Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

The safety and efficacy of weekly rituximab 375 mg/m 2 (؋4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n ‫؍‬ 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 ؋ 10 9 /L and 38% > 150 ؋ 10 9 /L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P ‫؍‬ .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P ‫؍‬ .04), especially in whites, with a mean reduction of 7 days (P ‫؍‬ .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P ‫؍‬ .0011).There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713. (Blood. 2011;118(7): 1746-1753)

and14 Manchester Royal Infirmary, Manchester, United Kingdom Key Points• In women presenting with an initial diagnosis of TTP during pregnancy, cTTP was more common than acquired TTP.• Active monitoring and management during pregnancy results in positive pregnancy outcomes.Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/ postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes. (Blood. 2014;124(2):211-219)

To cite this article: Westwood J-P, Webster H, McGuckin S, McDonald V, Machin SJ, Scully M. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. J Thromb Haemost 2013; 11: 481-90.Summary. Background: Rituximab has been documented in the treatment of acute ( 3 days from admission), relapsed/refractory thrombotic thrombocytopenic purpura (TTP) and given as prophylaxis in selected cases to prevent acute relapse. The precise timing of rituximab in acute TTP has not been determined. Objective: To perform a retrospective analysis of rituximab use in a large TTP referral center over an 8-year period. Patients/ Methods: We assessed response to treatment and outcome for all patients treated with rituximab, including 91 patients presenting with 104 episodes of acute TTP and 15 patients given rituximab as prophylaxis to prevent relapse. In the acute TTP group we assessed the benefit of giving early ( 3 days from admission) vs. later (> 3 days) rituximab. Results: In acute de novo TTP, previously untreated with rituximab, rituximab was given 3 days from admission to 54 patients and > 3 days from admission to 32 patients. Earlier administration ( 3 days) was associated with faster attainment of remission (12 vs. 20 days, P < 0.001), fewer plasma exchanges (16 vs. 24, P = 0.03) and shorter hospital stay (16 vs. 23 days, P = 0.01). Eighty-two patients (95%) achieved complete remission within 14 days (4-52 days); four patients died acutely. Eleven out of 82 (13.4%) relapsed at a median of 24 months (4-49 months). Rituximab prophylaxis was associated with normalization of ADAMTS13 levels within 3 months in all but one case, with only one acute relapse at follow-up. Conclusions: Although limited by being retrospective and non-randomized, this study demonstrates the potential benefit of early administration of rituximab in acute TTP, and prophylactic use to prevent acute relapse.

Vaccine‐induced immune thrombocytopenia and thrombosis (VITT) following ChAdOx1 nCOV‐19 vaccine has been described, associated with unusual site thrombosis, thrombocytopenia, raised D‐dimer and high titre immunoglobulin‐G (IgG) class anti‐Platelet Factor 4 (PF4) antibodies. Enzyme linked immunosorbent assays (ELISA) have been shown to detect anti‐PF4 in patients with VITT, but chemiluminesence assays do not reliably detect them. ELISA assays are not widely available in diagnostic laboratories, and, globally, very few laboratories perform platelet activation assays. Assays which are commercially available in the United Kingdom were evaluated for their ability to identify anti‐PF4 antibodies in samples from patients with suspected VITT. Four IgG‐specific ELISAs, two polyspecific ELISAs and four rapid assays were performed on samples from 43 patients with suspected VITT from across the UK. Cases were identified after referral to the UK Expert Haematology Panel multi‐disciplinary team and categorised into unlikely, possible or probable VITT. We demonstrated that the HemosIL AcuStar HIT‐IgG, HemosIL HIT‐Ab, Diamed PaGIA gel and STic Expert assays have poor sensitivity for VITT in comparison to ELISA. Where these assays are used for heparin induced thrombocytopenia diagnosis, laboratories should ensure that requests for suspected VITT are clearly identified so that an ELISA is performed. No superiority of IgG‐ELISAs over polyspecific‐ELISAs in sensitivity to VITT could be demonstrated. No single ELISA method detected all possible/probable VITT cases; if a single ELISA test is negative, a second ELISA or a platelet activation assay should be considered where there is strong clinical suspicion.

Key Points• High anti-ADAMTS13 antibody and low ADAMTS13 antigen levels adversely affect outcome in immunemediated TTP with greater mortality seen.• A raised troponin at presentation confers a sixfold increase and reduced GCS a nine-fold increase in mortality in acute TTP.Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n 5 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P 5 .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P 5 .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P 5 .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality. (Blood. 2017;130(4):466-471)

To cite this article: Scully M, Brown J, Patel R, McDonald V, Brown CJ, Machin S. Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link. J Thromb Haemost 2010; 8: 257-62.Summary. Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, acute, life-threatening disorder, associated with a deficiency in ADAMTS 13. The majority of acute, idiopathic, adult TTP cases are associated with anti-ADAM-TS 13 IgG antibodies. However, the factor(s) precipitating an acute TTP episode are not always obvious; indeed, a multifactorial etiology is likely. Objectives and Methods: DNA was used for human leukocyte antigen (HLA) class II typing, using polymerase chain reaction (PCR)-sequencespecific primer and PCR-sequence-specific oligonucleotide probe to methodology to investigate 50 European acquired idiopathic TTP cases. Results: There was an increase in the frequency of HLA-DQB1*0301 (HLA-DQ7) in patients with TTP as compared with controls [58.0% vs. 34.5% (P = 0.048)]. The frequencies of HLA-DRB1*11 and HLA-DRB3* were also significantly increased in TTP patients as compared with controls [44.0% vs. 12.0% (P = 0.0024) and 84.0% vs. 58.0% (P = 0.024)], although it remains uncertain whether susceptibility is influenced by HLA-DQ or HLA-DR molecules or other genes in this haplotype. The frequencies of HLA-DRB1*04 and HLA-DRB4 (HLA-DR53) were significantly decreased in the patient group as compared with controls [10.0% vs. 35.0% and 26.0% vs. 61.5% (P = 0.0096 and P = 0.0024, respectively)], and may have a protective effect against the development of TTP. Conclusion: Analysis identified HLA class II types associated with susceptibility to and a protective effect against the development of acute acquired TTP in European patients. This provides the first description of a genetic factor predicting the risk of developing acquired antibody-mediated TTP.

To cite this article: McDonald V, Manns K, Mackie IJ, Machin SJ, Scully MA. Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost 2010; 8: 1201-8.Summary. Background: Increasingly, patients with acute, idiopathic, antibody mediated thrombotic thrombocytopenic purpura (TTP) are being treated with rituximab to achieve a durable remission, however, there is the potential that it is removed by plasma exchange (PEX). Objectives: To look at the pharmacokinetics and pharmacodynamics of rituximab in patients with acute idiopathic TTP undergoing PEX. Patients and methods: Patients who received rituximab for acute idiopathic TTP (group 1, n = 30) and a control group (group 2, n = 3) of TTP patients in remission receiving rituximab electively as maintenance were included. Rituximab levels were measured before/after each infusion, before/after PEX and in follow-up. ADAMTS-13 activity, anti-ADAMTS-13 IgG and CD19% were measured to assess response. Results: The median number of PEX to remission after rituximab was 10 (range 4-25). In group 1 there was no significant incremental rise in the peak serum rituximab level until dose 4. Trough levels were lower in patients who had had PEX since their last rituximab infusion. In the control group, there was an incremental rise in the peak serum rituximab level and all patients had detectable trough levels. The median fall in rituximab per PEX was 65%. All patients achieved CD19 < 1%. In group 1, the median time to undetectable rituximab was 5 months (range 0-12 months) and to B cell return was 7 months (range 3-24 months). ADAMTS-13 increased and anti-ADAMTS-13 fell after therapy. There were three deaths and two relapses in group 1. Relapse was not temporally related to B cell return.