A Long-Term Phenotype Analysis Of 51 Patients With Upshaw–Schulman Syndrome In Japan, With Special References To Pregnancy and Renal Failure That Requires Hemodialysis

The classic hallmarks of Upshaw Schulman syndrome (USS) are severe newborn jaundice with a negative Coombs test that requires an exchange transfusion and repeated childhood episodes of thrombocytopenia and microangiopathic hemolytic anemia that are reversed by infusions of fresh frozen plasma. But now, it is well established that USS is a hereditary deficiency in the activity of von Willebrand factor (VWF)-cleaving protease, termed ADAMTS13. The inheritance mode is autosomal recessive, and their parents are usually asymptomatic carriers having one disease-causing mutation (DCM) of the gene.

In the absence of ADAMTS13, unusually large VWF multimers (UL-VWFMs) released from vascular endothelial cells are inappropriately cleaved, leading to platelet hyperagglutination under high shear stress. Thus, USS is alternatively called congenital thrombotic thrombocytopenic purpura (TTP). But, unlike acquired TTP, clinical signs of USS patients are usually mild during childhood and often an isolated thrombocytopenia is found. Further, now it is known that TTP-bouts are aggravated or initiated by the following factors: 1) severe infections such as influenza, 2) pregnancy, 3) 1-deamino-8-D-arginine vasopressin (DDAVP) administration, 4) interferon therapy, 5) heavily drinking alcohol, and 6) aging.

So far, in worldwide approximately 150 patients with USS have been found, of which we identified 51 patients in Japan. Among them, 48 patients were received ADAMTS13 gene analysis, and a pair of DCMs, either homozygotes or compound heterozygotes, was identified in all patients except for one. Interestingly, these DCMs are quite different from those found in patients of Western countries and United States, but several DCMs in Japanese patients are also found in Korean and Chinese patients. Thus, it appears that Caucasians and Asians have two different DCM routs for ADAMTS13. Further, since USS is an extremely rare disease, no one can predict the life-long clinical outcome in these patients. Thus, in this study using our cohort of 51 Japanese USS patients, we have extensively analyzed a long-term phenotype, with special references to pregnancy and renal failure that requires hemodialysis.

ADAMTS13 activity and its neutralizing antibodies (inhibitors) were determined by chromogenic ADAMTS13-act-ELISA [Kato et al. Transfusion, 2006], and the IgG type binding antibodies were assayed as described [Ferrari et al, JTH 2009]. Fifty-one patients with USS (19 males and 32 females, born in 1931-2013) were enrolled in this study. None of the patients had the neutralizing antibodies, but 6 patients (6/51, 12%) developed the IgG type non-neutralizing antibodies.

Pregnancy: We identified 26 episodes of pregnancy in 15 patients with USS (Table 1). Briefly, 22 pregnancies were identified before a diagnosis of USS, and as consequence 3 episodes are related to abortion, 10 episodes to stillbirth, and 9 episodes to live birth, in which 6 babies were premature. In contrast, 4 pregnancies were after a diagnosis of USS, and they all had the planned FFP infusions from the early phase of pregnancy, resulting in all successful deliveries, but with 2 premature babies.

Renal failure: We identified that 6 male patients finally fell into the end-stage severe renal diseases that required hemodialysis, of which 4 patients were deceased (Table 2). Median time from a diagnosis of USS to dialysis initiation was 15 years (range 1-25). Curiously, all these patients except for one had received FFP infusions biweekly after a diagnosis of USS. Causes of death in these 4 patients were the followings: heart failure (n=1), renal failure (n=1), and sudden death (n=2). The reason why all the patients, who fell into severe renal dysfunction, are male left unaddressed.

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Fujimura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees. Matsumoto:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees.