Abstract

The term Thrombotic Thrombocytopenic Purpura (TTP)-Hemolytic Uremic Sindrome (HUS) describes acute syndromes which although have different pathogeneses, different prognoses and different responses to treatment, in the same time present many features which are similar in many patients, such as microangiopathic hemolytic anemia without any apparent cause and, in many patients, neurologic and/ or renal complications.
Some patients have more neurologic complications with minimal renal disorders, and these patients are considered to represent classical TTP with severe deficiency of ADAMTS13 activity.
Other patients, on the contrary, have predominant renal failure with minimal neurologic disorders, and these patients are considered by some authors to represent HUS. However, some patients have both severe neurologic symptoms, such as seizures and coma, and acute renal impairment, and in these cases the distinction can be difficult.  Some patients may have thrombocytopenia and microangiopathic hemolytic anemia without neurologic or renal complications.  About half of patients with severe deficiency of ADAMTS13 activity have not any or mild neurologic or renal symptoms. (1) (www.uptodate.com 2014)  The term TTP-HUS is the most appriopriate term to describe these syndromes in adults patients, especially at the beginning of their evaluation,  because the distinction between these two entities is not clear and, on the other hand, the treatment with plasma exchange is the same, independently of the pathogenesis, except in rare cases of familial complement mutations, or in case of typical childhood HUS caused by Shiga toxin-producing Escherichia coli, typically E.coli 0157 : H7. (1) (www.uptodate.com 2014) In this outstanding review by George James N. et al., are reported important results of the Oklahoma TTP-HUS registry, that let us understand clinical characteristics and pathogenesis of this syndrome.
Since 1995, the Oklahoma TTP-HUS Registry has measured ADAMTS13 activity on 299 (93%) of 321 consecutive patients. Of the 68 patients (from 1995 to 2010) with severe deficiency of ADAMTS13 activity (activity < 10%), 54 (79%) were considered idiopathic. Of the 14 remaining patients,  3 were postpartum;  3  had autoimmune diseases;  2 had bloody diarrhea and were initially suspected to have TTP-HUS associated with E.coli O157 : H7 infection;  1  had severe Graft Versus Host Disease (GVHD) following allogenic hematopoietic stem cell transplantation;  4  had systemic infections;1 had a systemic malignancy.Therefore the authors conclude that “although severely deficient ADAMTS13 activity,defined as ADAMTS13 activity < 10%, is clinically important to identify patients who are at risk for relapse, it is not completely specific for patients with TTP-HUS. “ (1) (www.uptodate.com 2014) (2) (Blood 2010 vol. 115 (8) pp. 1500-1511) Patients with severely deficient ADAMTS13 activity also have a higher frequency of blood group 0. (3) (Transfusion 2011 vol. 51 pp. 2237-2243) To understand the pathogenesis of TTP-HUS syndrome, we must consider that von Willebrand factor is synthesized in endothelial cells and assembled in large multimers called Unusually Large Von Willebrand factor (ULVWf). These large multimers are rapidly degraded into the normal size range of VWf multimers by a specific von Willebrand factor-cleaving metalloproteinase called ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) (4) (Nature 2001 vol. 413 pp. 488-494) Mutations in the ADAMTS13 gene,leading to congenital TTP (Upshaw-Schulman syndrome) and antibodies to this enzyme, leading to acquired TTP, provoke an inherited and an acquired deficiency of ADAMTS13 activity respectively. (5) (Blood 2008 vol. 112 pp. 11-18) In patients who do not have deficient ADAMTS13 activity have been proposed other causes as endothelial injury, increased platelet aggregation, and genetic factors.
The presence of TTP-HUS must be suspected in every patient who present some or all the following clinical manifestations without another clinical apparent cause :
1) Microangiopathic hemolytic anemia
2) Thrombocytopenia, often with purpura but not usually severe bleeding
3) Renal function may be normal , but acute renal insufficiency may be present, associated with anuria and may require acute dialysis
4) Neurologic symptoms, usually fluctuating, are common, but patients may have no neurologic symptoms
5) Fever is rare; high fever with chills suggests sepsis rather than TTP-HUS
Before the treatment with plasma exchange many patients died, and it was possible to observe all the five clinical manifestations, but now it is rare to find all these symptoms in the same patient.
In the current clinical practice, the only presence of thrombocytopenia and microangiopathic hemolytic anemia without any apparent cause can permit to make a clinical diagnosis of TTP-HUS syndrome and we can start a prompt treatment with plasma exchange.
Patients with an ADAMTS13 activity > 10% at the time of clinical diagnosis rarely relapse. About 20% of patients will have persistent ADAMTS13 deficiency that do not predict a risk for relapse. (2) (Blood 2010 vol. 115 (8) pp. 1500-1511) 
The “ gold standard”  treatment for most patients with TTP-HUS is plasma exchange, by which the patient’s plasma is removed by pheresis and replaced with donor plasma rather than another replacement fluid such as albumin.  Plasma exchange must be initiated even if we are not certain about the diagnosis of TTP-HUS, considering the potential dangers of rapid deterioration of TTP-HUS. As initial treatment, plasma exchange must be performed daily until the platelet count has normalized and hemolysis largely ceased, as evidenced by a return of the serum lactate dehydrogenase (LDH) to normal or nearly normal levels. (6) (Blood 2010 vol. 116 (20) pp. 4060-4069)  Normally 7 to 16 daily exchanges are required to induce remission, but the variability is large and unpredictable.  Prednisone at the dosage of 1 mg/kg per day orally, or methylprednisolone at the dosage of 125 mg IV twice daily  may also be useful in the treatment of TTP-HUS syndrome. Other immunosuppressive agents as Rituximab, Vincristine and cyclophosphamide have been used in patients with primary refractory or relapsing TTP, with decrease or disappearance of the inhibitor to ADAMTS13 and subsequently improvement of ADAMTS13 levels in responder patients. (7) (www.uptodate.com 2014)  A phase 2 trial in which plasma exhange + rituximab were effective in relapsed or refractory thrombotic thrombocytopenic purpura has been presented at the 56th American Society of Hematology Annual Meeting and Exposition in San Francisco, December 6-9, 2014. (8) (Blood 2014 vol. (21) 56th ASH annual meeting 2014 abstracts 4191) See details in the treatment and prognosis section. In a recent paper and in a comment about this paper both published in Blood in march 2015 the role of rituximab in the treatment of TTP has been evaluated. Based on their review the authors suggest that rituximab be considered for initial therapy (grade 2C) and recommend its use in refractory patients (grade 1C) along with plasma exchange and corticosteroids. On the contrary the authors make a strong recommendation against the use of prophylactic rituximab in asymptomatic patients with low ADAMTS13 activity (grade 1C). (9) Blood 2015 vol. 125 (10) pp. 1526-1531) However, Adam Cuker in a comment on this article notes that in some cases the TTP relapses are "terrifying and highly disruptive to patients' lives, remaining fatal in approximately 10% of cases" that many patients, especially those with multiply related diseases, may be willing to accept the uncertain benefits and potential harms of rituximab. (10) (Blood 2015 vol. 125 (10) pp. 1514-1515)  see section on "Treatment and prognosis". In a recent very interesting review, Sayani and collegues  describe how they treat refractory TTP. At the moment there are limited data and consensus on the management of the refractory TTP.In this review they discuss use of rituximab, increased plasma exchange, splenectomy, immunosuppressive option, including cyclophosphamide, vincristine and cyclosporine.They also analyze the use of new agents such as bortezomib, N-acetylcisteine, recombinant ADAMTS13 and anti-VWF therapy. (11) (Blood 2015 vol. 125 (25) pp. 3860-3867)  
 
 
References  :
 
1 ) George James N., Leung Lawrence L.K., Tirnauer Jennifer S.  : Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults.  www.uptodate.com  2014
2 ) Kremer Hovinga J.A., Vesely S.K., Terrell D.R. et al.  : Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115 (8) : 1500-1511
3 ) Terrell D.R., Motto D.G., Kremer Hovinga J.A. et al.  : Blood group 0 and black race are independent risk factors for thrombotic thrombocytopenic purpura associated with severe ADAMTS13 deficiency. Transfusion 2011; 51 : 2237-2243
4 ) Levy G.G., Nichols W.C., Lian E.C. et al.  : Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413 : 488-494
5 ) Sadler J.E.  : Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112 : 11-18
6 ) George J.N. :  How I treat patients with thrombotic thrombocytopenic purpura. Blood 2010; 116 (20) : 4060-4069
7 ) Kaplan Andre A., George James N., Leung Lawrence L.K. et al. : Treatment and prognosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndromes in adults. www.uptodate.com 2014  
8 ) Foley Stephen Ronan, Rock Gail, Barth David et al.  : A phase II study evaluating the efficacy of rituximab in the management of patients with relapsed of  refractory TTP. Abstract 4191 www.bloodjournal.org/content/124/21/4191
9 ) Lim Wendy, Vesely Sara K. and George James N. :  The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood 2015; 125 (10) : 1526-1531
10 ) Cuker Adam : ITP and TTP : interpreting evidence in light of patient value. Blood 2014; 125 (10) : 1514-1515
11 ) Sayani Farzana A. and Abrams Charles S. :  How I treat refractory thrombotic thrombocytopenic purpura. Blood 2015; 125 (25) : 3860-3867

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