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Background Severe deficiency in ADAMTS-13 (

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombomicroangiopathy caused by deficiency of ADAMTS13. Acute neurological involvement is well described, but its long-term impact requires evaluation. One-hundred thirty-one patients, following an acute TTP event, with severe headache or neurological symptoms had a cerebral MRI. Fifty-six percent had abnormal imaging, more commonly in patients with neurological symptoms than headaches only (80% vs. 18%, P < 0·0001). In remission, 27% (n = 35) reported persistent cognitive symptoms: specifically, impaired memory (66%), difficulty concentrating (26%), and word-finding difficulties not secondary to an acute stroke (26%). Sixty-five percent also reported depression and 55% reported anxiety, regardless of presenting neurology. The frontal lobe was disproportionally affected in patients with marked intellectual impairment, seen in 67% of patients compared to 19% of patients without intellectual impairment (P = 0·002). The primary MRI finding in these patients was hyperintense white matter lesions. An abnormal MRI was associated with a lower median verbal IQ (85 vs. 99, P = 0·02) and performance IQ (83 vs. 100, P = 0·02). In conclusion, neurological symptoms are frequently associated with an abnormal cerebral MRI scan, and white matter frontal lobe lesions are particularly significant, leading to marked intellectual impairment. Anxiety and depression were evident in over half of patients, regardless of neurological involvement at presentation.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

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 77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody 11%) (P = .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.

To promote trainee-led clinical research and audit in non-malignant haematology. Haematology Specialty Trainee Audit and Research (HaemSTAR) is a national network of haematology trainees. HaemSTAR is a new initiative, conceived in 2016 and supported by the National Institution for Health Research (

Introduction Severe COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers. Methods Plasma exchange was carried out in seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio 800 IU/L and D dimer>1000 µg/L (or doubling from baseline). Patients received a daily single volume 3 litre plasma exchange for a minimum of five days. No other immunomodulatory medications were initiated during this period. Effects on organ function, thrombo-inflammatory markers and complications were monitored. Seven patients matched for age and baseline biochemistry were a comparator group. Results Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen:ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following five days of plasma exchange, plasma levels of all the above, and ferritin levels, were significantly reduced (p Conclusion Plasma exchange was associated with an improvement in oxygenation, decreased incidence of AKI, normalisation of lymphocytes and reduction in circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio. Disclosures Thomas: Ablynx: Honoraria, Other: Advisory Board; Bayer: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board. Scully:Takeda: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau.

Acute antibody-mediated thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy with high morbidity and mortality. Rituximab is highly effective as prophylaxis in patients at risk of acute TTP relapse, but the ideal dosing regimen is unknown. A multicenter retrospective cohort study evaluated outcomes of patients given rituximab prophylaxis to prevent TTP relapse. Rituximab was given in 76 episodes to 45 patients (34 women and 11 men). Four once-per-week infusions of standard- (375 mg/m2 [24 episodes]), reduced- (200 mg [19 episodes]), and intermediate- (500 mg [17 episodes]) dose rituximab were given; in the remaining 16 episodes, patients received 100 to 1000 mg rituximab in 1 to 5 doses. Patients were deemed at high risk of TTP relapse on the basis of ADAMTS13 activity dropping to ≤15% from the normal range. Preprophylaxis median ADAMTS13 level was 5% (range

BACKGROUND Patients presenting with acute episodes of thrombotic microangiopathies (TMAs) require urgent access to plasma exchange (PEX). OctaplasLG, a solvent/detergent fresh-frozen plasma product that has undergone viral inactivation and prion reduction step, has been used in our institution since 2013, replacing Octaplas. STUDY DESIGN AND METHODS We prospectively reviewed 981 PEX procedures where OctaplasLG was the replacement fluid in 90 patients admitted acutely with a TMA presentation within our institution from January 1, 2013, to December 31, 2015. We recorded citrate toxicities, plasma reactions, viral transfer, complications related to central venous catheter, and venous thrombotic events (VTEs). RESULTS Citrate toxicities were 5.4%, plasma reactions were 2%, and all were classified as Grade 1 or 2. VTE had an incidence of 12.2%, although 50% of the episodes occurred in early remission when patients were not receiving PEX. No line insertions complications were recorded. Line-associated infections were 2.2%. Hepatitis B and C serology and human immunodeficiency virus (HIV) were checked on admission. There were four patients who may have had passive transient transfer of hepatitis B antibodies from pooled plasma. No hepatitis C or HIV viral transfer was documented after treatment and no seroconversion was detected after treatment. CONCLUSION Our data have demonstrated that the incidence of complications during PEX is low and using OctaplasLG is comparable to the low incidence of reactions. No cases of anaphylaxis, transfusion-related acute lung injury, or fatal plasma reactions were seen. There was no evidence of viral transmission or seroconversion after treatment.

Introduction Congenital TTP (cTTP) is an ultra-rare disorder in which deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) results in circulating ultra large Von Willebrand Factor (VWF) multimers and subsequent microthrombi formation. Regular prophylactic therapy aims to improve outcomes from long-term complications, but also ongoing symptoms, including lethargy, headaches and abdominal pain, despite normal blood counts. Existing methods of quantifying ADAMTS13 activity lack the sensitivity to enable their use for evaluating treatment response in patients with cTTP. We present a novel flow-based assay with the aim of assessing treatment response, novel therapeutic options and analyzing the impact of different mutations on disease severity. Method A VenaFlux semi-automated microfluidic system was used to provide shear flow to mimic in vivo flow rates. Using whole blood, we analyzed platelet adhesion, aggregation and thrombi formation on microchannels coated with type I collagen and mounted onto the stage of an inverted epifluorescence microscope. Fresh, citrated whole blood was treated with DiOC6 to achieve platelet fluorescence and a macro on Image-Pro Premier was designed for automated calculation of total surface coverage. Surface coverage represented increasing thrombus formation with total coverage by thrombus within 180 seconds quantified as 100% coverage. Results were compared to a normal range developed using 43 normal controls (26=female, 17=male) with normal hemoglobin, platelet count and hematocrit. The surface coverage normal range was 6-39%. cTTP samples were analyzed for complete blood count, ADAMTS13 activity, VWF antigen, VWF activity and percentage surface coverage. Samples were taken 30 minutes before and after prophylactic treatment, either plasma infusion or BPL-8Y. Recombinant ADAMTS13 was added in-vitro on all pre-treatment samples with 15 minutes incubation time. Further re-measurement was undertaken after initiation of aspirin for at least ten days. Results Eighteen patients with cTTP confirmed by genetic analysis and ADAMTS13 levels The median pre-treatment surface coverage was 90% (range 47% - 100%). There was no significant difference in surface coverage considering genetic mutation type (median coverage for homozygous patients 88%, heterozygous 67%, p=0.99), mutation location (pre-spacer mutation surface coverage 67%, post spacer mutation surface coverage 84%, p=0.84), or age of first symptom onset (childhood onset surface coverage 59%, adult onset 86%, p=0.19). Plasma infusion improved surface coverage results with pre treatment coverage of 90% compared to 44% post plasma infusion (p=0.0003). In vivo recombinant ADAMTS13 administration on pre prophylaxis samples, resulted in normalization of surface coverage in all patients (p Conclusion Plasma infusion and aspirin synergistically reduce surface coverage by thrombus in patients with cTTP, demonstrated on peak and trough samples. Furthermore, in vitro addition of recombinant ADAMTS13 completely normalized thrombus formation. There were no major differences in surface coverage by genetic mutation. The newly developed flow-based assay presented can be used to assess treatment options and efficacy in cTTP in addition to demonstrating cTTP disease pathophysiology that has not previously been identified. In combination with clinical symptoms it offers potential to improve and personalize treatment for patients with cTTP. Figure. Figure. Disclosures Liesner: Bayer: Consultancy, Research Funding; Sobi: Speakers Bureau; Roche: Research Funding; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau.

Objectives CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin-methatrexate/ifusamide, etoposide, cytarabine) chemotherapy is commonly used to treat Burkitt lymphoma and in the HIV-negative population. Rituximab is often added with suggested survival benefits. Concerns over increased toxicity in an already immunocompromized population have prevented its routine addition in people living with HIV (PLWH). This study evaluated the effect on treatment-related toxicity and efficacy of adding rituximab to CODOX-M/IVAC chemotherapy in PLWH. Design Retrospective review of 91 PLWH (74 men) with Burkitt lymphoma treated in five London centers between 2003 and 2013. All patients received combination antiretroviral therapy. Results Forty-nine patients received CODOX-M/IVAC and 42 rituximab (R)-CODOX-M/R-IVAC. The addition of rituximab did not confer any significant increase in grade 3/4 toxicities including infections, mucositis, diarrhea, renal impairment, and tumor lysis syndrome. There was no significant difference in toxic deaths between groups (P = 0.14). The 2-year overall survival (OS) was greater for patients receiving rituximab {2-year OS 72% [95% confidence interval (CI) 0.22-0.92, hazard ratio 0.46] vs. 55% [95% CI 1.1-4.5, hazard ratio 2.2]; log-rank P = 0.04}. Similarly, the 2-year progression-free survival (PFS) was greater in the rituximab cohort [2-year PFS 81% (95% CI 0.21-0.99, hazard ratio 0.46) vs. 55% (95% CI 1.0-4.8, hazard ratio 2.2); log-rank P = 0.04]. Conclusion Our multicenter analysis is the largest to date in this population and showed that the addition of rituximab to CODOX-M/IVAC chemotherapy confers no increase in toxicity and results in significantly improved OS and PFS in PLWH with Burkitt lymphoma who receive concomitant combination antiretroviral therapy.

Background: Acute immune-mediated Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening disorder caused by acquired antibodies to the Von Willebrand factor cleaving protease ADAMTS13. Its prevalence has been estimated at four to thirteen cases per million per year and is characterized by hemolytic anemia, thrombocytopenia and multiorgan microthrombi. Untreated, mortality has been documented at 90% but even with treatment, it remains around 10-20%. Plasma Exchange (PEX) is the mainstay of treatment but immunosuppressive/immunomodulatory therapy is often also required. Whilst understanding of the disease process has increased greatly in recent times and a number of factors been implicated as possible markers of disease severity, there has been little evaluation of the effect of ADAMTS13 antigen levels on clinical outcome. Since January 2009, the United Kingdom TTP registry has been collecting information on all acute presentations of TTP across the country. Aims: A prospective study to evaluate the effect of the ADAMTS13 antigen titer on clinical outcomes in acute, immune-mediated TTP. Methods: Acute, immune-mediated TTP was defined as microangiopathic hemolytic anemia and thrombocytopenia with ADAMTS13 activity Results: There were 312 acute episodes of acquired TTP involving 292 patients over 87 months. Median ADAMTS13 activity was 11.65%) (p=0.0046). Patients with relapsed TTP had significantly higher presenting ADAMTS13 antigen levels compared to new presentations (new presentation 3.25% vs relapse 10%, p Patients with ADAMTS13 antigen 4% median IgG 28% (5-189%), p Conclusion: ADAMTS13 antigen levels appear to correlate with the clinical outcome in acute, immune-mediated TTP. A presenting antigen level below 4% was associated with an increased risk of mortality, more refractory disease and a greater prevalence of severe cardiac events. Disclosures Alwan: Octapharma: Research Funding; Ablynx: Research Funding. Scully:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.