von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

Furlan, Miha; Robles, Rodolfo; Galbusera, Miriam; Remuzzi, Giuseppe; Kyrle, Paul A.; Brenner, B; Krause, Manuela; Scharrer, I.; Aumann, V.; Mittler, U; Solenthaler, Max; Lämmle, Bernhard

doi:10.1056/nejm199811263392202

Cited by 1,599 publications

(1,416 citation statements)

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“…Mutations in the ADAMTS13 gene were shown to cause congenital TTP [6], whereas IgG autoantibodies inhibit the enzyme in most cases of the acquired form of the disease [7][8]. The standard treatment of acquired idiopathic TTP consists of plasma exchange with fresh frozen plasma [9][10], thereby removing large VWF multimers as well as autoantibodies to ADAMTS13 and replacing the enzyme [11][12].…”

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confidence: 99%

“…Tsai et al [3] and Furlan et al [4] independently identified a VWF-cleaving protease (ADAMTS13) missing from the plasma of patients with congenital TTP [5] and severely deficient in patients with acquired idiopathic TTP. Mutations in the ADAMTS13 gene were shown to cause congenital TTP [6], whereas IgG autoantibodies inhibit the enzyme in most cases of the acquired form of the disease [7][8]." To avoid repetitions we left this part of the introduction as it was.…”

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Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab

et al. 2010

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Rituximab may be used to treat patients with thrombotic thrombocytopenic purpura (TTP) refractory to plasma exchange or recurrent disease. While initial response rates are reported to be high, long-term follow-up data of patients treated with rituximab are not available to date however important to estimate the safety and benefit of this treatment. 12 patients with non-familial idiopathic TTP refractory to plasma exchange or with recurrent disease treated with rituximab between 2000 and 2008 were re-examined. The median follow-up was 49.6 months, ranging from 11 to 97 months. All patients achieved initial complete remission after application of rituximab. During follow-up, nine patients remained disease-free and three patients suffered from recurrent disease. All patients with recurrent disease responded to subsequent rituximab therapy. No long-term side effects were noted during the follow-up period. In conclusion, rituximab represents an effective second-line treatment option in relapsing or refractory TTP. Still, patients need to be closely monitored for relapses with extended follow-up.Response to Reviewers: Reviewer #11. Abstract, line 2: I think "acceptable" is not appropriate until larger studies are done. I would suggest changing to: "Rituximab may be used to treat relapsed or refractory TTP" Changes were made accordingly. 2.Abstract, line 5: While initial response rates are "reported to be" high..Changes were made accordingly.3. Abstract, line 32: "Still, patients need to be closely monitored as the relapse rate increases with longer follow-up." Change to ".monitored for relapses with extended follow-up".Changes were made accordingly. 4.Introduction, line 41: Remove "not otherwise explained"Changes were made accordingly. 5.Introduction, line 51: Revise: "Acquired idiopathic TTP is differentiated from hereditary TTP (Upshaw-Schulman syndrome)." ie how are they differentiated?The differentiation between acquired and congenital TTP follows in detail in the next paragraph: "Large progress was made in recent years in understanding the pathophysiology of TTP. Moake et al. described unusually large von Willebrand factor (VWF) multimers in the plasma of patients with relapsing acquired or congenital TTP causing intravascular platelet aggregation occluding the microvasculature [2]. Tsai et al. [3] and Furlan et al. [4] independently identified a VWF-cleaving protease (ADAMTS13) missing from the plasma of patients with congenital TTP [5] and severely deficient in patients with acquired idiopathic TTP. Mutations in the ADAMTS13 gene were shown to cause congenital TTP [6], whereas IgG autoantibodies inhibit the enzyme in most cases of the acquired form of the disease [7][8]." To avoid repetitions we left this part of the introduction as it was. If the editor has a distinct opinion to this point, we are more than willing to change it. 6.Introduction, line 12 (2nd page of introduction) and throughout the paper: "plasma exchange against fresh frozen plasma" change to ". WITH fresh frozen plasma."Changes w...

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confidence: 99%

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Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab

et al. 2010

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“…Endothelial cell dysfunction and subsequent release of high amount of von Willebrand factor could be an important step in the sequence of events leading to intravascular platelet aggregation in TTP. Recently, additional ®ndings shed light on the pathophysiology of TTP [2,3]. Indeed, a de®ciency in von Willebrand factor-cleaving protease activity has been reported in TTP, whereas in hemolytic uremic syndrome (HUS), this enzyme activity was found normal [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, additional ®ndings shed light on the pathophysiology of TTP [2,3]. Indeed, a de®ciency in von Willebrand factor-cleaving protease activity has been reported in TTP, whereas in hemolytic uremic syndrome (HUS), this enzyme activity was found normal [2,3]. These ®ndings may account for the e cacy of plasma therapy, i.e., plasma infusion (PI) or plasma exchange (PE), in the treatment of TTP since it could restore missing plasma components.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: A report of two cases

et al. 2001

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Plasma infusion (PI) and plasma exchange (PE) are the most efficient treatment of thrombotic thrombocytopenic purpura (TTP), allowing achievement of complete remission in 60 to 90% of cases. Life‐threatening bleeding, related to severe thrombocytopenia, is one of the main complications of the disease. Thrombocytopenia may also preclude invasive procedures such as splenectomy, which may be required during the management of TTP. Platelet concentrates transfusions are usually thought to worsen the disease, especially if not associated with the appropriate treatment of this latter, and thus should be avoided. We report hereon 2 patients with TTP who experienced a surgical procedure i.e., a cholecystectomy for a cholecystitis, and a splenectomy for a refractory TTP. In both patients, the surgical procedure was preceded by a 60 mL/kg plasma exchange with solvent/detergent treated plasma as replacement fluid, followed by platelet transfusion, with a corrected count increment of 57.1% (Patient 1) and 69.3% (Patient 2). Using this sequential treatment, the patients did not experience any deterioration of their status. Both patients had a favorable outcome after surgery. However, until such a procedure will be validated on a larger series of patients, it should be restricted to patients presenting with a refractory life‐threatening thrombocytopenia and/or requiring surgery or any kind of invasive procedure. Am. J. Hematol. 68:198–201, 2001. Published 2001 Wiley‐Liss, Inc.

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“…A severely deficient ADAMTS13 activity correlates with increased amounts of highly active, high molecular weight multimers (HMWM) of VWF that cause a thrombotic microangiopathy, which is commonly referred to as thrombotic thrombocytopenic purpura (TTP) (9)(10)(11). TTP is caused either by mutations of the ADAMTS13 gene or by acquired autoantibodies that inhibit ADAMTS13 activity (12).…”

Section: Introductionmentioning

confidence: 99%

Mutation G1629E Increases von Willebrand Factor Cleavage via a Cooperative Destabilization Mechanism

Aponte-Santamaría

Lippok

Mittag

et al. 2017

Biophysical Journal

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The large multimeric glycoprotein von Willebrand Factor (VWF) plays a pivotal adhesive role during primary hemostasis. VWF is cleaved by the protease ADAMTS13 as a down-regulatory mechanism to prevent excessive VWF-mediated platelet aggregation. For each VWF monomer, the ADAMTS13 cleavage site is located deeply buried inside the VWF A2 domain. External forces in vivo or denaturants in vitro trigger the unfolding of this domain, thereby leaving the cleavage site solvent-exposed and ready for cleavage. Mutations in the VWF A2 domain, facilitating the cleavage process, cause a distinct form of von Willebrand disease (VWD), VWD type 2A. In particular, the VWD type 2A Gly1629Glu mutation drastically accelerates the proteolytic cleavage activity, even in the absence of forces or denaturants. However, the effect of this mutation has not yet been quantified, in terms of kinetics or thermodynamics, nor has the underlying molecular mechanism been revealed. In this study, we addressed these questions by using fluorescence correlation spectroscopy, molecular dynamics simulations, and free energy calculations. The measured enzyme kinetics revealed a 20-fold increase in the cleavage rate for the Gly1629Glu mutant compared with the wild-type VWF. Cleavage was found cooperative with a cooperativity coefficient n ¼ 2.3, suggesting that the mutant VWF gives access to multiple cleavage sites of the VWF multimer at the same time. According to our simulations and free energy calculations, the Gly1629Glu mutation causes structural perturbation in the A2 domain and thereby destabilizes the domain by~10 kJ/mol, promoting its unfolding. Taken together, the enhanced proteolytic activity of Gly1629Glu can be readily explained by an increased availability of the ADAMTS13 cleavage site through A2-domain-fold thermodynamic destabilization. Our study puts forward the Gly1629Glu mutant as a very efficient enzyme substrate for ADAMTS13 activity assays.

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von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

Cited by 1,599 publications

References 21 publications

Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab

Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab

Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: A report of two cases

Mutation G1629E Increases von Willebrand Factor Cleavage via a Cooperative Destabilization Mechanism

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