Before addressing whether ADAMTS-13 deficiency is or is not specific for thrombotic thrombocytopenic purpura (TTP), let us define TTP and hemolytic uremic syndrome (HUS) as clinical syndromes. According to widely recognized criteria, features of TTP are thrombocytopenia, microangiopathic hemolytic anemia, and neurological abnormalities [1], while HUS lesions of thrombotic microangiopathy (TMA) are mostly confined to the kidney [1]. Although attempts have been made to differentiate TTP from HUS, I believe that none of the proposed differentiating features clearly separates these two syndromes [2]. The clinical symptoms in TTP and HUS are often overlapping and routine laboratory findings are of no help in distinguishing the two conditions. In addition, the fundamental lesion which consists of vessel wall thickening, mostly capillaries and arterioles, with swelling and detachment of the endothelial cells from the basement membrane and intraluminal thrombosis, is identical in TTP and HUS [1, 3]. Patients with TTP and with HUS have been reported within the same family and even the same patient was classified as TTP or HUS during different episodes of disease manifestation. Interestingly, in his recent excellent review on evaluation and management of these syndromes in adults, James George [3] did not distinguish between TTP and HUS but rather preferred to classify all patients as TTP–HUS [3]. I have a story about childhood HUS: ‘1954–55. Dos estudiantes de medicina que trabajaban con Gianantonio tambien estudiante, en el Hospital de ninos haciendo guardias cada nueve dias internaron en una sala del Hospital lo siguiente. La primera vez un lactante de tez blanca, palido, con diarrea con sangre, edematoso que a los pocos dias comienza con convulsiones y con diagnostico de encefalitis muere dentro de la semana. En la proxima guardia aparece otro nino de tez blanca muy palido con diarrea sanguinolenta, che comienza con convulsiones y muere dentro de la semana. Diagnostico: encefalitis. En la proxima guardia aparece un nino con igual sintomatologia y lo internan. Al dia siguiente, por el edema que presentaba y por la tarde, fuera de la rutina de la sala, le piden al jefe del laboratorio que haga una urea que da muy elevada. Al dia siguiente van a discutir con la medica del servicio el diagnostico sigiriendo una lesion renal; por lo que son severmente amonestados por la Dra.’ The story tells of two students in medicine working with Carlos Gianantonio who saw three subsequent children presenting with bloody diarrhea, edema and convulsions. In the first two patients, who died within few days, a diagnosis of encephalitis was made. However, urea values evaluated in the third child were very high, and this led the students to suspect that the children had actually a renal disease. Those were cases of the epidemic form of childhood HUS, initiated by Escherichia coli producing Shiga-like toxin (Stx-HUS), who had neurologic signs and subsequent autopsy findings of similar cases revealed cerebral microthrombi with edema and gross and microscopic hemorrhages [4]. The fact that those children had brain lesions lessens the paradigm that neurological involvement is peculiar to TTP. What is true is that both in adults and in children, the clinical presentation does not help to distinguish between TTP and HUS. Recently, the observations that patients given diagnosis of TTP had little or no ADAMTS-13 activity in plasma whereas the plasma activity of the enzyme was normal in patients with HUS [5, 6] led Joel Moake to state that ‘a single laboratory test may enable physicians to distinguish TTP from HUS’[7]. I am not convinced that this is the case and I shall explain why. First of all, a substantial proportion of adult cases with TTP, ranging from 30% [8] to 38% [9] in two different series, have normal ADAMTS-13 levels. On the other hand, undetectable ADAMTS-13 activity was found in two adult patients, one female and one male with the familial form of HUS [10], in four adults with secondary forms of HUS [8] and in one adult woman with postdiarrheal HUS [11]. One may also state that cases with ADAMTS-13 deficiency reported as HUS should have been called TTP. However, complete deficiency of ADAMTS-13 activity was also found in few children with Stx-HUS: one was reported by Veyradier et al. [12] and another by Hunt et al. [13]. The latter case was an 18-month-old child with undetectable ADAMTS-13 activity due to a circulating autoantibody. Reasonably the above children did not have TTP. Here is a second story: Georges Deschenes reported [14] on a child with relapsing hereditary HUS and neonatal onset, who developed chronic renal failure at 10 years. Renal biopsy showed glomerular and arteriolar lesions of thrombotic microangiopathy with sclerosis affecting 50% of the glomeruli. Hematological feature of HUS improved following bilateral nephrectomy. The patient received a cadaveric kidney transplant, however, he had an early recurrence of HUS in the post-transplant period [14]. ADAMTS-13 assay showed a complete deficiency of the protease activity in the plasma of this patient in the absence of any detectable inhibitor. Is there any reader that would state that this child was affected by TTP? Additional children with recurrent HUS with a neonatal onset and complete ADAMTS-13 deficiency have been recently described: three were reported by us [10] and six by Agnes Veyradier and colleagues [12]. Two independent Japanese groups described three [15] and two [16] children with complete ADAMTS-13 deficiency suffering from repeated episodes of bleeding associated with chronic thrombocytopenia and microangiopathic hemolytic anemia with neonatal onset and frequent relapses. Mutations in ADAMTS-13 gene were found in two of the above patients [17]. Neither TTP nor HUS could fit fully with the highly variable clinical manifestations recorded in the above children ranging from no obvious symptoms of renal dysfunction or central nervous system damage to severe neurological symptoms to acute renal failure requiring dialysis. The above groups have revisited the nomenclature of Upshaw–Schulman syndrome, originally introduced in 1979 by Rennard and Abe [18] to describe this syndrome that someone also calls TTP with neonatal onset and frequent relapses [17]. To further complicate the picture, in the conclusion of the paper quoted above, Dr Veyradier [12] used two different terms to classify the six children with ADAMTS-13 deficiency: they were D-HUS all along the paper but the diagnosis was revised to Upshaw–Schulman in the conclusion. The most simplistic way to unravel this thorny issue is to call TTP everything that is clearly associated with ADAMTS-13 deficiency. If so, what about two healthy unrelated adults who had complete ADAMTS-13 deficiency [19]? Moreover, severe deficiency of ADAMTS-13 activity was found in patients with disorders of thrombocytopenia other than TTP and HUS: idiopathic thrombocytopenic purpura (one case) [20], systemic lupus erythematosus (two cases) [20], and disseminated intravascular coagulation (three cases) [20]. Also, some patients with metastatic carcinoma [21] and a subgroup of patients with liver cirrhosis [22] were found to have severe ADAMTS-13 deficiency. Maybe it is better to use the broader term TMA [1] and classify patients as Stx-TMA for the epidemic forms and TMA associated with ADAMTS-13 or factor H abnormalities for forms caused by congenital or acquired ADAMTS-13 deficiency or by factor H mutations. This classification will help tailoring therapeutic interventions such as new agents targeted to prevent or limit organ exposition to Shiga-like toxin for Stx-TMA [23] or plasma exchange in TMA associated with ADAMTS-13 deficiency. As for TMA patients with factor H mutations, plasma therapy may be helpful in providing normal factor H although not all patients really benefit from this treatment. Until recombinant factor H will be available for substitution therapy, novel strategies such as combined kidney and liver transplant could be a therapeutic option in patients with end-stage renal disease [24]. This leaves the question, how does ADAMTS-13 deficiency integrate into the prevailing model of the pathophysiology of von Willebrand factor (VWF)-mediated TMA? According to this paradigm, congenital or autoimmune dysfunction of ADAMTS-13 prevents the normal proteolysis of unusually large (UL) VWF multimers, which, in conditions of high shear stress, are capable of supporting platelet aggregation more efficiently than normal multimers. However, experimental findings also challenge the above hypothesis. First, ULVWF multimers were found in patients with recurrent TMA with normal ADAMTS-13 activity. Second, many TMA patients with complete deficiency of ADAMTS-13 activity did not have UL VWF multimers in their circulation either in the acute phase or in remission. Attempts to explain the absence of UL VWF multimers during an acute episode attributed the phenomenon to UL VWF multimers consumption in the microcirculation following high avidity binding to platelets during the intravascular aggregation that characterizes the syndrome [25]. This theory largely fails to explain the absence of UL VWF multimers after resolution of the acute episode [25]. In addition, due to the high concentration of VWF in the patient blood [26, 27], the UL VWF multimers bound to platelets during acute episodes are likely to be a negligible fraction of the whole UL VWF circulating pool. This possibility is supported by data that plasma VWF levels are normal or even higher than normal during the acute phase of TMA [26, 27]. Finally, a very neglected finding that has been barely quoted in publications on TTP and HUS is that nearly all TMA patients during the acute phase had increased in 176 and 140 kDa VWF proteolytic fragments, independent of whether they had normal or deficient ADAMTS-13 activity in their blood [26]. Because cleavage of VWF by ADAMTS-13 is known to generate the 176 and 140 kDa fragments, the latter observation suggests that other proteases may be involved in VWF cleavage in TMA patients. In addition, the UL VWF model of TMA pathogenesis requires the demonstration that VWF is the major physiological substrate of ADAMTS-13 and this assumption has as yet only indirect support. Although ADAMTS-13 clearly inhibits VWF function in vitro, it might prevent TMA by cleaving other unknown proteins involved in the coagulation system or in the regulation of endothelial integrity. Although the discovery of ADAMTS-13 has changed our approach to diagnosis and treatment of TMA, much work is still needed to clarify the pathophysiological link between ADAMTS-13 deficiency and TMA. I am indebted to my colleagues, Miriam Galbusera and Marina Noris for their collaboration over many years. This work has been supported by the Comitato 30 ore per la vita, and by a Telethon grant (No. GGP02162).
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Dec 22, 2022
Claudia Tersteeg + 7