Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. Accepted ArticleThis article is protected by copyright. All rights reserved. Running title: Terminology in TTP and TMAsKey words: ADAMTS-13 protein, human; thrombocytopenia; diagnosis, differential; thrombotic microangiopathy; thrombotic thrombocytopenic purpura Essentials• An international collaboration provides a consensus for clinical definitions.• This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).• The consensus defines diagnosis, disease monitoring and response to treatment.• Requirements for ADAMTS-13 are given. Abstract:Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic Microangiopathy is a broad pathophysiological process that leads to microangiopathic hemolytic anemia, thrombocytopenia and involves capillary and small vessel platelet aggregates. The most common cause being disseminated intravascular coagulation (DIC), which may be differentiated by abnormal Accepted ArticleThis article is protected by copyright. All rights reserved. IntroductionThe elucidation of the pathophysiology of TTP and HUS, in the past 20 years, has transformed our understanding of the phenotypes, genotypes and therapies for these life-threatening conditions. Work on standardization has been addressed [1], but this document aims to develop robust criteria for future clinical use, studies and trials.Clinical and pathophysiologic features of TTP, atypical Hemolytic Uremic Syndrome (aHUS) and disorders with similar presentations, their investigation and subsequent management vary. This consensus document aims to rationalize and standardize definitions. Conditions often included in the initial differential diagnosis of TTP are discussed. Definitions for remission, refractory and relapsing disease are defined.ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assays are central to diagnosis and are discussed. We therefore also describe the minimum requirements for validation of current and future assays. Methods:The development of this document involved key international, primarily clinical, experts in TTP and related TMAs. Accepted ArticleThis article is protected by copyright. All rights reserved.Hemostasis (ISTH) and American Society of Hematology (ASH) and all versions of the document have been reviewed and edited by the authors. Articles were identified by a computer-assisted search of the literature published in English using the National Library of Medicine PubMed database. The authors also undertook a focused review of the available literature. Where there was a lack of robust evidence, the international working group concluded a consensus-based approach was preferable. The conclusions are relevant to both children and adults. Thrombotic MicroangiopathyThe term TMA is a pathological term used to describe occlusive micro...
To cite this article: Peyvandi F, Oldenburg J, Friedman KD. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. 2016; 14: 248-61. Summary: Accurate and precise potency determination by manufacturers of different types of factor VIII product (plasma-derived and recombinant FVIII [rFVIII]) is vital to clinicians and patients using FVIII concentrates. A separate, but related, requirement is ascertaining the FVIII activity levels in clinical samples for diagnosing and treating hemophilia A. The one-stage clotting assay (OSA) and the chromogenic substrate assay (CSA) are the main assays used for these measurements, with both assays being used for potency assignments, and the OSA also being widely used for clinical monitoring. Although the assays can produce concordant results, discrepancies often occur, e.g. when measuring FVIII levels in patients with mild or moderate hemophilia A, or when assaying highpurity FVIII products. Modifications to rFVIII proteins, such as B-domain deletion (BDD), and technologies for improving the pharmacokinetic profile of rFVIII may exacerbate assay discrepancies. The CSA appears to be essentially unaffected by these modifications. However, the OSA underestimates the FVIII activity levels and therapeutic potential of some further modified BDD rFVIII products, especially those conjugated to poly(ethylene glycol); the extent of the effects is dependent on the specific OSA reagents used. Although the OSA remains the preferred choice for clinical monitoring in Europe and the USA, an awareness of the limitations of that assay has prompted more laboratories to adopt the CSA. J Thromb Haemost
The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties. 1A) (1-5), a metalloprotease that severs VWF and releases adherent platelets. Deficiency of ADAMTS13 disrupts this feedback regulatory mechanism and causes thrombotic thrombocytopenic purpura (TTP), which is characterized by life-threatening microvascular thrombosis (3, 6, 7).The recognition and cleavage of VWF is a formidable challenge. VWF and ADAMTS13 occur at ∼10 μg/mL and ∼1 μg/mL, respectively, compared with total plasma protein of ∼80,000 μg/mL. ADAMTS13 is constitutively active and has no known inhibitors in vivo. Nevertheless, VWF is the only identified ADAMTS13 substrate, and VWF is resistant to cleavage until subjected to fluid shear stress (8), adsorbed on a surface (9), or treated with denaturants (8, 10). This specificity depends on structural features of both ADAMTS13 and VWF that have not been characterized fully.The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains domains of ADAMTS13 bind to cryptic sites that are uncovered by unfolding VWF domain A2 (11-15) (Fig. 1B), and these interactions are required for efficient cleavage of VWF or peptide substrates. More distal ADAMTS13 domains bind to sites in or near VWF domain D4 that are always available (16-18). Deletion of distal ADAMTS13 domains impairs the cleavage of VWF multimers in vitro (16,19) and increases VWF-dependent microvascular thrombosis in vivo (20) but accelerates the cleavage of peptide substrates (12, 13). In addition, ADAMTS13 cleaves guanidine hydrochloride-treated VWF multimers with an apparent K m of ∼15 nM (21), which is 100-fold lower than the K m of ∼1.6-1.7 μM for peptide substrates that are based on the sequence of VWF domain A2 (12,14). These striking differences suggest that distal T or complement c1r/c1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains regulate ADAMTS13 activity. We have now shown that these distal domains inhibit ADAMTS13, and binding to VWF relieves this autoinhibition. Result...
The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of “VWF activity” by this assay and may not reflect a functional defect or true hemorrhagic risk.
Key Points Type 1 VWD in the United States is highly variable, including patients with very low VWF levels as well as those with mild or minimal VWF deficiency. The frequency of sequence variants in the VWF gene increases with decreasing VWF level, but BS does not vary by VWF level.
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