediated Thrombotic Thrombocytopenic Purpura: What Are the Outcomes?

Bonifacio,

Roselli,

Schifone

et al. 2023

JCM

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Endothelium damage triggers the multimeric protein von Willebrand factor (VWF) release and subsequent binding to platelets, which are recruited at sites of vascular injury. A complex and fragile equilibrium between circulating levels of von Willebrand factor and its metalloprotease, ADAMTS13, is responsible for the hemostatic balance. However, the presence of autoantibodies targeting ADAMTS13 results in an increase in von Willebrand factor, mainly in its ultra-large multimers. The latter lead to platelet aggregation, the formation of thrombi and microangiopathic hemolytic anemia. This pathologic condition, known as immune-mediated thrombotic thrombocytopenic purpura (iTTP), occurs with high morbidity and a high rate of relapses. In this work, the long-term follow-up of 40 patients with iTTP is reported. We assessed ADAMTS13 activity, plasmatic VWF levels and the ADAMTS13/VWF ratio, comparing iTTP relapsing patients with remitting ones. A decrease in the ADAMTS13/VWF ratio, along with a reduced ADAMTS13 activity, could serve as predictive and sensitive biomarkers of incoming relapses.

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Impact of the von Willebrand factor-ADAMTS-13 axis on the risk of future venous thromboembolism

Cited by 5 publications

References 58 publications

Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

The impact of von Willebrand factor on fibrin formation and structure unveiled with type 3 von Willebrand disease plasma

A Long-Term Follow-Up Study in Immune-Mediated Thrombotic Thrombocytopenic Purpura: What Are the Outcomes?

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