Deficient Activity of von Willebrand Factor-Cleaving Protease in Patients With Upshaw-Schulman Syndrome

Sasahara, Yoji; Kumaki, Satoru; Ohashi, Y; Minegishi, Masayoshi; Kano, Hiroki; Bessho, Fumio; Tsuchiya, Shigeru

doi:10.1007/bf02982559

Cited by 24 publications

(13 citation statements)

References 20 publications

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“…However, a careful routing analysis performed in this study revealed that 2 great-grandparents of patient B were from the same village in the Northeastern region of the Japanese mainland at the end of the 19 th century. More interestingly, one Japanese patient with USS reported by Sasahara et al 34 has the same homozygous mutation (Q449X) as our patient B (personal written communication from Drs David Ginsburg and Shigeru Tsuchiya, May 2003). This patient is a natural habitant of the same Northeastern region of Japan as patient B's ancestors.…”

Section: Discussionmentioning

confidence: 93%

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

Matsumoto

Kokame

Soejima

et al. 2003

Blood

144

116

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We report here 7 new mutations in the ADAMTS13 gene responsible for UpshawSchulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura, by analyzing 5 Japanese families. There were 3 mutations that occurred at exon-intron boundaries: 414؉1G>A at intron 4, 686؉1G>A at intron 6, and 1244؉2T>G at intron 10 (numbered from the A of the initiation Met codon), and we confirmed that 2 of these mutations produced aberrantly spliced messenger RNAs (mRNAs). The remaining 4 mutations were missense mutations: R193W, I673F, C908Y, and R1123C. In expression experiments using HeLa cells, all mutants showed no or a marginal secretion of ADAMTS13. Taken together with the findings in our recent report we determined the responsible mutations in a total of 7 Japanese patients with USS with a uniform clinical picture of severe neonatal hyperbilirubinemia, and in their family members, based on ADAMTS13 gene analysis. Of these patients, 2 were homozygotes and 5 were compound heterozygotes. The parents of one homozygote were related (cousins), while those of the other were not. Molecular models of the metalloprotease, fifth domain of thrombospondin 1 (Tsp1-5), and Tsp1-8 domains of ADAMTS13 suggest that the missense mutations could cause structural defects in the mutants. IntroductionThrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder, and its diagnosis is made according to the criteria of Moschcowitz's pentad 1 : thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fluctuating neurologic signs, renal failure, and fever. These criteria, however, are almost undistinguishable from those of hemolytic-uremic syndrome (HUS) with Gasser's triad 2 ; MAHA, thrombocytopenia, and renal insufficiency. Thus, the comprehensive term "TTP/HUS" or "thrombotic microangiopathy" 3 has frequently been used in clinical practice.Recent advances in elucidating the proteolytic processing of plasma von Willebrand factor (VWF) multimers have established assays for the activity of VWF-cleaving protease and its inhibitor (autoantibody). [4][5][6][7] These assays have largely made it possible to distinguish TTP from HUS, because the former has defective VWF-cleaving activity, whereas the latter has VWF-cleaving activity. 6,7 Studies by several groups of investigators have led to the identification of this enzyme as a new metalloprotease belonging to the ADAMTS (a disintegrinlike and metalloprotease with thrombospondin type 1 motif) family, which has been designated ADAMTS13. [8][9][10][11][12] This enzyme is produced in the liver. [10][11][12] The deduced amino acid residue number is 1427, and the gene contains 29 exons and is located on chromosome 9q34. [10][11][12] Upshaw-Schulman syndrome (USS) was originally reported as a disease complex with repeated episodes of thrombocytopenia and hemolytic anemia that quickly respond to infusions of fresh frozen plasma (FFP). [13][14][15][16] Clinical signs often develop in the patients during the newborn period or early infancy. In fact, the ea...

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Section: Discussionmentioning

confidence: 93%

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

Matsumoto

Kokame

Soejima

et al. 2003

Blood

144

116

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“…25,27,30,39 Experience with congenital TTP also suggests that ADAMTS13 levels of approximately 5% to 10% are sufficient to prevent thrombotic microangiopathy. [60][61][62][63] The same appears to be true for idiopathic TTP, 30,43 so that monitoring ADAMTS13 levels during treatment could be useful to determine whether plasma exchange should be intensified, decreased, or discontinued. In addition, monitoring during remission could identify patients with persistent or recurrent ADAMTS13 deficiency and a high risk of relapse, which might be forestalled by additional immunosuppressive therapy.…”

Section: Do We Need Real-time Adamts13 Assays?mentioning

confidence: 97%

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

Sadler

2008

Blood

508

400

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Discoveries during the past decade have revolutionized our understanding of idiopathic thrombotic thrombocytopenic purpura (TTP). Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves von Willebrand factor within nascent platelet-rich thrombi to prevent hemolysis, thrombocytopenia, and tissue infarction. Although approximately 80% of patients respond to plasma exchange, which removes autoantibody and replenishes ADAMTS13, one third to one half of survivors develop refractory or relapsing disease. Intensive immunosuppressive therapy with rituximab appears to be effective as salvage therapy, and ongoing clinical trials should determine whether adjuvant rituximab with plasma exchange also is beneficial at first diagnosis. A major unanswered question is whether plasma exchange is effective for the subset of patients with idiopathic TTP who do not have severe ADAMTS13 deficiency. Clinical features of idiopathic TTPIn January of 1924 1 and apparently for a second time in February, 2 Moschcowitz presented a case before the New York Pathological Society of "a hitherto undescribed disease (ref. 1 at 21)" that he felt was "remarkable, clinically and anatomically (ref. 2 at 89)." A healthy 16-year-old girl suddenly developed weakness in her arms, pain on moving her wrists and elbows, pallor, and fever (38°C-39°C). Her symptoms worsened and on the tenth day of illness she was admitted to the hospital with anemia, leukocytosis, a few petechiae on one arm, and occult blood in gastric contents and stool. The serum creatinine was normal. Four days later she developed mild left hemiparesis and facial paralysis. The next day she became comatose and died. A limited autopsy showed hyaline thrombi in terminal arterioles and capillaries of the heart, kidney, spleen, and liver; the lungs were spared. Moschcowitz did not obtain a platelet count and did not report schistocytes in the blood film, so we do not have a complete description from him of thrombocytopenia or microangiopathic hemolytic anemia. But based on the pathology at autopsy, we recognize this patient as the first published example of idiopathic thrombotic thrombocytopenic purpura (TTP).During the next 50 years, the clinical features of TTP became progressively better defined. Most patients were females between the ages of 10 and 39, and they usually exhibited a pentad of signs without obvious alternative causes: microangiopathic hemolytic anemia, thrombocytopenia, neurologic findings, renal damage, and fever. Unfortunately, the prognosis remained grim: mortality exceeded 90%, the average hospital stay was 14 days before death, and 80% of patients died within 3 months after the onset of symptoms. 3 Plasma therapyMoschcowitz also reported that one of his colleagues, Lederer, had seen 4 patients resembling his own case, and all recovered promptly after a single blood transfusion. 2 Lederer published his observations 4,5 but none of the patients had significant thrombocytopenia, which cast doubt on their diagnosis, a...

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“…Most patients under plasmatherapy have stopped having TTP relapses. Some cases of treatment failure may have been related to insufficient amounts of plasma infused or too long an interval between infusions [19,22,32,44,77]. No role of alloimmunization anti-ADAMTS13 has ever been demonstrated.…”

Section: Therapeutic Managementmentioning

confidence: 99%

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

et al. 2009

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Thrombotic thrombocytopenic purpura (TTP) related to a severely deficient activity of the von Willebrand factor cleaving protease, ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats) 13, is a life-threatening event, the onset of which may occur as early as childhood. TTP is either inherited (Upshaw-Schulman syndrome) via ADAMTS13 gene mutations (neonatal onset) or acquired via anti-ADAMTS13 autoantibodies (childhood onset). TTP is due to platelet- and von-Willebrand-factor-rich thrombi of the microvasculature, inducing mechanical hemolytic anemia, consumption thrombocytopenia, and multivisceral ischemia. Clinical course consists of relapsing acute events triggered mostly by infections, associated icterus and hyperbilirubinemia, severe hemolytic anemia with schistocytosis and a negative Coombs test, severe thrombocytopenia, and sometimes symptoms related to visceral ischemia (renal failure, central nervous system vascular events, other organ failure). The recently available ADAMTS13 laboratory investigation combining measurement of ADAMTS13 activity in plasma, search for an ADAMTS13 circulating inhibitor, and anti-ADAMTS13 IgG and ADAMTS13 gene sequencing is a crucial addition to TTP diagnosis. Plasma exchanges are first-line treatment of acquired TTP, combined with steroids and immunosuppressive drugs. Curative treatment of acute events in Upshaw-Schulman syndrome relies on plasma infusions (provider of active ADAMTS13). Guidelines for preventive treatment of relapses are not clearly established but should associate plasmatherapy and caution to triggers of relapses. Therapeutic perspectives are focused on the development of concentrated plasma-derived ADAMTS13 or recombinant ADAMTS13.

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Deficient Activity of von Willebrand Factor-Cleaving Protease in Patients With Upshaw-Schulman Syndrome

Cited by 24 publications

References 20 publications

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

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