Thrombotic thrombocytopenic purpura (TTP) is a rare (annual prevalence ~10 cases per million people), relapsing and life-threatening thrombotic microangiopathy (TMA).21 Acute TTP is defined by a mechanical hemolytic anemia, severe thrombocytopenia and systemic visceral ischemia causing multi-organ failure in the absence of urgent frontline therapeutic plasma exchange.21 In rare cases, TTP may cause sudden cardiac death related to myocardial infarction and cardiac arrhythmia.3 TTP is due to a severe functional deficiency (activity <10 IU/dL) of ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease.54 ADAMTS13 deficiency causes the accumulation of hyper-adhesive ultralarge von Willebrand factor multimers in blood which induce the spontaneous formation of platelet-rich microthrombi within arterioles and capillaries.51 So far, severe ADAMTS13 deficiency is the only highly sensitive and specific marker for acute TTP.6 Moreover, an altered open conformation of ADAMTS13 was recently reported to be a hallmark of acute TTP.87 In most cases, ADAMTS13 deficiency is acquired via specific auto-antibodies, increasing ADAMTS13 clearance and inhibiting its catalytic activity.51 These ADAMTS13 antibodies cause the immune-mediated form of TTP (iTTP). Several animal models of iTTP have been developed by directly transferring ADAMTS13 antibodies, especially the baboon model in which the venous injection of isolated ADAMTS13 antibodies triggers iTTP.9 To our knowledge, iTTP by passive transfer of ADAMTS13 antibodies has never been described in humans. In particular, in pregnancy-associated iTTP, no case of fetal TTP due to passive transfer of ADAMTS13 antibodies through the placenta has ever been described.10 We report here the cases of two patients with iTTP transmitted through renal transplantation from a single donor who suffered a sudden death.
A 29-year old man with no medical history was admitted to hospital after sudden cardiac arrest of unknown cause (Maastricht 2 classification). His blood cell count showed a thrombocytopenia of 35x10/L. The patient died and his kidneys were subsequently procured for transplantation into two unrelated recipients. The demographic, clinical and biological features of both recipients are presented in Table 1. Three days after surgery, both recipients developed a TMA syndrome including a microangiopathic hemolytic anemia and severe thrombocytopenia. Recipient 1 had a rapid, spontaneous correction of hemolysis and thrombocytopenia but his renal function did not improve necessitating continuous hemodialysis and de-transplantation 1 month later. In contrast, recipient 2 needed therapeutic plasma exchange and prednisolone to recover from hemolysis and thrombocytopenia but his renal function improved allowing discharge from hospital 15 days after transplantation. The occurrence of a de novo TMA in the two recipients of a kidney transplant from a single donor, who died suddenly, prompted us to retrospectively investigate ADAMTS13 in historical serum samples from the three patients. Informed consent was obtained from the patients or their families according to the Declaration of Helsinki. This study was approved by the ethical committees of Saint Antoine and La Pitié-Salpêtrière hospitals and registered at www.clinicaltrials.gov as NCT00426686.
Blood was collected from the donor prior to his death. The recipients’ blood for ADAMTS13 analysis was collected 3 days after transplantation (at the time of acute TMA, before therapeutic plasma exchange) and 1 month later (TMA remission). ADAMTS13 activity (normal range, 50-100 IU/dL), antigen (normal range, 350-730 ng/mL), IgG autoantibodies (positivity >15 IU/mL) and conformation [normal closed, conformation index (CI) <0.5] were measured in serum as previously described.117 The ADAMTS13 analysis supported the diagnosis of TTP in the three patients. The donor had a severe ADAMTS13 deficiency (ADAMTS13 activity <10 IU/dL and antigen 240 ng/mL), positive anti-ADAMTS13 IgG (32 IU/mL) and an open ADAMTS13 conformation (CI of 4.2), supporting a diagnosis of iTTP. The results of the ADAMTS13 analysis in both recipients, summarized in Table 1, also supported the disgnosis of iTTP, whereas their ADAMTS13 conformation was closed (CI < 0.5).
After kidney transplantation, TTP is very much less common than atypical hemolytic uremic syndrome.12 Indeed, post-transplantation TTP is extremely rare, occurs at least 1 week after transplantation and is usually not related to ADAMTS13 antibodies.1151 The TTP observed in our two kidney recipients did not, therefore, fit the classical framework. Moreover, the fact that both recipients shared the same donor suggested that their TMA was exceptionally related to an agent transmitted by the kidney transplants. A classical iTTP linked to endogenous ADAMTS13 auto-antibodies was likely responsible for the sudden death of the young and previously healthy male donor.3 In contrast, the recipients’ iTTP was most likely related to a kidney-mediated passive transfer of ADAMTS13 antibodies. Several arguments support this hypothesis. Firstly, the short period between the occurrence of TMA after transplantation likely reflects a fast release in blood of kidney-stocked, preformed ADAMTS13 antibodies and therefore excludes both allo-immunization against the donor’s ADAMTS13 and a transfer of ADAMTS13 antibody-producing B-lymphocytes from the donor. Secondly, the rapid improvement of hematologic signs, either spontaneously or after a short course of treatment with therapeutic plasma exchange, is compatible with a progressive clearance of exogenous ADAMTS13 antibodies. However, the irreversibility of the renal ischemia in one recipient and the persistence of a partial ADAMTS13 deficiency (activity ~30%) 1 month after acute TTP in both recipients suggest that ADAMTS13 antibodies clustered in the donor’s kidneys were still being released at low levels into the recipients’ blood several weeks after the acute TTP. Thirdly, our results on the conformation of ADAMTS13 may also indirectly argue in favor of passive transfer of ADAMTS13 antibodies (Figure 1). ADAMTS13 opening in iTTP is hypothesized to be initiated by a still unknown trigger and then enhanced by ADAMTS13 antibodies produced after exposure of a cryptic site.87 Interestingly, the ADAMTS13 conformation was open in the donor, which further supports the diagnosis of classical iTTP. In contrast, the ADAMTS13 conformation was closed in both recipients during acute iTTP suggesting that the ADAMTS13 antibodies detected in their serum were insufficient to unfold ADAMTS13, likely because an initial trigger was absent. Thus, in both recipients, the presence of ADAMTS13 antibodies can be explained by exogenous transfer but not by endogenous autoimmune synthesis.
As the patients’ kidney tissue samples were not workable for further histology, we immunized BALB/c mice with recombinant human ADAMTS13 (rhADAMTS13) produced as previously described,13 in order to provide evidence that kidneys may stock ADAMTS13 antibodies in iTTP. The presence of rhADAMTS13 antibodies in both serum and kidney lysates was determined using an enzyme-linked immunosorbent assay developed in-house as described previously.13 Murine antibodies in paraffin-embedded kidney sections were detected with a polyclonal rabbit-anti-murine immunoglobulin antibody (details in the legend to Figure 2). The rhADAMTS13 antibody titer in mice serum was above 1:105. Interestingly, rhADAMTS13 antibodies were detected in kidney lysates (Figure 2A). The presence of antibodies in the kidney was further visualized via immunohistochem ical analysis with anti-mouse immunoglobulins (Figure 2B-D). Specific rhADAMTS13 antibodies, however, could not be visualized in the kidney sections due to technical limitations. These findings show that ADAMTS13 antibodies can be captured in kidney tissue, and suggest that ADAMTS13 auto-antibodies can be transferred via kidney transplantation.
In conclusion, to our knowledge, this is the first case of iTTP likely induced by passive transfer of ADAMTS13 antibodies via an organ transplant. Other immune-mediated diseases, namely peanut allergy and an autoimmune thrombocytopenic purpura, were exceptionally reported to be transferred from a donor to a recipient by either combined liver and kidney transplantation14 or liver transplantation,15 respectively. This study highlights potential specific features of ADAMTS13 antibodies.
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