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The aim of the present study was to perform an economic evaluation of two alternative assays of ADAMTS13 activity (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, member 13) for diagnosing thrombotic thrombocytopenic purpura (TTP) in the Hospital of Lyon (France). The study approach was more economic than clinical. We retrospectively calculated the prescription costs of ADAMST13 activity from January to December 2019 for patients depending on the assay: manual ELISA (Technozym) or automated assay (AcuStar Werfen, Instrumentation Laboratory). Then, we compared the cost of therapeutic plasma exchange (TPE) consumption awaiting ADAMTS13 activity assay results. From an economic point of view, the automated assay was more cost-effective. From a clinical one, we supposed that the faster results given by AcuStar could improve patient care by reducing the number of TPEs. Automated assay could improve patient care without increasing costs in our institution.

ADAMTS13 is a zinc-containing metalloprotease that cleaves von Willebrand factor (VWF). Deficiency of plasma ADAMTS13 activity is accountable for a potentially fatal blood disorder thrombotic thrombocytopenic purpura (TTP). Understanding of ADAMTS13-VWF interaction is essential for developing novel treatments to this disorder.Despite the proteolytic activity of ADAMTS13 being restricted to the metalloprotease domain, the ancillary proximal C-terminal domains including the disintegrin domain, first TSP-1 repeat, cysteine-rich region, and spacer domain are all required for cleavage of VWF and its analogs. Recent studies have added to our understandings of the role of the specific regions in the disintegrin domain, the cysteine-rich domain, and the spacer domain responsible for its interaction with VWF. Additionally, regulative functions of the distal portion of ADAMTS13 including the TSP-1 2-8 repeats and the CUB domains have been proposed. Finally, fine mapping of anti-ADAMTS13 antibody epitopes have provided further insight into the essential structural elements in ADAMTS13 for VWF binding and the mechanism of autoantibody-mediated TTP.Significant progress has been made in our understandings of the structure-function relationship of ADAMTS13 in the past decade. To further investigate ADAMTS13-VWF interactions for medical applications, these interactions must be studied under physiological conditions in vivo.

Background: ADAMTS13 cleaves and inactivates von Willebrand factor (VWF), which binds collagen, facilitating platelet adhesion under vascular injury. But is still uncertain how ADAMTS13 activity is regulated. Thrombin and plasmin have been shown to cleave ADAMTS13. Based on the fact that elevated levels of FXI is an independent risk factor for deep vein thrombosis and ischemic stroke, we hypothesize that FXIa inactivates ADAMTS13 leading to platelet aggregation and thrombus formation. Aim: To determine the functional role of inactivation of ADAMTS13 by FXIa. Methods and Results: Recombinant ADAMTS13 (250 nM) was incubated with FXIa (50 nM) for increasing times (0-3 hours) at 37 o C before being analyzed by western blot using an anti-ADAMTS13 antibody against the two CUB domains (C-terminal) or against the metalloproteinase (MET) domain (N-terminal). Our results show that FXIa caused the disappearance of the ADAMTS13 band (~200 kDa) and the appearance of a band at ~150 kDa when the samples were analyzed with the anti-MET antibody and a ~50 kDa band when the samples were analyzed with the anti-CUB antibody. The presence of aprotinin, which inhibits FXIa activity, blocked the degradation of ADAMTS13. Kallikrein or FXIIa were unable to cleave ADAMTS13. Using a cell surface immunoassay we observed that after incubation with FXIa, the detection of the CUB domain from ADAMTS13 was lost from endothelial cells surface. The incubation of ADAMTS13 with FXIa caused an increase in ADAMTS13 activity as measured by a fluorogenic substrate (FRETS). Conclusion: ADAMTS13 circulates in a closed conformation, which is maintained by a CUB-spacer domain binding interaction. ADAMTS13 becomes conformationally activated through interaction of its CUBs domains with VWF. Here we show that FXIa-mediated deletion of ADAMTS13-CUB domains enhances its capacity to cleave FRETS and blocks the interaction with VWF. Our results suggest that FXIa may limit ADAMTS13-mediated VWF inactivation.

We report the case of a 68-year-old woman with acute thrombotic thrombocytopenic purpura (TTP) that developed after pneumococcal vaccination. She was found in a confusional state with high fever 15 days after vaccination. Laboratory data showed hemolytic anemia and thrombocytopenia, and blood smear showed fragmented erythrocytes. TTP was diagnosed based on the clinical presentation, and was subsequently confirmed by the absence of ADAMTS13 activity and the presence of inhibitor against ADAMTS13 in serum. She was successfully treated using plasma exchange and corticosteroids, and no recurrence has been identified. This appears to represent the first report of TTP following pneumococcal vaccination.

We aimed to evaluate the ADAMTS13 activity weekly after the hematopoietic stem cell transplantation and its relationship with clinical outcome. We studied 30 patients undergoing allogeneic hematopoietic stem cell transplantation with different conditioning regimens and 15 healthy controls. Plasmas were collected from patients 10 days before transplantation, the day of transplantation and 7th, 14th, 21st and 28th days after transplantation. Patients were followed for median period of 13 months (6-24 months). Patient plasmas were further collected when graft versus host disease (GVHD) developed. Enzyme activities of patients did not show a significant change through weeks [87% (39-145), 82% (16-110), 80% (36-134), 80% (36-134), 86% (47-127), 89% (11-127) and 90% (10-127)]. None of our patients had enzyme activity lower than 5% and had thrombotic microangiopathy, thromboembolism or hepatic veno-occlusive disease. Enzyme activity on the day of acute GVHD was not significantly different from the pretransplantation period (73 +/- 32 versus 87 +/- 20%, P = 0.231), but significantly lower than healthy controls (73 +/- 32 versus 97 +/- 16%, P = 0.02). Moreover, by the 28th day after transplantation, patients with acute GVHD had lower enzyme activity than the patients without acute GVHD (62 +/- 36 versus 95 +/- 22%, P = 0.009). ADAMTS13 activity was lower in samples taken from patients with chronic GVHD compared with baseline level (67 +/- 13 versus 91 +/- 30%, P = 0.15) and healthy controls (67 +/- 13 versus 97 +/- 16%, P = 0002). According to our data, transplantation does not have significant effect on ADAMTS13 activity. Acute or chronic GVHD causes a slight decrease of the enzyme that may indicate the possible cytokine effect.

We report a child with thrombotic thrombocytopenic purpura (TTP) secondary to systemic lupus erythematosus. The diagnosis was confirmed by low ADAMTS13 activity (5%) along with the presence of a low titer inhibitor. Her clinical course was complicated by systemic lupus erythematosus, immunosuppressant therapy, and septic shock. She responded to plasma exchange and ADAMTS13 activity levels recovered. This case illustrates the heterogeneity of TTP and the difficulty of making a diagnosis of TTP. ADAMTS13 activity assay can be useful in the differential diagnosis of diseases with clinical features of thrombotic microangiopathy in pediatric patients. However, treatment needs to be decided carefully case-by-case.