A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13

Schiviz, Alexandra; Wuersch, Kuno; Piskernik, Christina; Dietrich, Barbara; Hoellriegl, Werner; Rottensteiner, Hanspeter; Scheiflinger, Friedrich; Schwarz, Hans; Muchitsch, Eva-Maria

doi:10.1182/blood-2011-09-380535

Cited by 105 publications

(118 citation statements)

References 36 publications

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“…30 rADAMTS13 also prevented TTP development in a ADAMTS13 knockout mouse model. 31 These promising experimental data strongly suggest that rADAMTS13 administration could become a valuable therapeutic option in TTP. In line with this statement, a phase I clinical trial is underway to evaluate the safety and pharmacokinetics of rADAMTS13 in children and young adults with congenital TTP (BAX930; https:// clinicaltrials.gov/ct2/show/NCT02216084?termϭADAMTS13ϩ baxter&rankϭ1).…”

Section: Forthcoming Targeted Therapiesmentioning

confidence: 98%

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Coppo

Froissart

2015

Hematology

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Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of 80%-85%. However, relapses occur in ϳ40% of patients and refractory disease with fatal outcomes still occurs. In this context, the introduction of rituximab has probably been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, or even as frontline therapy, with high response rates. In more severe patients, salvage strategies may include twice-daily TPE, pulses of cyclophosphamide, vincristine, as well as splenectomy in more desperate cases.In this life-threatening disease, relapse prevention represents a major goal. Persistent severe acquired ADAMTS13 deficiency in patients who are otherwise in remission is associated with a high risk of relapse and preemptive treatment with rituximab may be considered in this context.In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, ideally international, clinical trials. Promising agents under evaluation include N-acetylcysteine, bortezomib, recombinant ADAMTS13, and inhibitors of the glycoprotein-Ib/IX-von Willebrand factor axis. Learning Objectives• Patients with acquired TTP who experience a suboptimal response (refractoriness or disease exacerbation) with standard management need a more intensive treatment • Salvage therapies typically include rituximab, and in the more severe cases twice daily plasma exchange, boluses of cyclophosphamide, vincristine, and splenectomy • A persistent severe acquired ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses

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Section: Forthcoming Targeted Therapiesmentioning

confidence: 98%

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Coppo

Froissart

2015

Hematology

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“…15 Briefly, we injected mice through their tail veins with VWF (5 mg/kg), VWF (5 mg/kg) plus HDL (2 mg), or saline and drew blood into 3.8% citrate from jugular veins before injection and 3 and 6 hours after injection. Both purified VWF and HDL (Sigma-Aldrich) were from human plasma.…”

Section: Thrombotic Microangiopathy In Adamts13 Knockout Micementioning

confidence: 99%

“…15 We injected 3 groups of ADAMTS13-deficient mice intravenously with purified human VWF (5 mg/kg), VWF (5 mg/kg) plus HDL (2 mg), or saline, respectively, and monitored their platelet counts. In mice injected with VWF only, the platelet counts decreased by more than 30% and 40% at 3 and 6 hours, respectively, whereas in the group injected with VWF plus HDL, platelet counts decreased only slightly (5% and 17%, respectively).…”

Section: Hdl Dampens Vwf-induced Thrombocytopenia In Micementioning

confidence: 99%

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Chung

Chen

Ling

et al. 2016

Blood

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• High-density lipoprotein and its major apolipoprotein ApoA-I prevent von Willebrand factor self-association. • Targeting von Willebrand factor self-association could be a new approach to treating thrombotic disorders.The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in selfassociated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders. are characterized by systemic endothelial activation and microvascular occlusion. In recent studies, von Willebrand factor (VWF) secreted from the endothelium as a result of systemic endothelial activation has been shown to contribute to microvascular dysfunction and occlusion. A portion of the newly secreted VWF remains attached to the endothelial surface, from which it is normally removed through cleavage by the plasma metalloprotease ADAMTS13. 6 However, when ADAMTS13 is inhibited, as during episodes of TTP, or when VWF removal is delayed, as in conditions of intense inflammation such as sepsis and malaria, 7 the secreted VWF self-associates into long, thick strands that bind platelets to form occlusive thrombi in the small blood vessels. 6 VWF synthesis is a complex process. VWF homodimers first form in the endoplasmic reticulum through disulfide bonds involving cysteine residues near the VWF carboxyl terminus. In the Golgi apparatus, these dimers are linked together into chains through disulfide bonds at the amino termini, producing a ladder of multimeric molecules, each differing from the next largest by the molecular mass of a VWF dimer. The largest multimers found in blood can be enormous, reaching a molecular mass of more than 20 million Da. These gargantuan molecules can form even larger structures by associating with other VWF multime...

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“…Antoine et al., showed the normalization of the ADAMTS13 activity in two brothers with congenital TTP when their plasma was mixed with rADAMTS13 obtained from transfected HEK293 cells 25. A preclinical model using ADAMTS13 knockout mice infused with high dose of recombinant human VWF to trigger the disease showed that prophylactic and therapeutic use of rADAMTS13 improved the hematological and pathologic parameters of TTP 26. A phase 1, multicenter, open label, dose‐escalation study involving 15 patients with cTTP between the ages of 12 to 65, with ADAMTS13 activity <6% showed that ADAMTS13 was well tolerated at the three doses tested (5, 20, or 40 U/kg).…”

Section: Recombinant Adamts13 (Radamts13 Bax930)mentioning

confidence: 99%

Novel therapies in thrombotic thrombocytopenic purpura

Masias

Cataland

2018

Research and Practice in Thrombosis and Haemostasis

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Essentials The standard of care for patients with TTP remains daily plasma exchange in addition to immune suppressive therapy.Despite the improved treatment options for TTP, the acute mortality of TTP remains between 15‐20%.Caplacizumab reduces the time to platelet recovery and the exacerbation rate in acute TTP.A better understanding of the cause and treatments of long‐term complications of TTP are needed. Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and a consumptive thrombocytopenia, as a result of severe deficiency of ADAMTS13. The standard of care of the acute episode is treatment with plasma exchange and immunosuppression. After the acute episode is resolved, patients face a significant risk of relapse and long‐term complications associated with significant morbidity and even mortality. Novel treatments have been under development and will be discussed in this review. Caplacizumab, a nanobody that blocks the interaction between VWF and platelets, has shown promising results in decreasing the time to recover from the acute events that will hopefully translate into long‐term clinical benefit for patients. In addition, identifying biomarkers to allow us to better predict the risk for relapse and the development of these long‐term complications in patients with TTP are a few of the challenges that require our attention moving forward.

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A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13

Cited by 105 publications

References 36 publications

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Novel therapies in thrombotic thrombocytopenic purpura

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