The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

Lancellotti, Stefano; Peyvandi, Flora; Pagliari, M; Cairo, Andrea; Abdel‐Azeim, Safwat; Chermak, Edrisse; Lazzareschi, Ilaria; Cavallo, Luigi; Oliva, Romina; Cristofaro, Raimondo De

doi:10.1160/th15-02-0119

Cited by 14 publications

(3 citation statements)

References 49 publications

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“…In both shear flow assays, we have found that sufficient VWF proteolysis could be achieved by almost all variants at 10% of the normal plasma concentration. Our data thus confirm previous suggestions that impaired secretion is the disease-causing variable for most variants [26,48,49]. Out of the variants investigated here, only p.Asp235Tyr and p.Arg349Cys exhibit significant residual secretion but strongly reduced activity under static as well as flow conditions (Table 1).…”

Section: Plos Onesupporting

confidence: 92%

Upshaw-Schulman syndrome-associated ADAMTS13 variants possess proteolytic activity at the surface of endothelial cells and in simulated circulation

et al. 2020

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ADAMTS13 regulates the hemostatic activity of von Willebrand factor (VWF). Determined by static assays, proteolytic activity <10IU/dL in patient plasma, in absence of ADAMTS13 autoantibodies, indicates Upshaw-Schulman syndrome (USS); the congenital form of Thrombotic Thrombocytopenic Purpura (TTP). We have recently functionally characterized sixteen USS-associated ADAMTS13 missense variants under static conditions. Here, we used two assays under shear flow conditions to analyze the activity of those seven mutants with sufficiently high residual secretion plus two newly identified variants. One assay determines cleavage of VWF strings bound to the surface of endothelial cells. The other, light transmission aggregometry-based assay, mimics degradation of VWF-platelet complexes, which are likely to be present in the circulation during TTP bouts. We found that 100 ng/ml of all variants were able to cleave about 80-90% of VWF strings even though 5 out of 9 exhibited activity �1% in the state-of-the-art static assay at the same concentration. These data indicate underestimation of ADAMTS13 activity by the used static assay. In simulated circulation, two variants, with missense mutations in the vicinity of the catalytic domain, exhibited only minor residual activity while all other variants were able to effectively break down VWFplatelet complexes. In both assays, significant proteolytic activity could be observed down to 100 ng/ml ADAMTS13. It is thus intriguing to postulate that most variants would have ample activity if secretion of 10% of normal plasma levels could be achieved.

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Section: Plos Onesupporting

confidence: 92%

Upshaw-Schulman syndrome-associated ADAMTS13 variants possess proteolytic activity at the surface of endothelial cells and in simulated circulation

et al. 2020

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“…However, a greater prevalence has been observed in the Central Norway Health Region, where the estimated prevalence of the p.R1060W mutation is 16.7 cases per million people [52]. More than 200 ADAMTS13 mutations have been identified in all of the ADAMTS13 protein domains [53][54][55]. Of note, some missense ADAMTS13 single-nucleotide polymorphisms have also been identified, which, in some cases, are in strong linkage disequilibrium with specific ADAMTS13 mutations, influencing their molecular effects [56][57][58].…”

Section: Clinical Symptoms Of First Episodes and Relapse Incidence Of...mentioning

confidence: 99%

Immune and Hereditary Thrombotic Thrombocytopenic Purpura: Can ADAMTS13 Deficiency Alone Explain the Different Clinical Phenotypes?

Lancellotti

Sacco

Tardugno

et al. 2023

JCM

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Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a hereditary or immune-mediated deficiency of the enzyme ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). TTPs are caused by the following pathophysiological mechanisms: (1) the presence of inhibitory autoantibodies against ADAMTS13; and (2) hereditary mutations of the ADAMTS13 gene, which is present on chromosome 9. In both syndromes, TTP results from a severe deficiency of ADAMTS13, which is responsible for the impaired proteolytic processing of high-molecular-weight von Willebrand factor (HMW-VWF) multimers, which avidly interact with platelets and subendothelial collagen and promote tissue and multiorgan ischemia. Although the acute presentation of the occurring symptoms in acquired and hereditary TTPs is similar (microangiopathic hemolytic anemia, thrombocytopenia, and variable ischemic end-organ injury), their intensity, incidence, and precipitating factors are different, although, in both forms, a severe ADAMTS13 deficiency characterizes their physiopathology. This review is aimed at exploring the possible factors responsible for the different clinical and pathological features occurring in hereditary and immune-mediated TTPs.

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“…Thus, <10% ADAMTS13 activity is used as a cut-off for diagnosing TTP patients (43). ADAMTS13 deficiency in TTP is generally associated with the formation of autoinhibitory ADAMTS13 antibodies; however, it can also be caused by mutations in the ADAMTS13 gene (31,(44)(45)(46)(47). Although TTP is not a common critical illness, its pathophysiology serves as an archetype for microvascular thrombosis caused by an imbalance in ADAMTS13 and VWF.…”

Section: Associations Between Vwf and Adamts13 In Diseasementioning

confidence: 99%

Reviewing the Dysregulation of Adamts13 and VWF in Sepsis

Madarati,

Singh,

Sparring

et al. 2023

Shock

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Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the Intensive Care Unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation (DIC) which is characterized by microvascular thrombosis. Von Willebrand Factor and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of Von Willebrand Factor and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their utility as markers of severe illness, and potential targets for new therapeutic development.

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The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

Abstract: The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura KAUST Repository

Cited by 14 publications

References 49 publications

Upshaw-Schulman syndrome-associated ADAMTS13 variants possess proteolytic activity at the surface of endothelial cells and in simulated circulation

Upshaw-Schulman syndrome-associated ADAMTS13 variants possess proteolytic activity at the surface of endothelial cells and in simulated circulation

Immune and Hereditary Thrombotic Thrombocytopenic Purpura: Can ADAMTS13 Deficiency Alone Explain the Different Clinical Phenotypes?

Reviewing the Dysregulation of Adamts13 and VWF in Sepsis

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