scholarly journals The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians

2020 ◽  
Vol 9 (10) ◽  
pp. 3379
Author(s):  
Ilaria Mancini ◽  
Elisa Giacomini ◽  
Silvia Pontiggia ◽  
Andrea Artoni ◽  
Barbara Ferrari ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Risk Allele ◽  
Absolute Risk ◽  
Disease Onset ◽  
Close Monitoring ◽  
Reference Allele ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated ◽  
The Impact ◽  
Risk Of Relapse

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30–50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β −3.34, 95%CI −6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

scholarly journals Open ADAMTS13 Conformation in Immune-Mediated Thrombotic Thrombocytopenic Purpura Is Induced By Anti-ADAMTS13 Autoantibodies and Corresponds with an Ongoing ADAMTS13 Pathology

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 222-222
Author(s):  
Elien Roose ◽  
An-Sofie Schelpe ◽  
Edwige Tellier ◽  
György Sinkovits ◽  
Gilles Kaplanski ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Conformational Changes ◽  
Clinical Signs ◽  
Advisory Board ◽  
Close Monitoring ◽  
Plasma Samples ◽  
Chi Square ◽  
Thrombocytopenic Purpura ◽  
Open Conformation ◽  
Immune Mediated

Abstract Background. Deficient ADAMTS13 activity (TS13:act <10%) induced by anti-ADAMTS13 autoantibodies (autoAbs) causes immune-mediated thrombotic thrombocytopenic purpura (iTTP). Recently we showed that an open ADAMTS13 conformation is characteristic for acute iTTP patients, while folded ADAMTS13 was found in 78% of iTTP patients in remission with an TS13:act >50%. However, also iTTP patients in remission with a persistent (<10%) or moderately restored (10-50%) TS13:act have been described, but their ADAMTS13 conformation is unknown. Intriguingly, the factor responsible for inducing open ADAMTS13 in iTTP patients remains elusive. Identifying the cause of open ADAMTS13 in iTTP will help better understand the pathophysiology of iTTP and could help appreciate the prognosis and better manage the prevention of subsequent relapses. Aim. Determine ADAMTS13 conformation in plasma of iTTP patients during acute TTP and remission when TS13:act is <10%, moderately restored (10-50%) or >50% and investigate if anti-ADAMTS13 autoAbs induce conformational changes in ADAMTS13. Methods. TS13:act was determined in 120 iTTP plasma samples from 4 different centers (Marseille, Milan, Budapest, Utrecht). Samples were categorized according to the presence of clinical symptoms (acute versusremission) and their TS13:act in remission (>50%, 10-50%,<10%). Next, ADAMTS13 conformation was determined in all samples using our ADAMTS13 conformation ELISA. Additionally, presence of anti-ADAMTS13 autoAbs was also determined via ELISA. Finally, IgG's from 18 acute iTTP plasma samples were purified and added to folded ADAMTS13 from healthy donor (HD) plasma to test whether iTTP IgG's are able to induce the open HD ADAMTS13 conformation. Results. Of the 120 iTTP plasma samples, 46 were obtained during the acute (clinical signs present) and 74 during the remission phase (clinical signs absent). Further subdividing remission samples showed that TS13:act was >50% in 41, 10-50% in 14 and <10% in 19 samples. ADAMTS13 was open in 98% (45/46) of the acute samples and folded in 71% (29/41) of the remission samples with TS13:act >50%, confirming our previous results. Interestingly, ADAMTS13 was open in 93% and 89% of remission samples with TS13:act 10-50% and <10%, respectively (chi square, P<0.0001). Since anti-ADAMTS13 autoAbs influence TS13:act in iTTP patients, we next could demonstrate that open ADAMTS13 conformation was linked with presence of anti-ADAMTS13 autoAbs (chi square, P<0.0001) suggesting that anti-ADAMTS13 autoAbs could be a factor able to induce an open ADAMTS13 conformation in iTTP patients. To further test this hypothesis, we purified IgG's from 18 acute iTTP plasma's with open ADAMTS13 and added them to HD plasma containing closed ADAMTS13, where 14 of the 18 patient IgG pools (78%) did induce the open conformation in HD ADAMTS13, indicating that patient anti-ADAMTS13 autoAbs indeed can induce conformational changes in ADAMTS13. Conclusion. We show that ADAMTS13 is not only in the open conformation in iTTP patient plasma during the acute phase but also in remission when TS13:act is <10% or 10-50%. Hence, the presence of open ADAMTS13 in those remission patients indicates that the underlying pathophysiology is still ongoing, emphasizing the need for a close monitoring of those patients. In addition, anti-ADAMTS13 autoAbs were identified as a factor responsible for the change in conformation in ADAMTS13 in iTTP. Disclosures Peyvandi: Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria. Coppo:Ablynx: Consultancy. Veyradier:LFB: Other: Investigator. Vanhoorelbeke:Shire: Consultancy; Ablynx: Consultancy.

scholarly journals Alternate-Day Dosing of Caplacizumab for Immune-Mediated Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2087-2087
Author(s):  
Lucas Kühne ◽  
Dennis A. Eichenauer ◽  
Paul Knöbl ◽  
Linus A. Völker ◽  
Jessica Kaufeld ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Autoimmune Disorder ◽  
Daily Treatment ◽  
Treatment Modalities ◽  
Close Monitoring ◽  
Dosing Regimen ◽  
Thrombocytopenic Purpura ◽  
Normal Platelet ◽  
Immune Mediated ◽  
Risk Patients

Abstract Background: The anti-VWF nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura, thereby adding a new therapeutic principle to the treatment of this autoimmune disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous. Methods: Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab, by thoroughly analyzing the timing and outcome of this treatment approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab in Austria and Germany between 2018 and 2021. Results: Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in the majority of patients, who were converted after a median time of 17 days daily treatment. Four patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application and/or other therapies. VWF activity was repeatedly measured in 17 out of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 hours, in line with published pharmacokinetics. Conclusion: Extension of caplacizumab injection intervals from daily to alternate-day dosing may be safely considered in selected patients after 30 days of daily treatment. Earlier modifications may be considered in low-risk patients, but require close monitoring for clinical and laboratory features of thrombotic microangiopathy. Disclosures Völker: Sanofi-Genzyme: Honoraria, Other: counselling fees.

Exome Sequencing Identifies Abnormalities in Glycosylation and ANKRD36C in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

2020 ◽  
Author(s):  
Malay Kumar Basu ◽  
Felipe Massicano ◽  
Lijia Yu ◽  
Konstantine Halkidis ◽  
Vikram Pillai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Protein Glycosylation ◽  
Healthy Controls ◽  
Major Pathway ◽  
Thrombocytopenic Purpura ◽  
Hematological Disorders ◽  
Blood Disorder ◽  
Immune Mediated

Abstract Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). However, the mechanism underlying anti-ADAMTS13 autoantibody formation is not known, nor it is known how genetic aberrations contribute to the pathogenesis of iTTP. Methods Here we performed whole exome sequencing (WES) of DNA samples from 40 adult patients with iTTP and 15 local healthy subjects with no history of iTTP and other hematological disorders. Results WES revealed variations in the genes involved in protein glycosylation, including O-linked glycosylation, to be a major pathway affected in patients with iTTP. Moreover, variations in the ANKRD gene family, particularly ANKRD36C and its paralogs, were also more prevalent in patients with iTTP than in the healthy controls. The ANKRD36 family of proteins have been implicated in inflammation. Mass spectrometry revealed a dramatic alternation in plasma glycoprotein profile in patients with iTTP compared with the healthy controls. Conclusion Altered glycosylation may affect the disease onset and progression in various ways: it may predispose patients to produce ADAMTS13 autoantibodies or affect their binding properties; it may also alter clearance kinetics of hemostatic and inflammatory proteins. Together, our findings provide novel insights into plausible mechanisms underlying the pathogenesis of iTTP.

scholarly journals Severely Deficient ADAMTS13 Activity Predicts Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Pregnancy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1098-1098
Author(s):  
Camila Masias ◽  
Krista Carter ◽  
Haiwa Wu ◽  
Shangbin Yang ◽  
Alcinda Flowers ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Research Funding ◽  
The Other ◽  
Clinical Relapse ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Second Hit ◽  
Immune Mediated ◽  
Risk Of Relapse ◽  
In Pregnancy

Background: It is commonly accepted that severely deficient ADAMTS13 activity in remission increases the risk for relapse, but relapse in severely deficient ADAMTS13 activity in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) is not uniform. Mouse models and published studies have suggested that a "second hit" is required in addition to severely deficient ADAMTS13 activity to lead to clinical relapse. Our initial published experience led us to preliminarily conclude that pregnancy could serve as the second hit in addition to severely deficient ADAMTS13 activity and lead to relapse. The aim of this study was to evaluate the risk of relapse and outcomes of pregnant patients with a diagnosis of iTTP. Methods: Since the initiation of the Ohio State University TTP Research Program in 2003, patients were consented at enrollment and followed longitudinally in our IRB approved iTTP registry, usually every three to six months. During pregnancy, patients were seen and CBC, LDH and ADAMTS13 activity were obtained monthly. Due to prior reports of iTTP relapses during pregnancy, it is our practice to offer prophylaxis with cyclosporine to pregnant patients with a diagnosis of iTTP and severely deficient ADAMTS13 activity. The clinical diagnosis of iTTP (defined as thrombocytopenia, microangiopathic hemolytic anemia, without an alternative explanation was confirmed by severely deficient ADAMTS13 activity (<10%) in all cases. ADAMTS13 activity was determined using a SELDI-TOF mass-spectrometer-based method. Results: During the study time, we have followed 11 pregnancies from eight patients with iTTP. Two pregnancies occurred at the time of their initial diagnosis, and nine pregnancies occurred during follow up. Two patients were black, nine were white. Median age was 26 ( range 20-36). Of the nine pregnancies in patients with a previous diagnosis of iTTP, three resulted in relapses, two in the same patient; one at 23 weeks that resulted in fetal demise, and the next one occurred one week after delivery at 36 weeks. The other patient relapsed at 35 weeks and the baby was delivered early at 36 weeks. All relapses were preceded by a documented ADAMTS13 <10%, with a normal platelet count, LDH and no associated symptoms, while none of the other pregnancies had a documented ADAMTS13 <10% (Figure 1). Interestingly, one of the relapses occurred while the patient was taking cyclosporine during pregnancy as preemptive therapy to prevent relapses. She initially responded to therapy with an increase in her ADAMTS13 activity but subsequently lost the response which preceded her relapse post-partum. Conclusions: Pregnancy in patients with a diagnosis of iTTP is a risk factor for iTTP relapse. To our knowledge, this is the first report of the relationship between ADAMTS13 and the risk of relapse during pregnancy. Our results demonstrate that severely deficient ADATMS13 activity uniformly leads to relapse in pregnancy. It also highlights the clinical relevance of monitoring ADAMTS13 activity closely in patients with a history of iTTP that become pregnant. Figure 1 Disclosures Masias: Rigel Pharmaceuticals: Consultancy. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. OffLabel Disclosure: the use of cyclosporine for prevention of TTP relapses

Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura

2018 ◽  
Vol 57 (2) ◽  
pp. 222-224 ◽  
Author(s):  
Esra Terzi Demirsoy ◽  
Ozgur Mehtap ◽  
Elif Birtas Atesoglu ◽  
Pinar Tarkun ◽  
Necmi Eren ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated

scholarly journals Insights from the Hereditary Thrombotic Thrombocytopenic Purpura Registry: Discussion of Key Findings Based on Individual Cases from Switzerland

2020 ◽  
Vol 40 (S 01) ◽  
pp. S5-S14
Author(s):  
Johanna A. Kremer Hovinga ◽  
Thomas R. Braschler ◽  
Florian Buchkremer ◽  
Stefan Farese ◽  
Heinz Hengartner ◽  
...  
Keyword(s):  
Cohort Study ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Myocardial Infarctions ◽  
Thrombocytopenic Purpura ◽  
Blood Disorder ◽  
A Disintegrin And Metalloproteinase ◽  
Systematic Collection ◽  
Plasma Infusions

AbstractThe Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1–2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0–70) and at clinical diagnosis 16.7 years (range: 0–69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107–2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here.

scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

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