Effectiveness of Caplacizumab Nanobody in Acquired Thrombotic Thrombocytopenic Purpura Refractory to Conventional Treatment

2021 ◽  
pp. 1-5
Author(s):  
Tomás Palanques-Pastor ◽  
Juan Eduardo Megías-Vericat ◽  
Virginia Bosó Ribelles ◽  
Inés Gómez Seguí ◽  
José Luis Poveda Andrés
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Von Willebrand Factor ◽  
Conventional Treatment ◽  
Significant Advance ◽  
Thrombocytopenic Purpura ◽  
Restoration Time ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Multiple Relapses

Acquired thrombocytopenic thrombotic purpura (aTTP) is an autoantibody-mediated disease against the enzyme A Disintegrin and Metalloprotease domain with ThromboSpondin-1 type motif 13, which until now has been treated with plasma exchange (PEX) and corticosteroids. A 29-year-old female patient, who presented with aTTP in the context of pregnancy, has developed multiple relapses after treatment with PEX, corticosteroids, and rituximab. Recently, caplacizumab, a nanobody against von Willebrand factor, has been approved for the treatment of aTTP. In our patient, caplacizumab achieved better disease control, with a lower platelet count restoration time, days of PEX and hospitalization duration, as compared to standard therapy, reproducing the results of clinical trials. Caplacizumab represents a significant advance in the treatment of aTTP, especially in cases of recurrent relapses.

scholarly journals Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2839-2846 ◽  
Author(s):  
Miha Furlan ◽  
Rodolfo Robles ◽  
Max Solenthaler ◽  
Bernhard Lämmle
Keyword(s):  
Platelet Count ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Protease Activity ◽  
Temporary Increase ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma of patients with thrombotic thrombocytopenic purpura (TTP) has been shown to contain unusually large von Willebrand factor (vWF) multimers that may cause platelet agglutination in vivo. Fresh frozen plasma infusions and plasma exchange represent the most efficient therapy of acute TTP. A specific protease responsible for cleavage of vWF multimers has been recently isolated from normal human plasma and was found to be deficient in four patients with chronic relapsing TTP. We examined the activity of the vWF-cleaving protease in plasma samples collected over a period of 400 days from a further patient with recurrent episodes of TTP who was treated by plasma exchange, plasma infusion, vincristine, corticosteroid therapy, and splenectomy. Complete deficiency of the vWF-cleaving protease was established during the first episode of TTP. The ensuing normalization of the platelet count was associated with the appearance of the protease activity. Three months after remission from the initial TTP event, the vWF-cleaving protease again disappeared and the platelet count gradually decreased. Relapses of severe thrombocytopenia occurred 7 and 11 months after the first acute episode of TTP. Deficient protease activity was associated with the presence in the patient plasma of an inhibitor that was found to be an IgG. Plasma exchange/infusion was followed by a temporary increase in the antibody titer, whereas treatment with vincristine led to a recovery of the platelet count without affecting the inhibitor concentration. Splenectomy and corticosteroid treatment resulted in disappearance of the autoantibody and normalization of the protease activity and of the platelet count. Our data suggest that the thrombocytopenia in this patient with TTP was associated with a lack of the vWF-cleaving protease activity depleted by an autoimmune mechanism. This case, together with our previously reported patients, leads us to conclude that acquired as well as constitutional deficiency of the vWF-cleaving protease may predispose to TTP.

scholarly journals Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3750-3750
Author(s):  
Matthew J. Stubbs ◽  
Ryan Low ◽  
Siobhan McGuckin ◽  
Rosalind Newton ◽  
John-Paul Westwood ◽  
...  
Keyword(s):  
Platelet Count ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Advisory Board ◽  
Thrombocytopenic Purpura ◽  
Infusion Reactions ◽  
The Mean ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Infective Complications

Abstract INTRODUCTION Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by immunoglobulin G (IgG) antibodies. These antibodies target the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is vital for cleavage of von Willebrand factor. The resulting ADAMTS13 deficiency leads to microthrombi through platelet aggregation to Ultra-Large von Willebrand factor. If untreated the mortality rate in iTTP is in excess of 90%, but the use of plasma exchange (PEX) and immunosuppression has significantly reduced this (to between 10%-20%). Rituximab (a humanised anti-CD20 antibody, MabThera; Roche Pharmaceuticals), is now used routinely in iTTP in relapsed/refractory patients, but also acutely to prolong disease free-survival. The pre-emptive administration of rituximab in patients with a low ADAMTS13 has been shown to be effective in preventing clinical relapse. In 2013 the patent for rituximab expired in Europe and will expire in 2018 in the United States. The European Medicine Agency has now approved two Rituximab biosimilars for use in Europe. Biosimilar products are designed to have no meaningful differences from the reference/originator product. Truxima (CT-P10, a rituximab biosimilar) is approved for the treatment of RA, CLL and NHL in Europe, and we began using Truxima in iTTP in May 2017. Many other rituximab biosimilars exist and are in development. METHODOLOGY Here we report a retrospective cohort study of our patients with iTTP. Data from 84 patients was examined from a two-year time period May 2016-and May 2018, based on our pharmacy registry (having switched to the rituximab biosimilar in May 2017). 45 patients were treated with MabThera and 39 with the rituximab biosimilar Truxima. Laboratory parameters recorded included the patient's platelet counts, ADAMTS13 activity, and CD19 levels at D1, D28 and 3months following treatment. In addition, adverse reactions, and infective complications following treatment were also recorded. Statistical analysis was performed and means +/- 90% confidence interval calculated, with clinical equivalency compared based on clinically significant values. RESULTS Following MabThera/Truxima administration on D1, at 28 days the mean platelet count (+/- SEM, x10^9/L) was 263.3 (+/-10.69) in patient treated with MabThera and 263.8 (+/-11.81) with Truxima (90% CI -24.95 to 27.91), and remained similar at 3months at 275.8 (+/- 10.05) and 275.9 (+/- 12.2) respectively (90% CI -25.96 to 26.2). The ADAMTS13 (+/- SEM) at 28 days was 50.87 iu/dL (+/-4.899) in patients treated with MabThera and 50.88 iu/dL (+/- 4.371) for Truxima (90% CI 11.01-11.03), rising to 85.4 iu/dL (+/- 5.237) and 81.35 iu/dL (+/- 4.549) respectively at 3 months (90% CI 15.84-7.71). CD19 levels at 28 days in patients treated with MabThera had fallen to 0.00259 (x10^9/L)(+/- 0.00049) and 0.02151 (+/- 001161) with Truxima (90% CI 0.00073 to 0.037120), and were 0.01782 (+/- 0.01033) and 0.02098 (+/- 0.01042) respectively at 3 months (90% CI -0.02139 to 0.02771), all demonstrating a marked reduction from baseline means of 0.3247(+/-0.05721) and 0.2456 (+/-0.03016) respectively. The median number of infusions in both groups was 4 (range 1-8). Infusion reactions were comparable between both groups, with infusion reactions occurring in 33% of the MabThera treated patients, and 40% in the Truxima group. Infective complications (principally urinary tract infections) were comparable between both groups, 15% in the MabThera group and 18% in the truxima cohort. The mean saving per patient per treatment course cost was >£4000. DISCUSSION Rituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications. Disclosures Cheesman: Celltrion: Other: Speaker Fee; Roche: Other: Advisory board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism

Blood ◽  
2021 ◽  
Author(s):  
Magnus Sandvik Edvardsen ◽  
Ellen-Sofie Hansen ◽  
Kristian Hindberg ◽  
Vânia Maris Morelli ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Platelet Reactivity ◽  
High Plasma ◽  
Combined Effects ◽  
Exposure Group ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, ≥9.5 fL) and platelet count (<230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.

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