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.

Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura

1999 ◽  
Vol 81 (01) ◽  
pp. 8-13 ◽  
Author(s):  
Rodolfo Robles ◽  
Beat Morselli ◽  
Pierre Sandoz ◽  
Bernhard Lämmle ◽  
Miha Furlan
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Half Life ◽  
Protease Activity ◽  
Plasma Therapy ◽  
Thrombocytopenic Purpura ◽  
Plasma Infusion ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryPlasma exchange using fresh-frozen plasma (FFP) for replacement was given to two brothers during a relapse of thrombotic thrombocytopenic purpura (TTP). A constitutional deficiency of von Willebrand factor(vWF)-cleaving protease had been previously established in both patients. No inhibitor of vWF-cleaving protease was present in patients’ plasmas. They received plasma exchange for four and three consecutive days, respectively. In both patients, the activity of vWF-cleaving protease after the first plasmapheresis session was evaluated and was found to be virtually identical to anticipated activity calculated from predicted patient plasma volume and volume of exchanged plasma. Pathologic platelet counts and lactate dehydrogenase levels were normalized in both patients within 4-6 days. The biologic half-life of vWF-cleaving protease was determined in these patients following the last plasma exchange. The respective half-lives of 3.3 and 2.1 days represent the lowest known clearance rates of proteases in circulating human plasma.Another patient with relapsing TTP was treated with plasma exchange and/or plasma infusion for 10 consecutive days during the first relapse, 221-231 days after the initial TTP event. Pharmacokinetic studies of vWF-cleaving protease were performed after plasma exchange on day 221 and after plasma infusion on day 231. High level of an IgG in patient plasma, capable of completely inhibiting protease activity in an equal volume of normal plasma, had been established prior to first plasmapheresis. There was no measurable protease activity at any time during plasma therapy. Following plasma exchange, the level of the inhibitor was transiently slightly depressed. After 10 days of plasma therapy, the concentration of the inhibitor in patient plasma was increased about 5-fold. We suggest that, in contrast to protease deficient patients without circulating inhibitor, complementary therapy including immunosuppressive treatment, vincristine and/or splenectomy is indicated in patients with acquired inhibitors of vWF-cleaving protease. Testing for vWF-cleaving protease inhibitor may be useful in predicting the response to plasma exchange in patients with TTP.

Von Willebrand Factor-Cleaving Protease Activity Remains at the Intermediate Level in Thrombotic Thrombocytopenic Purpura

2005 ◽  
Vol 113 (3) ◽  
pp. 198-203 ◽  
Author(s):  
Takeshi Sugimoto ◽  
Katsuyasu Saigo ◽  
Tomohiro Shin ◽  
Yohji Kaneda ◽  
Nobuya Manabe ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Protease Activity ◽  
Intermediate Level ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3611-3614 ◽  
Author(s):  
Hendrik B. Feys ◽  
Jan Roodt ◽  
Nele Vandeputte ◽  
Inge Pareyn ◽  
Harald Mottl ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Platelet Glycoprotein ◽  
Control Group ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Platelet Aggregates ◽  
New Treatment ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF–platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura

2006 ◽  
Vol 96 (10) ◽  
pp. 454-464 ◽  
Author(s):  
Roberta Donadelli ◽  
Federica Banterla ◽  
Miriam Galbusera ◽  
Cristina Capoferri ◽  
Sara Bucchioni ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Protease Activity ◽  
Mammalian Cells ◽  
Expression System ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13.We investigated the spectrum of ADAMTS13 gene mutations in patients with TTP and congenital ADAMTS13 deficiency to establish the consequences on ADAMTS13 processing and activity. We describe five missense (V88M, G1239V, R1060W, R1123C and R1219W), 1 nonsense (W1016Stop) and 1 insertion (82_83insT) mutations. In two patients no mutation was identified despite undetectable protease activity. Expression in HEK293 mammalian cells (V88M, G1239V, R1123C and R1219W) documented that three missense mutants were not secreted, whereas theV88M was secreted at low levels and with reduced activity. We also provide evidence that impaired secretion of ADAMTS13 mutants observed in vitro translates into severely reduced ADAMTS13 antigen levels in patients in vivo. To evaluate whether the small amounts of mutant protease present in the circulation of patients had VWF cleaving activity, WT and mutant rADAMTS13 were stably expressed in Drosophila S2 cells under the influence of the Drosophila BiP protein signal sequence, which allows protein secretion. Drosophila expression system showed a 40–60% protease activity in the mutants. Several single nucleotide polymorphisms (SNPs) within exons and intron boundaries were found in patients, suggesting that the interplay of SNPs could at least in part account for ADAMTS13 functional abnormalities in patients without mutations. In conclusion, defective secretion and impaired activity of the mutants concur to determine an almost complete deficiency of ADAMTS13 activity in patients with a homozygous or two heterozygous ADAMTS13 mutations.

scholarly journals Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 11-18 ◽  
Author(s):  
J. Evan Sadler
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Unanswered Question ◽  
Thrombocytopenic Purpura ◽  
The Past ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Intensive Immunosuppressive Therapy

Abstract Discoveries during the past decade have revolutionized our understanding of idiopathic thrombotic thrombocytopenic purpura (TTP). Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves von Willebrand factor within nascent platelet-rich thrombi to prevent hemolysis, thrombocytopenia, and tissue infarction. Although approximately 80% of patients respond to plasma exchange, which removes autoantibody and replenishes ADAMTS13, one third to one half of survivors develop refractory or relapsing disease. Intensive immunosuppressive therapy with rituximab appears to be effective as salvage therapy, and ongoing clinical trials should determine whether adjuvant rituximab with plasma exchange also is beneficial at first diagnosis. A major unanswered question is whether plasma exchange is effective for the subset of patients with idiopathic TTP who do not have severe ADAMTS13 deficiency.

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.

Sign in / Sign up

Export Citation Format

Share Document