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Editorials
3. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526(7574):525-530.
4. Mansouri L, Sutton LA, Ljungstrom V, et al. Functional loss of IkappaBepsilon leads to NF-kappaB deregulation in aggressive chronic lymphocytic leukemia. J Exp Med. 2015;212(6):833-843.
5. Puente XS, Bea S, Valdes-Mas R, et al. Non-coding recurrent muta- tions in chronic lymphocytic leukaemia. Nature. 2015;526(7574):519-524.
6. Rosenquist R, Ghia P, Hadzidimitriou A, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 2017;31(7):1477-1481.
7. Sutton LA, Hadzidimitriou A, Baliakas P, et al. Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification. Haematologica. 2017;102(6):968-971.
8. Byrd JC, O'Brien S, James DF. Ibrutinib in relapsed chronic lympho- cytic leukemia. N Engl J Med. 2013;369(13):1278-1279.
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10. Johnson AJ, Lucas DM, Muthusamy N, et al. Characterization of the
TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood. 2006;108(4):1334- 1338.
11. Patrussi L, Capitani N, Ulivieri C, et al. p66Shc deficiency in the Emu-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape. Haematologica. 2019;104(10):2040-2052.
12. Capitani N, Lucherini OM, Sozzi E, et al. Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood. 2010;115(18):3726-3736.
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Hereditary thrombotic thrombocytopenic purpura
Marie Scully
Department of Haematology, UCLH and Cardiometabolic Programme-NIHR UCLH/UC BRC London, UK E-mail: MARIE SCULLY - m.scully@nhs.net
doi:10.3324/haematol.2019.225896
The first description of thrombotic thrombocy- topenic purpura (TTP) by Moschowitz was pub-
1
lished nearly 100 years ago. This was likely to have
been an immune-mediated TTP episode and the author described multi organs affected with worsening, untreat- ed disease. Accounts of hereditary TTP were otherwise acknowledged to be Upshaw Shulman syndrome. In 1960, Schulman reported an 8-year old girl who had repeated episodes of thrombocytopenia and hemolytic anemia from infancy. Treatment with plasma was associ- ated with normalization of the platelet count and resolu- tion of hemolysis, and remission was maintained with prophylactic plasma every 1-2 weeks.2 Upshaw presented a 16-year old girl with relapsing hemolytic anemia and thrombocytopenia since infancy. The patient responded to blood transfusions. During the next 11 years, Upshaw treated 32 episodes of thrombocytopenia and microangio- pathic hemolysis with plasma infusions. The acute episodes invariably had a trigger, such as a minor infec- tion, surgical procedure, pregnancy, or pancreatitis. Acute intervals lasted from three weeks to 20 months, at which time the platelet count was normal and there was a com- pensated hemolysis. Between these acute episodes, it was observed that intravascular platelet and red cell survival was shortened; these abnormalities normalized after the infusion of two units of plasma.3
In this edition of Haematologica, Van Dorland et al.4 pres- ent an international collaborative study on hereditary TTP. As an ultra-rare disorder, collection of meaningful data is critical to understand the clinical features of this condition, the therapy, and the long-term impact. The international registry presents data from over an 11-year period, incorpo- rating 123 patients from four continents who presented the disease from the neonatal period, up to the seventh decade of life. We know, from numerous publications relating to the mutations identified in hereditary TTP, that there is a heterogenous distribution throughout the ADAMTS 13 gene.5-8 There are, however, two specific variants that have been identified at increased frequency in hereditary TTP.
R1060W, exon 24, is prominent in Caucasians presenting
with late onset congenital TTP specifically associated with
9,10
pregnancy. Within the international hereditary TTP reg-
istry, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was prevalent, specifically within northern Europe, and was ini- tially described at increased prevalence from central Norway.11 Further cases were documented in the interna- tional registry, confirming that those patients with com- pound heterozygous mutations were more likely to have an earlier presentation, specifically in the neonatal period. There were other mutations which have been identified in more than one individual in the international registry. This allows us to predict the impact of such variations within the ADAMTS 13 gene with respect to clinical features. Such observations are only possible within the breadth of a reg- istry.4
The international registry has identified the significant delay in diagnosis of hereditary TTP; overall median age of overt presentation was 4.5 years but the clinical diagnosis was not made until a median of 16.7 years. Acute TTP episodes occurred at a median rate of 0.1 per year, ranging up to nine per year, and triggers included infections, child- birth, trauma, and in males, excess alcohol intake. The median time to resolution following an acute presentation was seven days.
There was an equal male to female ratio; this is in con- trast to immune-mediated disease, which has a female pre- ponderance. Residual ADAMTS 13 activity could not reli- ably predict age of onset or, indeed, disease severity, despite a cut-off of 1%. This may also help to explain why patients with identical genetic variants have significant dif- ferences in the clinical phenotype. What is particularly striking and important is the clinical impact of hereditary TTP: 1) the degree of end-organ damage symptoms, either at presentation or as complications of the disease; and 2) the proportion of patients with arterial thromboembolic events, present in 28% and covering all age groups. This was especially striking in 40-50 years old; >50% of these patients had at least one arterial thromboembolic event.
haematologica | 2019; 104(10)