A 14-Year Experience in the Management of Patients with Acquired Immune Thrombotic Thrombocytopenic Purpura in Northern Israel

Acquired idiopathic thrombotic thrombocytopenic purpura (I-TTP) is a life-threatening microangiopathic disorder usually treated with therapeutic plasma exchange (TPE). The current study assessed the role of rituximab in the treatment of complicated I-TTP. The sequence of TTP events was compared in a group of I-TTP patients treated with TPE and a cohort of refractory or relapsed patients who also received rituximab. This retrospective evaluation included 45 I-TTP patients, treated between January 2000 and October 2013, who underwent at least 3 TPE procedures and were followed up until December 2013 or death. Thirty-one patients with an uncomplicated course received TPE only. Fourteen patients had a complicated course due to either a primary refractory/exacerbated disease (n = 5) or relapse (n = 9) and received rituximab together with TPE. The median number of TPE procedures performed in the first TTP episode in the uncomplicated cohort and groups with primary refractory or relapsed TTP was 11, 27 and 45, respectively. The relapse rates per follow-up year in the uncomplicated I-TTP, primary refractory and relapsed I-TTP groups were 0.18, 0.2 and 0.6 episodes, respectively. After rituximab therapy this rate dropped to 0.2 per year in the relapsed subgroup. In conclusion, about a quarter of patients with I-TTP had a complicated course and experienced a major benefit from rituximab in terms of effectiveness and safety.

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Critical Care COVID-19 Patient with a Picture of Thrombotic Thrombocytopenic Purpura

European Journal of Case Reports in Internal Medicine ◽

10.12890/2020_002143 ◽

2020 ◽

Author(s):

Rehab AL-Ansari ◽

Mohanad Bakkar ◽

Leena Abdalla ◽

Khaled Sewify

Keyword(s):

Mechanical Ventilation ◽

Critical Care ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Kidney Injury ◽

Therapeutic Plasma Exchange ◽

Thrombocytopenic Purpura ◽

Threatening Condition ◽

Life Threatening

Background: Thrombotic thrombocytopenic purpura (TTP) is an uncommon haematological disease which can occur at any age and may present with COVID-19. This case describes a COVID-19 complication associated with a presentation resembling TTP. Case description: A 51-year-old man who had received a kidney transplant and was on immunosuppressant medication, was admitted to a critical care unit with severe COVID-19 pneumonia/acute respiratory distress syndrome (ARDS) which required intubation, mechanical ventilation and inotropic support. The course was complicated by the classic pentad of thrombocytopenia, intravascular haemolysis, acute kidney injury, neurological symptoms and fever, which prompted the diagnosis of probable TTP. After five sessions of therapeutic plasma exchange, the patient’s general status improved, he was weaned off mechanical ventilation and his renal panel and haemolytic markers normalized. Conclusion: TTP is a life-threatening condition which requires urgent management with therapeutic plasma exchange. This case highlights some possible complications of COVID-19 generally and in immunocompromised patients specifically. The potential role of plasma exchange in COVID-19 patients without a positive diagnosis of TTP (the so-called ‘TTP resembling presentation’) is an area of further research.

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Preemptive Rituximab Infusions Efficiently Prevent Relapses In Acquired Thrombotic Thrombocytopenic Purpura. Experience Of The French Thrombotic Microangiopathies Reference Center

Blood ◽

10.1182/blood.v122.21.448.448 ◽

2013 ◽

Vol 122 (21) ◽

pp. 448-448

Author(s):

Miguel HIE ◽

Julie Gay ◽

Lionel Galicier ◽

Francois Provot ◽

Sandrine Malot ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Median Number ◽

Continuous Variables ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

History Of ◽

Adamts13 Deficiency ◽

Group 2 ◽

Group 1

Context Acquired thrombotic thrombocytopenic purpura (TTP) results from a severe, antibody-mediated, deficiency in the von Willebrand factor-cleaving protease ADAMTS13. Rituximab is increasingly used in this indication in patients with a suboptimal response to plasma exchange. When severe acquired ADAMTS13 deficiency persists during remission, the estimated incidence rate is of 0.4/year. So far, it is still controversial whether preemptive rituximab efficiently prevents relapses in these patients. Patients and methods We defined two groups of patients with a history of acquired TTP who displayed a persistent severe ADAMTS13 deficiency during remission. Patients of group 1 were treated with preemptive infusions of rituximab. Patients of group 2 were managed in centers in which preemptive rituximab infusions were not the standard of care. The relapse incidence was evaluated and compared between both groups. Patients were treated according to National recommendations and enrolled from 12 French centers during a 12-year period. Patients were explored for ADAMTS13 activity and peripheral B-cell count every 3 months. Only patients with a > 12-month follow-up after rituximab administration are reported here. Median (25th - 75th percentile) was determined for all continuous variables. Wilcoxon’s test was used to compare continuous variables and the chi-square test or Fisher’s exact test to compare binary data. Relapse-free survival was compared between both groups using the Kaplan-Meier estimator with the corresponding 95% confidence interval. Results Forty-eight patients (20.6%) with a history of acquired TTP displayed a persistent severe ADAMTS13 deficiency on remission or experienced a subsequent severe ADAMTS13 deficiency (24 cases each) after a median follow-up of 17 months (12-29 months). Anti-ADAMTS13 antibodies concentration was 44 U/mL (24-59 U/mL). Thirty patients received preemptive infusions of rituximab (group 1), whereas 18 others had no therapeutical intervention (group 2). In group 1, 16 patients experienced a past history of TTP with a median number of 2 (1-3) episodes, corresponding to a relapse incidence of 0.22 (0-0.57)/year. Rituximab infusions were performed 14.5 months (6.5-27.4 months) after the last TTP episode. A median number of 4 (1-4) rituximab infusions were performed. The median follow-up between the first preemptive infusion of rituximab and the last ADAMTS13 evaluation is of 36 months (24-65 months). After preemptive rituximab administration, only 3 patients experienced a clinical relapse (0 [0] episode/year), corresponding to a significant reduction in the relapse incidence (P < .01). ADAMTS13 activity was 58.5% (30.5%-86.3%). Three months after the first rituximab infusion, ADAMTS13 activity was 46% (30-68); it further increased until the 12th month, and subsequently decreased. Accordingly, B-cell lymphocytes remained undetectable until the 6th month, and progressively increased at the 9th month to reach normal values at the 18th month. Nine patients (30%) required one (5 cases), two (2 cases), three (1 case) or ten (1 case) additional courses of rituximab for a further decrease or a persistent undetectable ADAMTS13 activity, which allowed to maintain a detectable ADAMTS13 activity in all but one patients. The time between two consecutive courses of rituximab was 26 months (5-59 months). At the end of follow-up, ADAMTS13 activity remained normal in 18 patients; 10 patients had a moderate ADAMTS13 deficiency, and 2 patients had a persistently undetectable ADAMTS13 activity. In four patients (13%), rituximab alone failed to increase durably ADAMTS13 activity, which required additional immunosuppressive drugs. In group 2, 14 patients relapsed after a 66-month follow-up (36-105 months), corresponding to a higher relapse incidence than in patients who received preemptive infusions of rituximab (0.23 [0.1-0.46] relapse/year, P<.01). Moreover, 2 patients died of TTP in group 2, whereas no fatal outcome was recorded in group 1. Relapse free survival over time was significantly longer in group 1 (Log-rank test: P = .049). Five patients experienced adverse effects including benign infections in 2 cases. Conclusion Rituximab efficiently prevents TTP relapses in most patients with a persistent acquired ADAMTS13 deficiency, with acceptable side effects. Disclosures: Off Label Use: Rituximab Rituximab may prevent relapses in acquired thrombotic thrombocytopenic purpura.

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Efficacy and Safety of Rituximab for Refractory and Relapsing Thrombotic Thrombocytopenic Purpura: A Cohort of 10 Cases

Clinical Medicine Insights: Blood Disorders ◽

10.4137/cmbd.s25326 ◽

2015 ◽

Vol 8 ◽

pp. CMBD.S25326 ◽

Cited By ~ 7

Author(s):

Halima El Omri ◽

Ruba Y. Taha ◽

Amna Gamil ◽

Firyal Ibrahim ◽

Hisham Al Sabah ◽

...

Keyword(s):

Complete Remission ◽

Thrombotic Thrombocytopenic Purpura ◽

Dose Range ◽

Thrombocytopenic Purpura ◽

Clinical Criteria ◽

Severe Deficiency ◽

Life Threatening ◽

Multiple Relapses

Objective Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder mediated by autoantibodies directed against ADAMTS13. This provides a rationale for the use of rituximab in this disorder. We report our experience and the outcome of 10 cases of TTP (9 refractory and 1 relapsing) successfully treated with rituximab in combination with plasma exchange (PE) and other immunosuppressive treatments. Methods The diagnosis of TTP was based on clinical criteria and supported by severe deficiency of ADAMTS13 activity and presence of inhibitors in seven cases. Rituximab was started after a median of 18.6 sessions of PE (range: 5-35) at the dose of 375 mg/m2/week for 4-8 weeks. Results Complete remission was achieved in all patients after a median time of 14.4 days of the first dose (range: 6-30). After a median follow-up of 30 months (range: 8-78), eight patients were still in remission and two developed multiple relapses, treated again with the same therapy, and achieved complete responses; they are alive, and in complete remission after a follow-up of 12 and 16 months. Conclusion Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. However, longer follow-up is recommended to assess relapse and detect possible long-term side effects of this therapy.

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The South East England Thrombotic Thrombocytopenic Purpura Registry.

Blood ◽

10.1182/blood.v108.11.1064.1064 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1064-1064

Author(s):

Marie Scully ◽

Helen Yarranton ◽

Ri Liesner ◽

Jamie Cavenagh ◽

Beverley Hunt ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Oral Prednisolone ◽

Median Number ◽

The South ◽

Thrombocytopenic Purpura ◽

Treatment Protocols ◽

Abdominal Symptoms ◽

Life Threatening ◽

South East England ◽

Prompt Diagnosis

Abstract Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life threatening disorder. We present data from the South East (SE) England registry for TTP, from April 2002–December 2005. Included are 156 patients and 179 acute episodes. Seventy four percent of cases were female and 26% males, median age at presentation, 41 and 47.5 years respectively. Mortality to December 2003 was 12%, and from January 2004 to December 2005 was 5%; 5/12 died before treatment was instigated. The main ethnic groups were Caucasian (63%), Afro Caribbean (22%) and Asian (12%). In 61%, this was their first TTP episode; 39% represented with acute relapse. Precipitating events (n=123); idiopathic (56%), a defined infection (11%), pregnancy (6%), HIV disease (7%), congenital (5%) and associated autoimmune disease (6%). Features at presentation include: neurological disease (39%), temperature (15%), abdominal symptoms (12%), renal impairment (10%), symptomatic cardiac disease (7%), symptoms related to low platelets (17%) and no symptoms (2%). From April 2002–December 2003, the median number of plasma exchanges until complete remission (CR) recorded in 36 patients was 20 (5–79). One patient received plasma infusion (PI) in conjunction with PEX. 33 patients received 3 doses of pulsed intravenous methylprednisolone (IV MP) and 9 orally. Other therapies used were Rituximab (1), defibrotide (5), cyclosporine (9) and vincristine (15). In the second cohort (January 2004–December 2005), the median number of PEX to CR in 88 episodes was 8 (3–80). PI was used in 5 cases, 48 patients received 3 doses of pulsed IV MP on admission and 6 patients oral prednisolone. Other therapies used were Rituximab (26), defibrotide (2), cyclosporine (3), vincristine (5) and BPL 8Y (9). The latter is an intermediate purity Factor VIII concentrate used in congenital TTP. The median Haemoglobin (Hb) was 9.9g/dL at presentation and platelet count 18 ×109/L. The 2002–2003 group had 48% cases with platelet counts <150 ×109/L at 7 days, but only 25% of cases in 2004–2005. ADAMTS 13 activity, measured by collagen binding assay (CBA) (normal range 66–126%), in 136 episodes was <5% in 60%, 5–40% in 21%, 40–66 in 12% and >66% in 7% at presentation. Antibody to ADAMTS 13 (determined by mixing studies using CBA and/or anti-ADAMTS 13 IgG antibodies) was present in 61% of all cases. In those patients with acute idiopathic TTP, 93% had associated antibody. In conclusion: Improved recognition and prompt diagnosis of TTP may be associated with reduction in mortality and changes in treatment protocols reduced the number of PEX to achieve CR. Acute idiopathic TTP is the most common presentation, but improved identification of subgroups such as HIV and congenital TTP have resulted in appropriate tailoring of therapy.

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THU0517 THE ROLE OF ULTRASOUND-DEFINED SYNOVITIS GRADE I IN PATIENTS PRESENTING WITH INFLAMMATORY ARTHRALGIA, A RETROSPECTIVE STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4886 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 497.2-497

Author(s):

J. Arroyo Palomo ◽

M. Arce Benavente ◽

C. Pijoan Moratalla ◽

B. A. Blanco Cáceres ◽

A. Rodriguez

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Arthritis ◽

Statistical Tests ◽

Median Number ◽

Painful Joint ◽

Significant Difference ◽

The Mean ◽

Specialized Unit

Background:Musculoeskeletal ultrasound (MSUS) is frequently used in several rheumatology units to detect subclinical inflammation in patients with joint symptoms suspected for progression to inflammatory arthritis (IA). Synovitis grade I (EULAR-OMERACT combined score) is known to be a casual finding in healthy individuals, but studies headed to unravel its possible role on rheumatic diseases are sparse.Objectives:To investigate the correlation between synovitis grade I, and the diagnosis of IA made after a year follow-up period since MSUS findings, in patients of an MSUS-specialized unit of a Rheumatology Department.Methods:We conducted a descriptive, retrospective and unicentric study. 30 patients were selected from the MSUS-specialized unit of our Rheumatology Department from July-18 to January-19. Patients presenting synovitis grade 0 (exclusively), 2 and/or 3 on combined score were excluded. Data collection at baseline included age, sex, immunological profile and previous physical examination to the MSUS findings, as well as the diagnosis made by the rheumatologist in 1-year visit follow-up: dividing the patient sample into two groups: those who were diagnosed with IA and those not. Non-parametric statistical tests for comparing means were used.Results:The mean age was 51,6 years and 70% were females. 6 (20%) patients were diagnosed with inflammatory arthritis after a year follow-up: 2 (4,8%) psoriatic arthritis, 1 (3,3%) undifferentiated arthritis, 1 (3,3%) rheumatoid arthritis, 1 (3,3%) Sjögren’s syndrome. Non-inflammatory arthropathies were also found 24 (80%), of which, 12 (40%) were non-specific arthralgias and 8 (19%) osteoarthritis.In the group of patients who did not developed an IA the mean C-reactive protein (CPR) value was 3,12 mg/L and erythrocyte sedimentation rate (ESR) was 8,2 mm; all of them were rheumatoid factor (RF) positive and ACPA-negative except one patient. 5 (31,3%) patients presented low antinuclear antibodies (ANAs) levels. In those who HLA B-27 and Cw6 were tested (4,25%); both were negative except for one that was HLA B-27 positive. The median number of swollen and painful joint count was 0, and the mean of joints with MSUS involvement was 3,5; the mean involved metacarpophalangeal (MCP) joints was 1,83; proximal interphalangeal (PIP) joints was 1,48 and distal interphalangeal (DIP) joints 0,21.Among the group of patients that developed an IA the mean of CPR and ESR was 9,27 mg/L and 14,17 mm respectively; 2 (33%) patients were RF- positive, and 1 ACPA-positive. ANAs were positive in 3 cases (50%). The median of swollen joint count was 2 and for painful joint count was 0, the median of joints with MSUS involvement was 4,5. The mean of MSUS involvement was for MCP, PIP and DIP joints: 1,67, 2 and 0. Comparing the means of CPR values in the two groups with Student’s t-test we obtained a statistically significant difference (p=0,023). No other significant differences were found.Conclusion:Despite the limitations and possible statistical bias, the presence of MSUS-defined synovitis grade I and elevated CRP levels could be related to further diagnoses of inflammatory arthropathy. Besides, the absence of synovitis in DIP joints might have a diagnostic role. Normal physical exploration and normal levels of CRP might suggest low MSUS value. However, further research is needed to clarify the role of MSUS-defined synovitis grade I.References:[1]D’Agostino MA et al. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce-Part 1: definition and development of a standardized, consensus-based scoring system. RMD Open. 2017;3(1):e000428.[2]Van den Berg R et al. What is the value of musculoskeletal ultrasound in patients presenting with arthralgia to predict inflammatory arthritis development? A systematic literature review. Arthritis Research & Therapy (2018) 20:228.Disclosure of Interests:None declared

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Thrombotic thrombocytopenic purpura presenting as a severe peripartum cardiogenic shock: Role of myocardial biopsy and assist device for diagnosis and resuscitation

European Heart Journal Acute Cardiovascular Care ◽

10.1177/2048872617740829 ◽

2017 ◽

Vol 9 (7) ◽

pp. NP8-NP9 ◽

Cited By ~ 1

Author(s):

Sébastien Champion ◽

Dominique Belcour ◽

Bernard Alex Gaüzère

Keyword(s):

Cardiogenic Shock ◽

Thrombotic Thrombocytopenic Purpura ◽

Cardiac Involvement ◽

Life Support ◽

Extracorporeal Life Support ◽

Complete Recovery ◽

Myocardial Biopsy ◽

Assist Device ◽

Thrombocytopenic Purpura

We describe the case of a peripartum thrombotic thrombocytopenic purpura with fulminant cardiogenic shock treated with extracorporeal life support. Thrombotic thrombocytopenic purpura should be considered in the case of thrombotic microangiopathy with several or severe organ involvement and needs emergent treatment with plasmapheresis (with or without rituximab). In the case of cardiac involvement, aggressive treatment should be considered given the high mortality and the potential complete recovery.

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Plasma levels of bigEndothelin-1 are associated with renal insufficiency and in-hospital mortality of immune thrombotic thrombocytopenic purpura

Thrombosis and Haemostasis ◽

10.1055/a-1508-8347 ◽

2021 ◽

Author(s):

Ruinan Lu ◽

X. Long Zheng

Keyword(s):

Hospital Mortality ◽

Thrombotic Thrombocytopenic Purpura ◽

Plasma Levels ◽

Thrombus Formation ◽

Microfluidic Channel ◽

Thrombocytopenic Purpura ◽

Severe Deficiency ◽

Bioactive Product ◽

First Time

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of plasma ADAMTS13 activity. Despite advances in early diagnosis and management, the mortality rate of acute iTTP remains high in a large part of world where access to some of the most novel therapies is limited. To determine the role of plasma bigEndothelin-1 (bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients with iTTP on admission and during remission, as well as in healthy controls; moreover, the biological effect of ET-1 in thrombus formation was determined by a microfluidic assay. We show that plasma levels of bigET-1 were dramatically increased in patients with acute iTTP on admission, which was significantly decreased during clinical response/remission; elevated admission levels of plasma bigET-1 were associated with low estimated glomerular filtration rate, the need for intensive care unit admission or intubation, and in-hospital mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial cells in a microfluidic channel dramatically accelerated the rate of thrombus formation under arterial flow. Our results demonstrate for the first time a potential role of measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity and risk of in-hospital mortality, which may help stratify patients for a more aggressive monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1, may result in acute renal injury in TTP patient, likely through its vasoconstriction and prothrombotic properties.

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Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura

Thrombosis and Haemostasis ◽

10.1160/th15-07-0564 ◽

2016 ◽

Vol 115 (05) ◽

pp. 1034-1043 ◽

Cited By ~ 2

Author(s):

György Sinkovits ◽

Péter Farkas ◽

Dorottya Csuka ◽

Katalin Rázsó ◽

Marienn Réti ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Acute Phase ◽

Complement Activation ◽

Endothelial Activation ◽

Factor H ◽

Healthy Controls ◽

Activation Markers ◽

Thrombocytopenic Purpura ◽

Endothelin 1

SummaryThrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT-proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP.Supplementary Material to this article is available online at www.thrombosis-online.com.

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