1,820 results on '"ADAMTS13 Protein"'
Search Results
2. Excessive cleavage of von Willebrand factor multimers by ADAMTS13 may predict the progression of transplant-associated thrombotic microangiopathy
- Author
-
Shinya Yamada, Kazuya Sakai, Masayuki Kubo, Hirokazu Okumura, Hidesaku Asakura, Toshihiro Miyamoto, and Masanori Matsumoto
- Subjects
ADAMTS13 protein ,hematopoietic stem cell transplantation ,proteolysis ,thrombotic microangiopathy ,von Willebrand factor ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of hematopoietic stem cell transplantation and is characterized by severe thrombocytopenia, hemolytic anemia, and organ dysfunction. In response to several possible triggers, dynamic multimetric change in von Willebrand factor (VWF) may contribute to inducing microthrombi in circulation in TA-TMA. Objectives: By performing VWF multimer analysis and measuring VWF-degradation product (DP), we unraveled the relationship between multimeric changes in circulating VWF and the pathogenesis of TA-TMA. Methods: This study analyzed 135 plasma samples from 14 patients who underwent allogeneic hematopoietic stem cell transplantation at a single institute. VWF-associated markers, namely VWF:antigen (VWF:Ag), VWF-DP/VWF:Ag ratio, VWF:ristocetin cofactor activity, VWF:ristocetin cofactor activity/VWF:Ag ratio, and ADAMTS13 activity, were analyzed in these samples collected every 7 days. Results: There were 2 patients with definite thrombotic microangiopathy (TMA) and 6 patients who presented with probable TMA that did not progress to definite TMA. Each plasma sample was classified into 3 groups: definite TMA, probable TMA, and non-TMA. VWF multimer analysis showed the absence of high-molecular-weight VWF multimers in probable TMA, whereas the appearance of unusually large VWF multimers was observed in definite TMA. The median value of the VWF-DP/VWF:Ag ratio in probable TMA was elevated to 4.17, suggesting that excessive cleavage of VWF multimers by VWF cleaving enzyme, ADAMTS13, resulted in the loss of high-molecular-weight VWF multimers. Conclusion: During the transition from probable to definite TMA, drastic VWF multimer changes imply a switch from bleeding to thrombotic tendencies. Extensive VWF-DP and VWF multimer analyses provided novel insights.
- Published
- 2024
- Full Text
- View/download PDF
3. Comparison of thrombomodulin, vWF, and ADAMTS13 levels between preeclampsia and normal pregnancy
- Author
-
Aisha Ahmad, Ghulam Mustafa, Nazish Mazari, and Muhammad Asif
- Subjects
Thrombomodulin ,vWF ,ADAMTS13 protein ,Pre-eclampsia ,Medicine - Abstract
Objective: To determine and compare plasma thrombomodulin, von Willebrand factor and von Willebrand factor-cleaving protease levels between pre-eclamptic and healthy pregnant females. Method: The cross-sectional, comparative study was conducted at the Department of Haematology, University of Health Sciences, Lahore, Pakistan, from November 2019 to December 2020, and comprised pregnant females who were divided into healthy pregnant group A and pre-eclamptic group B. Plasma thrombomodulin and von Willebrand factor-cleaving protease levels were determined by using commercially available enzyme-linked immunosorbent assay kit, and von Willebrand factor level was determined by using immuno-turbidimetric assay kit. Data was analysed using SPSS 25. Results: Of the 88 participants, there were 44(50%) females with mean age 25.5±6 years in group A and 44(50%) in group B with mean age 26±5 years. Median thrombomodulin level in group B was significantly higher than group A (p=0.003). Median von Willebrand factor-cleaving protease levels were lower in group B compared to group A (p=0.838). A significant difference in von Willebrand factor level was observed between the groups (p=0.038). Conclusion: Females with pre-eclampsia had significantly higher plasma levels of von Willebrand factor and thrombomodulin than healthy pregnant subjects. Key Words: Thrombomodulin, vWF, ADAMTS13 protein, Pre-eclampsia.
- Published
- 2023
- Full Text
- View/download PDF
4. The Specificities of Thrombotic Thrombocytopenic Purpura at Extreme Ages: A Narrative Review.
- Author
-
Joseph, Adrien, Joly, Bérangère S., Picod, Adrien, Veyradier, Agnès, and Coppo, Paul
- Subjects
- *
THROMBOTIC thrombocytopenic purpura , *TRANSITION to adulthood , *VON Willebrand factor , *DELAYED diagnosis , *OLDER patients , *SYMPTOMS - Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) related to a severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. This deficiency is often immune-mediated (iTTP) and related to the presence of anti-ADAMTS13 autoantibodies that enhance its clearance or inhibit its VWF processing activity. iTTP management may be challenging at extreme ages of life. International cohorts of people with TTP report delayed diagnoses and misdiagnoses in children and elderly people. Child-onset iTTP shares many features with adult-onset iTTP: a female predominance, an idiopathic presentation, and the presence of neurological disorders and therapeutic strategies. Long-term follow-ups and a transition from childhood to adulthood are crucial to preventing iTTP relapses, in order to identify the occurrence of other autoimmune disorders and psychosocial sequelae. In contrast, older iTTP patients have an atypical clinical presentation, with delirium, an atypical neurological presentation, and severe renal and cardiac damages. They also have a poorer response to treatment and prognosis. Long-term sequelae are highly prevalent in older patients. Prediction scores for iTTP diagnoses are not used for children and have a lower sensitivity and specificity in patients over 60 years old. ADAMTS13 remains the unique biological marker that is able to definitely confirm or rule out the diagnosis of iTTP and predict relapses during follow-ups. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness
- Author
-
Plautz, William E, Matthay, Zachary A, Rollins‐Raval, Marian A, Raval, Jay S, Kornblith, Lucy Z, and Neal, Matthew D
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Sepsis ,Hematology ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Cardiovascular ,ADAMTS13 Protein ,Acute Kidney Injury ,Blood Coagulation ,Blood Coagulation Disorders ,Critical Illness ,Endothelium ,Vascular ,Humans ,Inflammation Mediators ,Wounds and Injuries ,von Willebrand Factor ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
The endothelial exocytosis of high-molecular-weight multimeric von Willebrand factor (vWF) may occur in critical illness states, including trauma and sepsis, leading to the sustained elevation and altered composition of plasma vWF. These critical illnesses involve the common process of sympathoadrenal activation and loss of the endothelial glycocalyx. As a prothrombotic and proinflammatory molecule that interacts with the endothelium, the alterations exhibited by vWF in critical illness have been implicated in the development and damaging effects of downstream pathologies, such as disseminated intravascular coagulation and systemic inflammatory response syndrome. Given the role of vWF in these pathologies, there has been a recent push to further understand how the molecule may be involved in the pathophysiology of related diseases, such as trauma-induced coagulopathy and acute renal injury, which are also known to develop secondarily to critical illness states. Elucidation of the role of vWF across the broader spectrum of generalized pathologies may provide a basis for the development of novel preventative and restorative measures, while also bolstering the scaffold of more widely used treatments, such as the administration of plasma-containing blood products.
- Published
- 2020
6. Two ischemic stroke events within 48 h: a case report of an unusual presentation of thrombotic thrombocytopenic purpura.
- Author
-
Jameie, Melika, Heydari, Sanaz, Ghabaee, Mojdeh, and Amirifard, Hamed
- Subjects
- *
THROMBOTIC thrombocytopenic purpura , *ISCHEMIC stroke , *NEUROLOGICAL disorders , *COMPUTED tomography , *THROMBOLYTIC therapy , *STROKE - Abstract
Background: Thrombotic thrombocytopenic purpura (TTP) considers a rare cause of ischemic stroke (IS). We reported a case of a newly diagnosed patient with acquired immune-mediated TTP (iTTP), in whom two IS events developed during 48 h. Case presentation: A 59-year-old diabetic male was presented to the hospital 24 h after symptoms onset, including left hemiparesis, dysarthria, and decreased consciousness. A brain CT scan was performed with the suspicion of acute IS, indicating infarct lesions in the right middle cerebral artery (MCA) territory. The patient was not eligible for thrombolytic therapy due to admission delay. Over the next 24 h, the patient's neurological condition deteriorated, and the second brain CT scan showed new ischemic lesions in the left MCA territory. Initial laboratory evaluation indicated thrombocytopenia without evidence of anemia. However, in the following days, thrombocytopenia progressed, and microangiopathic hemolytic anemia (MAHA) developed. The ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and inhibitors assay confirmed the diagnosis of iTTP. The patient underwent plasma exchange activity and inhibitors assay confirmed the diagnosis of iTTP. The patient underwent and pulse IV methylprednisolone. Rituximab was also added due to the refractory course of the disease. After a prolonged hospital course, he had considerable neurologic recovery and was discharged. Conclusions: Clinicians should consider two points. First, TTP should be considered in any patient presenting with IS and having thrombocytopenia or anemia without other symptoms of TTP. Second, worsening the patient's condition during hospitalization may indicate a new stroke and should be investigated immediately. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. High sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Pregnancy-Onset Thrombotic Thrombocytopenic Purpura.
- Author
-
Béranger, Nicolas, Tsatsaris, Vassilis, Coppo, Paul, Veyradier, Agnès, and Joly, Bérangère S.
- Published
- 2023
- Full Text
- View/download PDF
8. Caplacizumab in pediatric immune thrombotic thrombocytopenic purpura: the UK TTP Registry experience.
- Author
-
Taylor A, Keogh L, Dickens E, Dutt T, Grainger J, Gregory R, Mapplebeck C, Richards M, Stokley S, Salta S, Taylor T, and Scully M
- Subjects
- Humans, Child, United Kingdom, Child, Preschool, Female, Male, Adolescent, Infant, ADAMTS13 Protein, Retrospective Studies, Treatment Outcome, Platelet Count, Plasma Exchange, Purpura, Thrombotic Thrombocytopenic drug therapy, Purpura, Thrombotic Thrombocytopenic therapy, Registries, Single-Domain Antibodies therapeutic use
- Abstract
Abstract: Pediatric thrombotic thrombocytopenic purpura (TTP) is an ultrarare disease. Immune TTP (iTTP) is driven by anti-ADAMTS13 autoantibodies causing an imbalanced von Willebrand factor (VWF):ADAMTS13 axis, and rarer still in children, but potentially life-threatening. Caplacizumab is licensed for iTTP treatment in adults and adolescents aged ≥12 years who weigh ≥40 kg. There is a need to clarify whether caplacizumab can be used in younger children. We retrospectively described caplacizumab use in 16 patients under 18 years of age from the UK TTP Registry, including 4 children aged <12 years. For patients weighing <40 kg (n = 3), caplacizumab was dosed at 5 mg once dailyThe youngest patient was 33 months old at diagnosis. Plasma exchange (PEX) was used in 15 patients, with a median of 5 exchanges required before platelet count normalization (range, 2-9). One patient was managed without PEX. All patients achieved normalization of platelet count (median, 5.5 days; range, 3-28) and ADAMTS13 activity (median, 35 days; range, 8-149), with a median hospital admission of 11 days (range, 5-26). There were no refractory patients. One patient relapsed 9 months after presentation. Bleeding requiring VWF supplementation and reduction of caplacizumab use occurred in 1 patient with severe epistaxis, with no significant intracranial or gastrointestinal bleeding. We demonstrated the efficacy and safety of caplacizumab in the pediatric population, which is synonymous with the adult trial data: primarily, reduction of PEX compared with the precaplacizumab era. This has implications for the intensification and duration of admission, particularly relevant in pediatric care., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
9. Diagnostic Challenges in a Case of Immune-Mediated Thrombotic Thrombocytopenic Purpura With Severe ADAMTS13 Deficiency.
- Author
-
Escoto-Pineda K, Alas-Pineda C, Pavón-Varela DJ, and Cortés D
- Abstract
Thrombotic Thrombocytopenic Purpura (TTP) is rare and potentially life-threatening thrombotic microangiopathy (TMA) caused by acquired immune-mediated or congenital deficiency of the von Willebrand factor regulatory enzyme, a Disintegrin And Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS13) which cause microthrombi to form and occlude the microvasculature. The occurrence of acute kidney injury (AKI) in TTP is rare and often underestimated due to confusion with hemolytic uremic syndrome (HUS). A 23-year-old Mestizo male patient presented with altered mental status, hemolytic anemia, thrombocytopenia, intermittent fever, laboratory tests suggestive of thrombotic microangiopathy, and clinical findings consistent with acute kidney injury. Predictive values of the platelet count, lactate dehydrogenase, absent active cancer, schistocytes, mean corpuscular volume, international normalized ratio, creatinine (PLASMIC) score, were used to assess the likelihood of ADAMTS13 deficiency, were employed, and enzymatic activity testing confirmed severe protein deficiency. Honduras' lack of advanced diagnostic capabilities is underscored, emphasizing the urgent need to invest in precision medical technology. ADAMTS13 testing allows for a more precise diagnosis of TTP, which is crucial for early diagnosis and timely treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Escoto-Pineda et al.)
- Published
- 2024
- Full Text
- View/download PDF
10. Annual trends in atypical haemolytic uremic syndrome management in Japan and factors influencing early diagnosis and treatment: a retrospective study.
- Author
-
Tatematsu Y, Imaizumi T, Michihata N, Kato N, Kumazawa R, Matsui H, Fushimi K, Yasunaga H, and Maruyama S
- Subjects
- Humans, Japan epidemiology, Female, Retrospective Studies, Male, Adult, Middle Aged, Adolescent, ADAMTS13 Protein, Young Adult, Aged, Child, Child, Preschool, Renal Dialysis, Atypical Hemolytic Uremic Syndrome diagnosis, Atypical Hemolytic Uremic Syndrome therapy, Atypical Hemolytic Uremic Syndrome epidemiology, Early Diagnosis, Plasma Exchange, Antibodies, Monoclonal, Humanized therapeutic use
- Abstract
Atypical haemolytic uremic syndrome (aHUS) is a rare disorder characterised by complement-mediated thrombotic microangiopathy (TMA). Despite clinical guidelines, the diagnosis and treatment of aHUS in its early stages remains challenging. This study examined the annual trends in aHUS clinical practices in Japan and explored factors influencing early diagnosis and treatment. Using data from the 2011-2020 Diagnosis Procedure Combination database, 3096 cases with the HUS disease code were identified, of which 217 were confirmed as aHUS and treated with eculizumab or plasma exchange. Early initiation, defined as starting eculizumab or plasma exchange within 7 days of admission, was the focus of the study. Our study revealed no significant changes over time in the number of aHUS diagnoses, cases treated with eculizumab, or early initiation cases. Early initiation cases underwent haemodialysis earlier and had ADAMTS13 activity measured earlier, shorter hospital stays, and lower hospitalisation costs than late initiation cases. In conclusion, we found no increase in the number of newly diagnosed aHUS cases or early treatment initiation over time. Early recognition of TMA and differentiation of the causative disease are crucial for identifying potential aHUS cases, which may lead to better patient prognoses., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
11. Recombinant ADAMTS13: an effective rescue therapy for acute cTTP during pregnancy.
- Author
-
Dadoun S, Adam K, Hensch L, Boyd TK, Ibrahimi S, George JN, Scully M, and Sukumar S
- Subjects
- Humans, Pregnancy, Female, Adult, Treatment Outcome, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic therapy, Recombinant Proteins therapeutic use
- Published
- 2024
- Full Text
- View/download PDF
12. Excessive cleavage of von Willebrand factor multimers by ADAMTS13 may predict the progression of transplant-associated thrombotic microangiopathy.
- Author
-
Yamada S, Sakai K, Kubo M, Okumura H, Asakura H, Miyamoto T, and Matsumoto M
- Abstract
Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of hematopoietic stem cell transplantation and is characterized by severe thrombocytopenia, hemolytic anemia, and organ dysfunction. In response to several possible triggers, dynamic multimetric change in von Willebrand factor (VWF) may contribute to inducing microthrombi in circulation in TA-TMA., Objectives: By performing VWF multimer analysis and measuring VWF-degradation product (DP), we unraveled the relationship between multimeric changes in circulating VWF and the pathogenesis of TA-TMA., Methods: This study analyzed 135 plasma samples from 14 patients who underwent allogeneic hematopoietic stem cell transplantation at a single institute. VWF-associated markers, namely VWF:antigen (VWF:Ag), VWF-DP/VWF:Ag ratio, VWF:ristocetin cofactor activity, VWF:ristocetin cofactor activity/VWF:Ag ratio, and ADAMTS13 activity, were analyzed in these samples collected every 7 days., Results: There were 2 patients with definite thrombotic microangiopathy (TMA) and 6 patients who presented with probable TMA that did not progress to definite TMA. Each plasma sample was classified into 3 groups: definite TMA, probable TMA, and non-TMA. VWF multimer analysis showed the absence of high-molecular-weight VWF multimers in probable TMA, whereas the appearance of unusually large VWF multimers was observed in definite TMA. The median value of the VWF-DP/VWF:Ag ratio in probable TMA was elevated to 4.17, suggesting that excessive cleavage of VWF multimers by VWF cleaving enzyme, ADAMTS13, resulted in the loss of high-molecular-weight VWF multimers., Conclusion: During the transition from probable to definite TMA, drastic VWF multimer changes imply a switch from bleeding to thrombotic tendencies. Extensive VWF-DP and VWF multimer analyses provided novel insights., (© 2024 The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
13. [Lupus nephritis and thrombotic microangiopathy: A review].
- Author
-
Bobrova LA and Kozlovskaya NL
- Subjects
- Humans, Antiphospholipid Syndrome complications, Antiphospholipid Syndrome physiopathology, Antiphospholipid Syndrome diagnosis, Prognosis, ADAMTS13 Protein, Thrombotic Microangiopathies etiology, Thrombotic Microangiopathies physiopathology, Thrombotic Microangiopathies therapy, Thrombotic Microangiopathies diagnosis, Lupus Nephritis diagnosis, Lupus Nephritis physiopathology, Lupus Nephritis complications
- Abstract
Lupus nephritis (LN) is one of the most common organ-specific manifestations of systemic lupus erythematosus (SLE). Various clinical signs of LN develop in at least 50% of patients with SLE. In addition to LN, the spectrum of renal lesions associated with SLE also includes vascular pathology. One of the variants of renal microvascular injury is thrombotic microangiopathy (TMA), the mechanisms of which are diverse. The review focuses on the main forms of TMA, including antiphospholipid syndrome and nephropathy associated with antiphospholipid syndrome, TMA caused by complement system regulation disorders and deficiency of ADAMTS13. In most cases, these forms of TMA are combined with LN. However, they may also exist as a single form of kidney damage. This article discusses the TMA pathogenesis, the impact on kidney prognosis, and treatment options.
- Published
- 2024
- Full Text
- View/download PDF
14. The Specificities of Thrombotic Thrombocytopenic Purpura at Extreme Ages: A Narrative Review
- Author
-
Adrien Joseph, Bérangère S. Joly, Adrien Picod, Agnès Veyradier, and Paul Coppo
- Subjects
thrombotic microangiopathy ,thrombotic thrombocytopenic purpura ,ADAMTS13 protein ,diagnosis ,prognosis ,child ,Medicine - Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) related to a severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. This deficiency is often immune-mediated (iTTP) and related to the presence of anti-ADAMTS13 autoantibodies that enhance its clearance or inhibit its VWF processing activity. iTTP management may be challenging at extreme ages of life. International cohorts of people with TTP report delayed diagnoses and misdiagnoses in children and elderly people. Child-onset iTTP shares many features with adult-onset iTTP: a female predominance, an idiopathic presentation, and the presence of neurological disorders and therapeutic strategies. Long-term follow-ups and a transition from childhood to adulthood are crucial to preventing iTTP relapses, in order to identify the occurrence of other autoimmune disorders and psychosocial sequelae. In contrast, older iTTP patients have an atypical clinical presentation, with delirium, an atypical neurological presentation, and severe renal and cardiac damages. They also have a poorer response to treatment and prognosis. Long-term sequelae are highly prevalent in older patients. Prediction scores for iTTP diagnoses are not used for children and have a lower sensitivity and specificity in patients over 60 years old. ADAMTS13 remains the unique biological marker that is able to definitely confirm or rule out the diagnosis of iTTP and predict relapses during follow-ups.
- Published
- 2023
- Full Text
- View/download PDF
15. Diagnosis and follow‐up of thrombotic thrombocytopenic purpura with an automated chemiluminescent ADAMTS13 activity immunoassay
- Author
-
Nicolas Beranger, Sandrine Benghezal, Bérangère S. Joly, Sophie Capdenat, Adeline Delton, Alain Stepanian, Paul Coppo, and Agnès Veyradier
- Subjects
ADAMTS13 protein ,biological monitoring ,chemiluminescent assay ,diagnosis ,thrombotic thrombocytopenic purpura ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening thrombotic microangiopathy (TMA) caused by a severe functional deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats‐13), the specific von Willebrand factor (VWF) cleaving protease. ADAMTS13 activity is essential to diagnose TTP but remains challenging to assess, as reference ADAMTS13 activity assays are manual and time consuming. Current techniques also lack robustness in low detectable ADAMTS13 activity range, which could prove problematic for therapy‐driven monitoring. Objectives The HemosIL AcuStar ADAMTS13 activity assay is a fast, automated chemiluminescent assay, the performance of which remains to be evaluated prospectively on very large cohorts of patients with TMA and in real‐life conditions. Patients and Methods Our study was conducted over two successive sequences: a retrospective evaluation followed by a “real‐life” prospective evaluation. Overall, we evaluated the HemosIL AcuStar ADAMTS13 activity assay on 539 citrated plasma samples. We extensively studied linearity, limit of detection, contamination, intra‐assay and interassay precisions with a specific focus on levels
- Published
- 2021
- Full Text
- View/download PDF
16. Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in a renal transplant recipient case report
- Author
-
John Fredy Nieto-Rios, Monica Zuluaga-Quintero, Julio Cesar Valencia-Maturana, Diana Carolina Bello-Marquez, Arbey Aristizabal-Alzate, Gustavo Adolfo Zuluaga-Valencia, Lina Maria Serna-Higuita, and Luis Fernando Arias
- Subjects
Thrombotic Microangiopathies ,Hemolytic-Uremic Syndrome ,Shiga Toxin ,Kidney Transplantation ,ADAMTS13 Protein ,Complement Pathway, Alternative. ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Thrombotic microangiopathies are disorders characterized by nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and multi-systemic failure. They are classified as thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome, and typical hemolytic uremic syndrome. The latter is associated with intestinal infections by Shiga toxin-producing bacteria. Typical hemolytic uremic syndrome in adults is an extremely rare condition, characterized by high morbidity and mortality. It has been seldom described in solid organ transplant recipients. Here is presented the case of a kidney transplant recipient who had typical hemolytic uremic syndrome with multisystem commitment, refractory to management and with a fatal outcome.
- Published
- 2020
- Full Text
- View/download PDF
17. Hemostatic Markers and Long-Term Risk of Intracerebral Hemorrhage in Postmenopausal Women
- Author
-
Lee, Ju-Mi, Siddique, Juned, Kim, Hyeon Chang, Green, David, Van Horn, Linda, Allison, Matthew, Wassertheil-Smoller, Sylvia, and Greenland, Philip
- Subjects
Reproductive Medicine ,Biomedical and Clinical Sciences ,Stroke ,Hematology ,Clinical Research ,Aging ,Cardiovascular ,ADAMTS13 Protein ,Age Factors ,Aged ,Biomarkers ,Case-Control Studies ,Cerebral Hemorrhage ,Female ,Hemostasis ,Humans ,Middle Aged ,Platelet Count ,Postmenopause ,Predictive Value of Tests ,Prognosis ,Risk Factors ,Sex Factors ,Time Factors ,Tissue Plasminogen Activator ,United States ,Urokinase-Type Plasminogen Activator ,von Willebrand Factor ,Cerebral hemorrhage ,von Willebrand factor ,ADAMTS13 ,plasminogen activators ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundKnown risk factors for intracerebral hemorrhage (ICH) include age, hypertension, smoking, alcohol intake, and anticoagulant use. Some previous reports have indicated that hemostatic factors measured many years before the onset of ICH might predict the later occurrence of ICH. The objective of this analysis was to test whether selected hemostatic factors measured years before the onset of ICH could identify patients at higher risk for future ICH.MethodsWe performed a nested case-control study within the Women's Health Initiative (WHI) cohort. Postmenopausal women aged 50-79 years (mean 68) at baseline (1993-1998) were enrolled at 40 Clinical Centers in the United States and followed for adjudicated ICH for a mean of 11.4 years. ICH cases (N = 75) and controls (N = 75) were matched on age, ethnicity, blood pressure, anticoagulant use, and treated hypertension. Stored blood samples from the baseline WHI examination were tested for von Willebrand factor (vWF), a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13 (ADAMTS13), tissue plasminogen activator (t-PA), and urokinase plasminogen activator (u-PA). Platelet count, white blood cell count, and hemoglobin concentration were also measured.ResultsMean baseline levels of vWF (1.03 and .95 U/mL), ADAMTS13 (1.0 and 1.1 µg/mL), vWF : ADAMTS13 ratio (.99 and .92), t-PA (14.75 and 14.80 IU/mL), and u-PA (.09 and .10 IU/mL) were not significantly different by case-control status. Significant differences were also not identified for platelet count, hemoglobin, white blood count, or reported alcohol use.ConclusionNone of the 4 baseline hemostatic factors nor the platelet count was predictive of future ICH risk in this long-term study of older postmenopausal women.
- Published
- 2016
18. Immune-mediated thrombotic thrombocytopenic purpura in patients with and without systemic lupus erythematosus: a retrospective study
- Author
-
Cai Yue, Jian Su, Xiaohong Fan, Li Song, Wei Jiang, Jinghua Xia, Tao Shi, Xuan Zhang, and Xuemei Li
- Subjects
ADAMTS13 protein ,Acquired thrombotic thrombocytopenic purpura ,Systemic lupus erythematosus ,Thrombotic microangiopathies ,Medicine - Abstract
Abstract Background Thrombotic thrombocytopenic purpura (TTP) is associated with more deleterious outcomes in patients with systemic lupus erythematosus (SLE). However, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels and ADAMTS13 inhibitor were not routinely assayed in most previous studies. The objective of this study is to compare the characteristics and outcomes of immune-mediated TTP (iTTP) in patients with and without SLE. Methods The medical data of 28 patients with iTTP from Peking Union Medical College Hospital were analysed. ADAMTS13 activity and ADAMTS13 inhibitor were measured in all patients. Results All 28 patients had ADAMTS13 inhibitor and severe ADAMTS13 deficiency. iTTP was considered SLE-related (SLE-TTP) in 10 patients and primary (primary iTTP) in 18 patients. Renal involvement on presentation was more severe in patients with primary iTTP as determined by higher serum creatinine (162.7 ± 110.6 vs 73.3 ± 13.4 μmol/L, p
- Published
- 2020
- Full Text
- View/download PDF
19. Generation and validation of small ADAMTS13 fragments for epitope mapping of anti‐ADAMTS13 autoantibodies in immune‐mediated thrombotic thrombocytopenic purpura
- Author
-
Kadri Kangro, Elien Roose, An‐Sofie Schelpe, Edwige Tellier, Gilles Kaplanski, Jan Voorberg, Simon F. De Meyer, Andres Männik, and Karen Vanhoorelbeke
- Subjects
ADAMTS13 protein ,antibodies ,epitopes ,human serum albumin ,thrombotic thrombocytopenic purpura ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background In immune‐mediated thrombotic thrombocytopenic purpura (iTTP), patients develop an immune response against the multidomain enzyme ADAMTS13. ADAMTS13 consists of a metalloprotease (M) and disintegrin‐like (D) domain, 8 thrombospondin type 1 repeats (T1‐T8), a cysteine‐rich (C), a spacer (S), and 2 CUB domains (CUB1‐2). Previous epitope mapping studies have used relatively large overlapping ADAMTS13 fragments. Objectives We aimed at developing small nonoverlapping ADAMTS13 fragments to fine map anti‐ADAMTS13 autoantibodies in iTTP patients. Methods A library of 16 ADAMTS13 fragments, comprising several small (M, DT, C, S, T2‐T5, T6‐T8, CUB1, CUB2), and some larger fragments with overlapping domains (MDT, MDTC, DTC, CS, T2‐T8, CUB1‐2, MDTCS, T2‐C2), were generated. All fragments, and ADAMTS13, were expressed as a fusion protein with albumin domain 1, and purified. The folding of the fragments was tested using 17 anti‐ADAMTS13 monoclonal antibodies with known epitopes. An epitope mapping assay using small ADAMTS13 fragments was set up, and validated by analyzing 18 iTTP patient samples. Results Validation with the monoclonal antibodies demonstrated that single S and CUB1 were not correctly folded, and therefore CS and CUB1‐2 fragments were selected instead of single C, S, CUB1, and CUB2 fragments. Epitope mapping of antibodies of patients with iTTP confirmed that 6 nonoverlapping ADAMTS13 fragments M, DT, CS, T2‐T5, T6‐T8, and CUB1‐2 were sufficient to accurately determine the antibody‐binding sites. Conclusion We have developed a tool to profile patients with iTTP according to their anti‐ADAMTS13 antibodies for a better insight in their immune response.
- Published
- 2020
- Full Text
- View/download PDF
20. Optimization of plasma-based BioID identifies plasminogen as a ligand of ADAMTS13.
- Author
-
Madarati H, DeYoung V, Singh K, Sparring T, Kwong AC, Fredenburgh JC, Teney C, Koschinsky ML, Boffa MB, Weitz JI, and Kretz CA
- Subjects
- von Willebrand Factor metabolism, ADAMTS13 Protein, ADAM Proteins metabolism, Ligands, Plasminogen metabolism, Fibrinolysin metabolism, Tranexamic Acid
- Abstract
ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
21. Evaluating the potential mediating role of ADAMTS13 activity in the relationship between obesity and the severity of COVID-19: A retrospective cohort study.
- Author
-
Hafez W, Rashid A, Abuelsaoud HM, Jose M, Kishk S, Gador M, Emoshe T, Abdulaal F, Nair N, Ahmad M, Rashid VJ, Faheem Y, John S, Ahmed S, Daraghmi A, Soliman R, Abdelrahman A, Mohamed AA, and Ghanem M
- Subjects
- Humans, ADAMTS13 Protein, Body Mass Index, Obesity complications, Retrospective Studies, COVID-19
- Abstract
Obesity and low enzyme A disintegrin and metalloproteinase with thrombospondin type-1 motif-13 (ADAMTS13) activity have been linked to poor coronavirus disease 2019 (COVID-19). Given that obesity may influence ADAMTS13 activity, it is feasible; however, it remains unclear whether ADAMTS13 activity acts as a mediator between obesity and COVID-19 outcomes. We investigated the link between body mass index (BMI) and COVID-19 outcomes, using ADAMTS13 activity as a mediator. ADAMTS13 activity was measured in 86 hospitalized COVID-19 patients. BMI, ADAMTS13 activity, and COVID-19 outcomes were assessed. Obese patients had a high odds ratio for low ADAMTS13 levels. When different levels of ADAMTS13 activity were considered, the severity of COVID-19 in obese patients was 4.5 times that in the normal BMI group. Furthermore, increased coagulopathy indicators correlated with low ADAMTS13 activity. Patients with elevated ALT and AST levels showed a 3 to 4-fold increase in the chances of low ADAMTS13 activity (OR:3.19, 95% CI:1.22-8.90, P = .021; OR:2.17, 95% CI:0.91-5.27, P = .082, respectively). When ADAMTS13 activity was considered, obese patients had greater COVID-19 severity and slower viral clearance than those with normal BMI. Low ADAMTS13 activity and impaired liver function are associated with poor COVID-19 outcomes. These findings encourage researchers to use molecular component identification to study the effects of obesity on the von Willebrand factor (VWF)/ADAMTS13 axis, COVID-19 pathogenesis, and outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2024
- Full Text
- View/download PDF
22. Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura.
- Author
-
Moroniti JJ, Vrbensky JR, Nazy I, and Arnold DM
- Subjects
- Humans, ADAMTS13 Protein, Blood Platelets metabolism, Plasma metabolism, von Willebrand Factor therapeutic use, von Willebrand Factor metabolism, Purpura, Thrombotic Thrombocytopenic, Thrombosis
- Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach., Competing Interests: Declaration of competing interests None of the authors have any competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
23. Diagnosis and clinical management of thrombotic thrombocytopenic purpura (TTP): a consensus statement from the TTP Catalan group.
- Author
-
Muñoz NG, Ortega S, Solanich X, Cid J, Díaz M, Moreno AB, Ancochea Á, Santos M, Hernández I, Sanchez JM, Luaña A, García J, Escoda L, Medina L, Ferrer GJ, López J, Céspedes R, Díaz JA, Pons V, Valcárcel D, and Grifols JR
- Subjects
- Humans, ADAMTS13 Protein, Consensus, von Willebrand Factor, Recurrence, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy, Purpura, Thrombotic Thrombocytopenic etiology, Purpura, Thrombocytopenic, Idiopathic
- Abstract
Thrombotic thrombocytopenic purpura (TTP) is a low prevalence disease characterized by severe deficiency of the enzyme ADAMTS13, leading to the development of thrombotic microangiopathy (TMA) and often resulting in severe organ disfunction. TTP is an extremely serious condition and, therefore, timely and appropriate treatment is critical to prevent life-threatening complications.Over the past 25 years, significant advances in the understanding of the pathophysiology of immune TTP have led to the development of readily available techniques for measuring ADAMTS13 levels, as well as new drugs that are particularly effective in the acute phase and in preventing relapses. These developments have improved the course of the disease.Given the complexity of the disease and its various clinical and laboratory manifestations, early diagnosis and treatment can be challenging.To address this challenge, a group of experienced professionals from the Catalan TTP group have developed this consensus statement to standardize terminology, diagnosis, treatment and follow up for immune TTP, based on currently available scientific evidence in the field. This guidance document aims to provide healthcare professionals with a comprehensive tool to make more accurate and timely diagnosis of TTP and improve patient outcomes.
- Published
- 2024
- Full Text
- View/download PDF
24. ADAMTS-13: A Prognostic Biomarker for Portal Vein Thrombosis in Japanese Patients with Liver Cirrhosis.
- Author
-
Suzuki J, Namisaki T, Takya H, Kaji K, Nishimura N, Shibamoto A, Asada S, Kubo T, Iwai S, Tomooka F, Takeda S, Koizumi A, Tanaka M, Matsuda T, Inoue T, Fujimoto Y, Tsuji Y, Fujinaga Y, Sato S, Kitagawa K, Kawaratani H, Akahane T, Mitoro A, Matsumoto M, Asada K, and Yoshiji H
- Subjects
- Humans, Portal Vein metabolism, ADAMTS13 Protein, Prognosis, Japan, Liver Cirrhosis pathology, Biomarkers, von Willebrand Factor metabolism, Venous Thrombosis complications
- Abstract
Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21-3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC.
- Published
- 2024
- Full Text
- View/download PDF
25. Coagulation Profile in Neonates with Congenital Heart Disease: A Pilot Study.
- Author
-
Papadogeorgou P, Valsami S, Boutsikou M, Pergantou E, Mantzou A, Papassotiriou I, Iliodromiti Z, Sokou R, Bouza E, Politou M, Iacovidou N, and Boutsikou T
- Subjects
- Infant, Newborn, Child, Humans, Infant, von Willebrand Factor metabolism, ADAMTS13 Protein, Pilot Projects, Heart Defects, Congenital complications, Hemostatics
- Abstract
Background and Objectives : congenital heart disease (CHD), cyanotic and, to a lesser degree, acyanotic, often are accompanied by coagulation abnormalities, impacting substantially morbidity and mortality. Until now, no consistent hemostatic patterns have been demonstrated in neonates and children with CHD because they represent a variable and heterogenous population. The aim of the present study is to investigate the hemostatic profile, as well as the role of ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type-1 motives), the cleaving protein of von Willebrand factor (VWF) in neonates with CHD and compare them to healthy age-matched controls. Materials and Methods : twenty neonates with a mean gestational age of 37.1 ± 2.5 weeks were included in the CHD group, and 18 healthy neonates with a mean gestational age of 38.2 ± 1.5 weeks were in the control group. Results: prothrombin time was significantly prolonged, and accordingly, factor VII (FVII) levels were significantly decreased in the CHD group in comparison to controls. Factor VIII (FVIII), VWF, and ristocetin cofactor activity (Rcof) levels were significantly higher in the study vs. control group. Concentrations of ADAMTS-13 were decreased in the CHD vs. control group, but the difference was not statistically significant. Our results, in combination, indicate a balanced hemostatic mechanism, although with greater variability in neonates with CHD, while developmental aspects of coagulation are evident in the specific patient population. Conclusions: the coagulation profile is moderately impaired early in the course of CHD, though increased thrombogenicity is already present and should not be ignored.
- Published
- 2024
- Full Text
- View/download PDF
26. Clinical characteristics of anti-GBM disease with thrombotic microangiopathy: a case report and literature review.
- Author
-
Nakamura Y, Kato N, Tatematsu Y, Arai Y, Mori N, Shibata K, Yamazaki M, Yasui H, Fujiwara S, Yamakawa T, and Maruyama S
- Subjects
- Female, Humans, Aged, ADAMTS13 Protein, Anti-Glomerular Basement Membrane Disease, Thrombotic Microangiopathies diagnosis, Thrombotic Microangiopathies therapy, Purpura, Thrombotic Thrombocytopenic diagnosis, Respiratory Insufficiency
- Abstract
The coexistence of anti-glomerular basement membrane (anti-GBM) disease with thrombotic microangiopathy (TMA) is rarely encountered, and the clinical characteristics of this phenomenon are not well known.A 76-year-old Japanese woman with a history of idiopathic pulmonary disease was diagnosed with anti-GBM disease due to rapidly progressive glomerulonephritis and a positive anti-GBM antibody test result. We treated the patient with hemodialysis, glucocorticoids, and plasmapheresis. During treatment, the patient suddenly became comatose. TMA was then diagnosed because of thrombocytopenia and microangiopathic hemolytic anemia. The activity of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS-13) was retained at 48%. Although we continued the treatment, the patient died of respiratory failure. An autopsy revealed the cause of respiratory failure to be an acute exacerbation of interstitial pneumonia. The clinical findings of the renal specimen indicated anti-GBM disease; however, there were no lesions suggestive of TMA. A genetic test did not reveal an apparent genetic mutation of the atypical hemolytic uremic syndrome.We conducted a literature review of past case reports of anti-GBM disease with TMA. The following clinical characteristics were obtained. First, 75% of the cases were reported in Asia. Second, TMA tended to appear during the treatment course for anti-GBM disease and usually resolved within 12 weeks. Third, ADAMTS-13 activity was retained above 10% in 90% of the cases. Fourth, central nervous system manifestations occurred in more than half of the patients. Fifth, the renal outcome was very poor. Further studies are required to understand the pathophysiology of this phenomenon., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)
- Published
- 2024
- Full Text
- View/download PDF
27. Alterations in the von Willebrand factor/ADAMTS-13 axis in preeclampsia.
- Author
-
Neave L, Thomas M, de Groot R, Doyle AJ, Singh D, Adams G, David AL, Maksym K, and Scully M
- Subjects
- Pregnancy, Female, Humans, Placenta Growth Factor, von Willebrand Factor, Case-Control Studies, ADAMTS13 Protein, Vascular Endothelial Growth Factor Receptor-1, Receptor Protein-Tyrosine Kinases, Vascular Endothelial Growth Factor A, Biomarkers, Pre-Eclampsia diagnosis
- Abstract
Background: Preeclampsia is a gestational hypertensive disorder characterized by maternal endothelial activation and increased ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) inhibitor to placental growth factor (PlGF). The von Willebrand factor (VWF)/ADAMTS-13 axis is of interest because of the underlying endothelial activation and clinical overlap with pregnancy-associated thrombotic thrombocytopenic purpura., Objectives: To assess VWF, ADAMTS-13, and VWF/ADAMTS-13 ratio in preeclampsia and look for associations with sFlt-1/PlGF ratio and clinical features., Methods: Thirty-four preeclampsia cases and 48 normal pregnancies were assessed in a case-control study. Twelve normal pregnancies in women with a history of preeclampsia formed an additional comparator group. VWF antigen (VWF:Ag) and VWF activity (VWF:Ac [VWF:glycoprotein IbM]) were measured via automated immunoturbidimetric assay, ADAMTS-13 activity was measured via fluorescence resonance energy transfer-VWF73 assay, and sFlt-1 and PlGF were measured via enzyme-linked immunosorbent assay., Results: VWF:Ag was higher in preeclampsia than in normal pregnancy (median, 3.07 vs 1.87 IU/mL; P < .0001). ADAMTS-13 activity was slightly lower (median, 89.6 vs 94.4 IU/dL; P = .02), with no severe deficiencies. Significant elevations in VWF:Ac were not observed in preeclampsia, resulting in reduced VWF:Ac/VWF:Ag ratios (median, 0.77 vs 0.97; P < .0001). VWF:Ag/ADAMTS-13 ratios were significantly higher in preeclampsia (median, 3.42 vs 2.06; P < .0001), with an adjusted odds ratio of 19.2 for a ratio of >2.7 (>75th centile of normal pregnancy). Those with a history of preeclampsia had similar ratios to normal pregnant controls. VWF:Ag/ADAMTS-13 and sFlt-1/PlGF were not correlated. However, percentage reduction in platelets correlated positively with VWF:Ac (P = .01), VWF:Ac/VWF:Ag ratio (P = .004), and sFlt-1/PlGF ratio (P = .01)., Conclusion: The VWF/ADAMTS-13 axis is significantly altered in preeclampsia. Further investigation of potential clinical utility is warranted., Competing Interests: Declaration of competing interests L.N. has served on an advisory board for Alexion. M.T. has served on advisory boards for Ablynx, Sanofi, and Bayer; received speaker fees for Bayer, Sanofi, and Anthos; and received consultancy fees from Bayer. M.S. has received speaker fees from and has served on advisory boards for Alexion, Novartis, Takeda, Sanofi, and Octapharma and has received research grants from Shire and Alexion. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
28. Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.
- Author
-
De Waele L, Sakai K, Mancini I, Sinkovits G, Falter T, Inoue T, Agosti P, Rossmann H, Von Auer C, Tersteeg C, De Meyer SF, Joly BS, Veyradier A, Coppo P, Fijnheer R, Peyvandi F, Prohászka Z, Lämmle B, and Vanhoorelbeke K
- Subjects
- Humans, Autoantibodies, Proportional Hazards Models, Recurrence, Risk Factors, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Background: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission., Objectives: To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse., Methods: We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%., Results: During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively., Conclusion: Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse., Competing Interests: Declaration of competing interests K.V. is a member of the advisory board of Takeda. I.M. received honoraria for participating as a speaker at educational meetings organized by Instrumentation Laboratory and Sanofi. F.P. has received honoraria for participating as a speaker in education meetings organized by Grifols and Roche, and she is a member of the scientific advisory boards of BioMarin, Roche, Sanofi, Sobi, and Takeda. B.L. is chairman of the Data Monitoring Committees of studies of recombinant ADAMTS-13 in patients with congenital thrombotic thrombocytopenic purpura (TTP) and immune-mediated TTP by Takeda (Takeda 2811 02, TAK-755-3002, Takeda SHP 605-201). He is chairman of the Data Monitoring Committees of a study investigating therapy of immune-mediated TTP with caplacizumab and immunosuppression without plasma exchange by Sanofi. He received lecture fees and/or congress travel support from Ablynx, Alexion, Siemens, Bayer, Roche, Sanofi, and Takeda. P.C. is a member of the Clinical Advisory Board of and received speaker fees from Alexion, Sanofi, and Takeda. A.V. is a member of the Advisory board for caplacizumab Sanofi and rhADAMTS-13 Takeda. Other coauthors do not have any conflicts of interest to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
29. Comparison of thrombomodulin, vWF, and ADAMTS13 levels between preeclampsia and normal pregnancy
- Author
-
Ahmad A, Mustafa G, Mazari N, and Naveed MA
- Subjects
- Pregnancy, Female, Humans, Child, Young Adult, Adult, Male, von Willebrand Factor analysis, Sofosbuvir, ADAMTS13 Protein, Thrombomodulin, Cross-Sectional Studies, Tertiary Care Centers, Neoplasms, Pre-Eclampsia, Hepatitis C, Carbamates, Imidazoles, Pyrrolidines, Valine analogs & derivatives
- Abstract
Objectives: To determine and compare plasma thrombomodulin, von Willebrand factor and von Willebrand factorcleaving protease levels between pre-eclamptic and healthy pregnant females., Methods: The cross-sectional, comparative study was conducted at the Department of Haematology, University of Health Sciences, Lahore, Pakistan, from November 2019 to December 2020, and comprised pregnant females who were divided into healthy pregnant group A and pre-eclamptic group B. Plasma thrombomodulin and von Willebrand factor-cleaving protease levels were determined by using commercially available enzyme-linked immunosorbent assay kit, and von Willebrand factor level was determined by using immuno-turbidimetric assay kit. Data was analysed using SPSS 25., Results: Of the 88 participants, there were 44(50%) females with mean age 25.5±6 years in group A and 44(50%) in group B with mean age 26±5 years. Median thrombomodulin level in group B was significantly higher than group A (p=0.003). Median von Willebrand factor-cleaving protease levels were lower in group B compared to group A (p=0.838). A significant difference in von Willebrand factor level was observed between the groups (p=0.038)., Conclusion: Females with pre-eclampsia had significantly higher plasma levels of von Willebrand factor and thrombomodulin than healthy pregnant subjects.
- Published
- 2024
- Full Text
- View/download PDF
30. Outcomes and Costs in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving Front-Line Versus Delayed Caplacizumab: A US Hospital Database Study.
- Author
-
Arnaud A, Schilsky S, Lucia J, Maia M, Laredo F, Marques AP, Okada H, and Roberts AW
- Subjects
- Adult, Humans, Retrospective Studies, Plasma Exchange, ADAMTS13 Protein, Hospitals, Purpura, Thrombotic Thrombocytopenic drug therapy, Single-Domain Antibodies adverse effects, Purpura, Thrombocytopenic, Idiopathic drug therapy, Thrombosis drug therapy
- Abstract
European real-world data indicate that front-line treatment with caplacizumab is associated with improved clinical outcomes compared with delayed caplacizumab treatment. The objective of the study was to describe the characteristics, treatment patterns, and outcomes in hospitalized patients with an immune-mediated thrombotic thrombocytopenic purpura (iTTP) episode treated with front-line versus delayed caplacizumab in the US. This retrospective cohort analysis of a US hospital database included adult patients (≥18 years) with an acute iTTP episode (a diagnosis of thrombotic microangiopathy and ≥1 therapeutic plasma exchange [TPE] procedure) from January 21, 2019, to February 28, 2021. Unadjusted baseline characteristics, treatment patterns, healthcare resource utilization, and costs were compared between patients who received front-line versus delayed (<2 vs ≥2 days after TPE initiation) caplacizumab treatment. Out of 39 patients, 16 (41.0%) received front-line and 23 (59.0%) received delayed treatment with caplacizumab. Baseline characteristics and symptoms were similar between the two groups. Patients who received front-line caplacizumab treatment had significantly fewer TPE administrations (median: 5.0 vs 12.0); and a significantly shorter hospital stay (median: 9.0 days vs 16.0 days) than patients receiving delayed caplacizumab therapy. Both of these were significantly lower in comparison of means (t-test P < .01). Median inpatient costs (inclusive of caplacizumab costs) were 54% higher in the delayed treated patients than in the front-line treated patients (median: $112 711 vs $73 318). TPE-specific cost was lower in the front-line treated cohort (median: $6 989 vs $10 917). In conclusion, front-line treatment with caplacizumab had shorter hospitalizations, lower healthcare resource utilization, and lower costs than delayed caplacizumab treatment after TPE therapy., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.A., M.M., and H.O. are employees of Sanofi and hold stocks or stock options in the company. A.M. is an employee of Sanofi. S.S., J.L., and A.R. are employees of Aetion Inc. and hold stocks or stock options in the company. F.L. was an employee of Sanofi when the study was conducted.
- Published
- 2024
- Full Text
- View/download PDF
31. ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation
- Author
-
Shannen J. Deconinck, Christoph Nix, Svenja Barth, Eveline Bennek‐Schöpping, Antoine Rauch, An‐Sofie Schelpe, Elien Roose, Hendrik B. Feys, Inge Pareyn, Aline Vandenbulcke, Joshua Muia, Christophe Vandenbriele, Sophie Susen, Bart Meyns, Claudia Tersteeg, Steven Jacobs, Simon F. De Meyer, and Karen Vanhoorelbeke
- Subjects
von Willebrand Diseases ,Hemostasis ,von Willebrand Factor ,Animals ,Humans ,ADAMTS13 Protein ,Cattle ,Heart-Assist Devices ,Collagen ,Hematology ,Article - Abstract
BACKGROUND: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired haemostasis which could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. METHODS: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/mL) or control anti-ADAMTS13 mAb 5C11 or PBS. VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella® pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13 and blood parameters were determined. RESULTS: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella®-induced aVWS calf model. CONCLUSION: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.
- Published
- 2022
32. Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections
- Author
-
Hagedoorn, NN, Boeddha, NP, Kohlfuerst, DS, Anderson, S, Carrol, ED, Agapow, P, Van der Flier, M, Hazelzet, J, Herberg, J, Kuijpers, T, Levin, M, Martinon-Torres, F, Van Rijswijk, A, Schlapbach, LJ, Vermont, C, Zenz, W, Dik, WA, Driessen, G, Emonts, M, EUCLIDS Consortium, European Commission, MUMC+: MA Kindergeneeskunde (3), Kindergeneeskunde, RS: GROW - R4 - Reproductive and Perinatal Medicine, Pediatrics, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, ARD - Amsterdam Reproduction and Development, Public Health, and Immunology
- Subjects
Staphylococcus aureus ,Thrombomodulin ,European Union Childhood Life-threatening Infectious Disease (EUCLIDS) Consortium ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,ADAMTS13 Protein ,1110 Nursing ,Neisseria meningitidis ,Critical Care and Intensive Care Medicine ,Pediatrics ,Hemostatics ,children ,Sepsis ,Humans ,Prospective Studies ,coagulation ,Child ,intensive care ,Hemostasis ,bacterial infection ,Bacterial Infections ,mortality ,Fibronectins ,Meningococcal Infections ,hemostasis proteins ,Pediatrics, Perinatology and Child Health ,1114 Paediatrics and Reproductive Medicine - Abstract
Contains fulltext : 287940.pdf (Publisher’s version ) (Open Access) OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.
- Published
- 2022
33. Mechanisms of ADAMTS13 regulation
- Author
-
Colin Kretz, Kanwal Singh, and Veronica DeYoung
- Subjects
Blood Platelets ,ADAM Proteins ,Purpura, Thrombotic Thrombocytopenic ,von Willebrand Factor ,Humans ,ADAMTS13 Protein ,Thrombosis ,Hematology - Abstract
Recombinant ADAMTS13 is currently undergoing clinical trials as a treatment for hereditary thrombotic thrombocytopenic purpura, a lethal microvascular condition resulting from ADAMTS13 deficiency. Preclinical studies have also demonstrated its efficacy in treating arterial thrombosis and inflammation without causing bleeding, suggesting that recombinant ADAMTS13 may have broad applicability as an antithrombotic agent. Despite this progress, we currently do not understand the mechanisms that regulate ADAMTS13 activity in vivo. ADAMTS13 evades canonical means of protease regulation because it is secreted as an active enzyme and has a long half-life in circulation, suggesting that it is not inhibited by natural protease inhibitors. Although shear can spatially and temporally activate von Willebrand factor to capture circulating platelets, it is also required for cleavage by ADAMTS13. Therefore, spatial and temporal regulation of ADAMTS13 activity may be required to stabilize von Willebrand factor-platelet strings at sites of vascular injury. This review outlines potential mechanisms that regulate ADAMTS13 in vivo including shear-dependency, local inactivation, and biochemical and structural regulation of substrate binding. Recently published structural data of ADAMTS13 is discussed, which may help to generate novel hypotheses for future research.
- Published
- 2022
34. Improvement of recombinant ADAMTS13 production through a more optimal signal peptide or an N-terminal fusion protein
- Author
-
Kadri Kangro, Elien Roose, Charlotte Dekimpe, Aline Vandenbulcke, Nuno A.G. Graça, Jan Voorberg, Mart Ustav, Andres Männik, Karen Vanhoorelbeke, Experimental Vascular Medicine, Landsteiner Laboratory, and ACS - Microcirculation
- Subjects
EXPRESSION ,cell culture techniques ,DNA, Complementary ,STRATEGIES ,Serum Albumin, Human ,Protein Sorting Signals ,recombinant proteins ,DOMAIN ,von Willebrand Factor ,Animals ,Humans ,thrombotic thrombocytopenic purpura ,BATCH ,Mammals ,ADAMTS13 protein ,Science & Technology ,Purpura, Thrombotic Thrombocytopenic ,HALF-LIFE ,CLEAVAGE ,Hematology ,Factor VII ,ADAM Proteins ,Uronic Acids ,Peripheral Vascular Disease ,human serum albumin ,CELLS ,Cardiovascular System & Cardiology ,SECRETION ,Life Sciences & Biomedicine - Abstract
BACKGROUND: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in mammalian cells, which makes the production of the protein time-consuming and labor-intensive. OBJECTIVES: We aimed at increasing the yield of rADAMTS13 by (1) using a more optimal signal peptide (SP) and (2) constructing an N-terminal fusion protein of ADAMTS13 with human serum albumin domain 1 (AD1-ADAMTS13). METHODS: Six SPs were investigated to select the most optimal SP. Expression plasmids containing the most optimal SP and ADAMTS13 cDNA or the fusion construct AD1-ADAMTS13 were generated and transiently transfected into CHOEBNALT85 cell-line. Expression levels of rADAMTS13 in expression medium were analyzed and compared with the expression level of rADAMTS13 with native SP (nat-SP). RESULTS: Expression of rADAMTS13 with coagulation factor VII (FVII) SP was 3-fold higher (16.00 μg/ml) compared with the expression with nat-SP (5.03 μg/ml). The highest yields were obtained with AD1-ADAMTS13 protein with a 15-fold higher concentration (78.22 μg/ml) compared with the expression with nat-SP. The rADAMTS13 expressed with FVII-SP retained its activity (104.0%) to cleave von Willebrand factor, whereas AD1-ADAMTS13 demonstrated even higher activity (144.3%). CONCLUSION: We succeeded in generating expression vectors that yield (1) rADAMTS13 at higher levels because of more optimal FVII-SP and (2) high levels of AD1-ADAMTS13 N-terminal fusion protein. The highest expression levels were obtained with AD1-ADAMTS13 N-terminal fusion protein, which is paving the way for highly efficient protein production. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:20 issue:10 pages:2379-2385 ispartof: location:England status: published
- Published
- 2022
35. Anti‐inflammatory protective effect of ADAMTS‐13 in murine arthritis models
- Author
-
Denisa Wagner, Long Chu, Sarah Gutch, Saeko Fukui, and Shoichi Fukui
- Subjects
Inflammation ,Interleukin-6 ,Arthritis ,Disintegrins ,ADAMTS13 Protein ,Thrombosis ,X-Ray Microtomography ,Hematology ,Article ,Mice ,Mice, Inbred DBA ,von Willebrand Factor ,Animals ,Humans - Abstract
BACKGROUND: Patients with rheumatoid arthritis (RA) have frequent thrombotic events with endothelial dysfunction. Von Willebrand factor (VWF) has been shown to bind neutrophil extracellular traps (NETs) and NETs are part of RA etiology. OBJECTIVES: This study aims to elucidate whether this prothrombotic status exacerbates inflammation in arthritis. Here we focus on the involvement of A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif, member 13 (ADAMTS-13), an enzyme cleaving VWF and its effect on NET deposition and RA development. METHODS: We evaluated the influence of the Adamts13 gene and recombinant human ADAMTS-13 (rhADAMTS-13) on arthritis in the mouse models of collagen-induced arthritis (CIA). We also assessed VWF and NETs in synovial tissue. RESULTS: Several Adamts13(−/−) mice developed arthritis, while Adamts13(+/+) siblings did not. Synovial tissue from Adamts13(−/−) showed accumulation of NETs. Treatment of DBA/1 J mice, an arthritis-susceptible strain, with well-tolerated doses of rhADAMT13 reduced arthritis incidence and alleviated the severity of arthritis. Mice treated with rhADAMT13 presented less serum interleukin 6 and less bone erosion determined by micro-computed tomography. The effects on arthritis severity were observed both when administering rhADAMTS-13 prophylactically and also when given after arthritis has developed. In both conditions, rhADAMTS-13 reduced VWF and NET deposition on proliferated synovial tissue evaluated by immunoblotting. CONCLUSIONS: Our results demonstrate the inhibitory role of Adamts13 in murine arthritis and the effectiveness of rhADAMTS-13 treatment. Additionally, this study suggests that deposition of VWF in the synovium and subsequent pathogenic NET retention promotes arthritis. Treatment with rhADAMTS-13 provides a potential therapeutic approach targeting inflammation and pro-thrombotic state in arthritis.
- Published
- 2022
36. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction
- Author
-
Helen Fogarty, Soracha E. Ward, Liam Townsend, Ellie Karampini, Stephanie Elliott, Niall Conlon, Jean Dunne, Rachel Kiersey, Aifric Naughton, Mary Gardiner, Mary Byrne, Colm Bergin, Jamie M. O'Sullivan, Ignacio Martin-Loeches, Parthiban Nadarajan, Ciaran Bannan, Patrick W. Mallon, Gerard F. Curley, Roger J.S. Preston, Aisling M. Rehill, Ross I. Baker, Cliona Ni Cheallaigh, James S. O'Donnell, Niamh O’Connell, Kevin Ryan, Dermot Kenny, and Judicael Fazavana
- Subjects
Neovascularization, Pathologic ,SARS-CoV-2 ,Osteoprotegerin ,Thrombin ,ADAMTS13 Protein ,COVID-19 ,Convalescence ,Hematology ,Platelet Factor 4 ,Hemostatics ,Angiopoietin-2 ,Post-Acute COVID-19 Syndrome ,von Willebrand Factor ,Humans - Abstract
Prolonged recovery is common after acute SARS-CoV-2 infection; however, the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF/ADAMTS-13 imbalance, dysregulated angiogenesis, and immunothrombosis are hallmarks of acute COVID-19. We hypothesized that VWF/ADAMTS-13 imbalance persists in convalescence together with endothelial cell (EC) activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation.Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS-13, Weibel Palade Body (WPB) proteins, and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n = 20) and acute COVID-19 patients (n = 36).ADAMTS-13 levels were reduced (p = 0.009) and the VWF-ADAMTS-13 ratio was increased in convalescence (p = 0.0004). Levels of platelet factor 4 (PF4), a putative protector of VWF, were also elevated (p = 0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively.Our data provide insights into sustained EC activation, dysregulated angiogenesis, and VWF/ADAMTS-13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immunothrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence.
- Published
- 2022
37. ADAMTS13 protease or lack of von Willebrand factor protects irradiation and melanoma‐induced thrombotic microangiopathy in zebrafish
- Author
-
Liang Zheng, Liyun Cao, and X. Long Zheng
- Subjects
Purpura, Thrombotic Thrombocytopenic ,Thrombotic Microangiopathies ,Fatty Acids ,ADAMTS13 Protein ,Hematology ,ADAM Proteins ,Cholesterol ,von Willebrand Factor ,Tumor Microenvironment ,Animals ,RNA ,Steroids ,Melanoma ,Phospholipids ,Zebrafish - Abstract
Severe deficiency of plasma ADAMTS13 activity may result in potentially fatal thrombotic thrombocytopenic purpura and relative deficiency of plasma ADAMTS13 activity may be associated with adverse outcomes of certain malignancies. Here, we report the role of ADAMTS13 or lack of von Willebrand factor (VWF) in reducing irradiation and melanoma-induced thrombotic microangiopathy (TMA) and mortality in zebrafish.Zebrafish melanoma cell line (ZMEL) was injected subcutaneously into wild-type (wt), adamts13Total body irradiation at 30 Gy alone resulted in a transient thrombocytopenia in both wt and a13Our results indicated that plasma ADAMTS13 or lack of VWF may offer a significant protection against the development of irradiation- and/or melanoma-induced TMA. Such a microenvironment may directly affect melanoma cell phenotypes via alternation in the oxidation-reduction and lipid metabolic pathways.
- Published
- 2022
38. Predictive value of ADAMTS-13 on concealed chronic renal failure in COPD patients
- Author
-
Zeng M, Chen QG, Liang WJ, He WM, Zheng HC, and Huang CR
- Subjects
chronic obstructive pulmonary disease ,renal insufficiency ,thrombosis ,inflammation ,ADAMTS13 protein ,Diseases of the respiratory system ,RC705-779 - Abstract
Mian Zeng, Qingui Chen, Wenjie Liang, Wanmei He, Haichong Zheng, Chunrong Huang Department of Medical Intensive Care Unit, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Background: Impaired renal function is often neglected in COPD patients. Considering that COPD patients usually have an ongoing prothrombotic state and systemic inflammation status, we investigated the association among them and explored the predictive value of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), on concealed chronic renal failure (CRF) in COPD patients.Methods: COPD patients were recruited from the First Affiliated Hospital of Sun Yat-Sen University between January 2015 and December 2016. Control was selected from contemporaneous hospitalized patients without COPD and matched by age and gender at a ratio of 1:1. Estimated glomerular filtration rate (eGFR) was calculated by using the Chronic Kidney Disease Epidemiology Collaboration formula, and all subjects were categorized as having normal renal function (eGFR ≥60 mL min–1 1.73 m–2) and having concealed CRF (normal serum creatinine while eGFR
- Published
- 2017
39. Púrpura trombocitopénica trombótica.
- Author
-
Morales-Montoya, Alejandra
- Abstract
Thrombotic thrombocytopenic purpura is a disease belongs to thrombotic microangiopathies caused by the deficiency or dysfunction of ADAMTS13 protein. It has three possible presentations: chronic, idiopathic or autoimmune, being the last one the most common. Clinical manifestations are variable depending on its time of evolution, it can cause fever, fatigue, arthralgia, abdominal and lumbar pain, as well as myocardial infarction, neurological alterations, renal failure, ischemic stroke and arterial and venous thrombosis. Given the complexity and diversity of the manifestations and complications related to this disease, early and effective diagnosis and treatment are still a little bit difficult; however, now there is a first line treatment which is mainly based on plasma replacement therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
40. Race, rituximab, and relapse in TTP
- Author
-
Shruti, Chaturvedi, Ana G, Antun, Andrew M, Farland, Ryan, Woods, Ara, Metjian, Yara A, Park, Gustaaf, de Ridder, Briana, Gibson, Raj S, Kasthuri, Darla K, Liles, Frank, Akwaa, Todd, Clover, Lisa, Baumann Kreuziger, J Evan, Sadler, Meera, Sridharan, Ronald S, Go, Keith R, McCrae, Harsh Vardhan, Upreti, Angela, Liu, Ming Y, Lim, Radhika, Gangaraju, X Long, Zheng, Jay S, Raval, Camila, Masias, Spero R, Cataland, Andrew, Johnson, Elizabeth, Davis, Michael D, Evans, and Marshall A, Mazepa
- Subjects
Purpura, Thrombotic Thrombocytopenic ,Adrenal Cortex Hormones ,Recurrence ,Immunology ,ADAMTS13 Protein ,Humans ,Thiamine ,Cell Biology ,Hematology ,Rituximab ,Biochemistry - Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.
- Published
- 2022
41. Distinguishing and overlapping laboratory results of thrombotic microangiopathies in HIV infection: Can scoring systems assist?
- Author
-
Susan Louw, Barry Frank Jacobson, and Elizabeth Sarah Mayne
- Subjects
Purpura, Thrombotic Thrombocytopenic ,Thrombotic Microangiopathies ,ADAMTS13 Protein ,HIV Infections ,Hematology ,General Medicine ,Disseminated Intravascular Coagulation ,Hemolysis ,Hemostatics ,Dacarbazine ,Hemoglobins ,South Africa ,Humans ,Thiamine ,Lactate Dehydrogenases ,Acute-Phase Proteins ,Retrospective Studies - Abstract
Patients with Human Immunodeficiency Virus (HIV) infection are at risk of thrombotic microangiopathies (TMAs) notably thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC). Overlap between laboratory results exists resulting in diagnostic ambiguity.Routine laboratory results of 71 patients with HIV-associated TTP (HIV-TTP) and 81 with DIC with concomitant HIV infection (HIV-DIC) admitted between 2015 and 2021 to academic hospitals in Johannesburg, South Africa were retrospectively reviewed. Both the PLASMIC and the International Society of Thrombosis and Haemostasis (ISTH) DIC scores were calculated.Patients with HIV-TTP had significantly (P .001) increased schistocytes and features of hemolysis including elevated lactate dehydrogenase (LDH)/upper-limit-of-normal ratio (median of 9 (interquartile range [IQR] 5-12) vs 3 (IQR 2-5)) but unexpectedly lower fibrinogen (median 2.8 (IQR 2.2-3.4) vs 4 g/L (IQR 2.5-9.2)) and higher D-dimer (median 4.8 (IQR 2.4-8.1) vs 3.6 g/L (IQR 1.7-6.2)) levels vs the HIV-DIC cohort. Patients with HIV-DIC were more immunocompromised with frequent secondary infections, higher platelet and hemoglobin levels, more deranged coagulation parameters and less hemolysis. Overlap in scoring systems was however observed.The laboratory parameter overlap between HIV-DIC and HIV-TTP might reflect a shared pathogenesis including endothelial dysfunction and inflammation and further research is required. Fibrinogen in DIC may be elevated as an acute phase reactant and D-dimers may reflect the extensive hemostatic activation in HIV-TTP. Inclusion of additional parameters in TMA scoring systems such the LDH/upper-limit-of-normal ratio, schistocytes count and wider access to ADAMTS-13 testing may enhance diagnostic accuracy and ensure appropriate utilization of plasma.
- Published
- 2022
42. How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge
- Author
-
Frank, Akwaa, Ana, Antun, and Spero R, Cataland
- Subjects
Purpura, Thrombocytopenic, Idiopathic ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,Recurrence ,Immunology ,ADAMTS13 Protein ,Humans ,Cell Biology ,Hematology ,Biochemistry ,Hospitals ,Patient Discharge - Abstract
Immune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids, rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up in the outpatient setting.
- Published
- 2022
43. Increased cleavage of von Willebrand factor by ADAMTS13 may contribute strongly to acquired von Willebrand syndrome development in patients with essential thrombocythemia
- Author
-
Masayuki Kubo, Kazuya Sakai, Masaki Hayakawa, Hirokazu Kashiwagi, Hideo Yagi, Yoshinobu Seki, Atsushi Hasegawa, Haruyuki Tanaka, Itsuto Amano, Yoshiaki Tomiyama, and Masanori Matsumoto
- Subjects
von Willebrand Diseases ,Platelet Count ,von Willebrand Factor ,ADAMTS13 Protein ,Humans ,Hemorrhage ,Hematology ,Thrombocythemia, Essential - Abstract
Patients with essential thrombocythemia (ET) often experience bleeding associated with acquired von Willebrand syndrome (AVWS) when the platelet count is markedly increased.We investigated whether von Willebrand factor (VWF) degradation is enhanced in patients with ET.Seventy patients with ET underwent VWF multimer (VWFM) analysis and measurement of VWF-related parameters. We calculated the VWFM index, defined as the ratio of intensities of a patient's molecular weight-categorized VWFMs, and those of a healthy subject's, using densitometric analysis. VWF degradation product (DP) was measured via ELISA using a monoclonal antibody that specifically recognizes Y1605 at the C-terminal boundary, which is exposed following ADAMTS13-mediated cleavage of the Y1605-M1606 bond of the VWF A2 domain.Patients with higher platelet counts had a significantly reduced high molecular weight (HMW)-VWFM index and an increased VWF-DP:VWF antigen (Ag) ratio compared to those with lower platelet counts. On multivariate analysis, the VWF-DP/VWF:Ag ratio was an independent predictor of the HMW-VWFM index. Patients who underwent cytoreductive therapy had a significantly higher HMW-VWFM index and lower VWF-DP/VWF:Ag ratio than those who did not. Among individual patients, there was also a significant increase in the HMW-VWFM index and a decrease in the VWF-DP/VWF:Ag ratio after cytoreductive therapy compared to pre-therapy values.In patients with ET, an increased platelet count is associated with enhanced cleavage of VWF at the Y1605-M1606 bond, primarily by ADAMTS13, leading to AVWS. Cytoreductive therapy reduces the platelet count, prevents excessive VWF cleavage, and improves VWFM distributions.
- Published
- 2022
44. Recent advances in therapeutic options for rare hemostatic disorders: selected poster extracts of recent research in hemophilia A, congenital hemophilia with inhibitors, von Willebrand disease, and thrombotic thrombocytopenic purpura presented at the 29th congress of the International Society on Thrombosis and Haemostasis (ISTH 2021, Jul 17–21; virtual congress)
- Author
-
Nisha, Jain, Johannes, Oldenburg, Margareth C, Ozelo, Shawn X, Sun, Leilei, Tang, and Spiros, Tzivelekis
- Subjects
Hemostatic Disorders ,Hemostasis ,von Willebrand Diseases ,Rare Diseases ,Purpura, Thrombotic Thrombocytopenic ,von Willebrand Factor ,ADAMTS13 Protein ,Humans ,Thrombosis ,Hematology ,Hemophilia A ,Hemostatics - Abstract
Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.
- Published
- 2022
45. Alternate‐day dosing of caplacizumab for immune‐mediated thrombotic thrombocytopenic purpura
- Author
-
Lucas Kühne, Jessica Kaufeld, Linus A. Völker, Ralph Wendt, Ulf Schönermarck, Holger Hägele, Thomas Osterholt, Dennis A. Eichenauer, Markus Bieringer, Anke von Bergwelt‐Baildon, Michael Fischereder, Veronika Buxhofer‐Ausch, Jan Menne, Paul T. Brinkkoetter, and Paul Knöbl
- Subjects
Purpura, Thrombotic Thrombocytopenic ,von Willebrand Factor ,ADAMTS13 Protein ,Humans ,Hematology ,Single-Domain Antibodies ,Retrospective Studies - Abstract
The anti-von Willebrand factor (VWF) nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura (iTTP), thereby adding a new therapeutic principle to the treatment of this disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous.Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab by thoroughly analyzing the timing and outcome of this approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab at seven different medical centers in Austria and Germany between 2018 and 2021.Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in most patients. Five patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application. VWF activity was repeatedly measured in 16 of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 h in line with published pharmacodynamics.Extension of caplacizumab application intervals from daily to alternate-day dosing may be safely considered in selected patients after 3 to 4 weeks of daily treatment. Earlier modifications may be discussed in low-risk patients but require close monitoring for clinical and laboratory features of thrombotic microangiopathy.
- Published
- 2022
46. Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients: The Roles of PLASMIC and French Scores
- Author
-
Baysal M, Hindilerden F, Ümit EG, Demir AM, Keklik Karadağ F, Saydam G, Akpınar S, Turgut B, Özkocaman V, Özkalemkaş F, Çiftçiler R, Özlü C, Demircioğlu S, İpek Y, and Diz Küçükkaya R
- Subjects
- Humans, Aged, Middle Aged, Retrospective Studies, Cross-Sectional Studies, Reproducibility of Results, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy, Thrombotic Microangiopathies diagnosis, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic therapy, Thrombosis
- Abstract
Objective: In recent years, new developments have been incorporated into daily practice in the management of immune thrombotic thrombocytopenic purpura (iTTP). In particular, clinical scoring systems could help clinicians with clinical decision-making and early recognition. However, older patients frequently present with more organ involvement and in unusual ways. The ways in which age could affect these clinical prediction scoring systems remain unclear. We evaluated the use of PLASMIC and French scores in patients over 60 years of age., Materials and Methods: We performed a retrospective cross-sectional analysis of patients over 60 years of age with a presumptive diagnosis of iTTP between 2014 and 2022 at 10 centers. We calculated PLASMIC and French scores and compared our data with a single-center analysis of younger patients presenting with thrombotic microangiopathy., Results: Our study included 30 patients over 60 years of age and a control group of 28 patients younger than 60 years. The diagnostic sensitivity and specificity of a French score of ≥1 were lower in older patients compared to the control group (78.9% vs. 100% and 18.2% vs. 57.1%, respectively). The diagnostic sensitivity and specificity of a PLASMIC score of ≥5 were 100% vs. 95% and 27.3% vs. 100% for the study group and control group, respectively. Our study showed a higher mortality rate in older patients compared to the control group (30% vs. 7.1%, p=0.043)., Conclusion: For a limited number of patients (n=6), our results showed that rituximab can reduce mortality. Given that the reliability of clinical prediction scores for iTTP in older patients may be lower, more caution must be undertaken in interpreting their results., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2023 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House.)
- Published
- 2023
- Full Text
- View/download PDF
47. Dynamic and functional linkage between von Willebrand factor and ADAMTS-13 with aging: an Atherosclerosis Risk in Community study.
- Author
-
Liu W, Patel K, Wang Y, Nodzenski M, Nguyen A, Teramura G, Higgins HA, Hoogeveen RC, Couper D, Fu X, Konkle BA, Loop MS, and Dong JF
- Subjects
- Humans, ADAMTS13 Protein, Cross-Sectional Studies, Aging, von Willebrand Factor metabolism, von Willebrand Diseases
- Abstract
Background: von Willebrand factor (VWF) is a multimeric glycoprotein critically involved in hemostasis, thrombosis, and inflammation. VWF function is regulated by its antigen levels, multimeric structures, and the state of enzymatic cleavage. Population studies in the past have focused almost exclusively on VWF antigen levels in cross-sectional study designs., Objective: To identify subjects in the Atherosclerosis Risk in Community study who had persistently low and high VWF antigen over 10 years and to quantify longitudinal changes in the biological activities and cleavage of VWF in these subjects., Methods: We measured VWF antigen, propeptide, adhesive activities, and cleavage by ADAMTS-13 quantified using a mass spectrometry method that detected the cleaved VWF peptide EQAPNLVY, as well as coagulation factor VIII activity., Results: We determined the mean subject-specific increase in VWF to be 22.0 International Units (IU)/dL over 10 years, with 95% between -0.3 and 59.7 IU/dL. This aging-related increase was also detected in VWF propeptide levels, ristocetin cofactor activity, and VWF binding to collagen. We identified 4.1% and 25.0% of subjects as having persistently low (<50 IU/dL) and high (>200 IU/dL) VWF antigen, respectively. Subjects with persistently low VWF had enhanced ristocetin cofactor activity, whereas those with persistently high VWF had elevated levels of ADAMTS-13, resulting in a comparable rate of VWF cleavage between the 2 groups., Conclusions: These results provide new information about the effects of aging on VWF antigens and adhesive activity and identify a functional coordination between VWF and the rate of its cleavage by ADAMTS-13., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
48. Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura.
- Author
-
Postmus T, Graça NAG, Ferreira de Santana J, Ercig B, Langerhorst P, Luken B, Joly BS, Vanhoorelbeke K, Veyradier A, Coppo P, and Voorberg J
- Subjects
- Humans, ADAMTS13 Protein, von Willebrand Factor metabolism, Blood Platelets metabolism, Autoantibodies, Purpura, Thrombotic Thrombocytopenic, Thrombosis, Purpura, Thrombocytopenic, Idiopathic
- Abstract
Background: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic disorder, with 1.5 to 6.0 cases per million per year. The majority of patients with TTP develop inhibitory autoantibodies that predominantly target the spacer domain of ADAMTS-13. ADAMTS-13 is responsible for cleaving von Willebrand factor (VWF) multimers, thereby regulating platelet adhesion at sites of high-vascular shear stress. Inhibition and/or clearance of ADAMTS-13 by pathogenic autoantibodies results in accumulation of VWF multimers that promotes the formation of platelet-rich microthrombi. Previously, we have shown that insertion of a single N-glycan (NGLY) in the spacer domain prevents the binding of antispacer domain antibodies., Objectives: To explore whether NGLY mediated shielding of the ADAMTS-13 spacer domain effectively prevents binding of pathogenic antispacer autoantibodies in patients with immune-mediated TTP (iTTP)., Methods: We screened 5 NGLY-ADAMTS-13 variants (NGLY3, NGLY7, NGLY8, NGLY3+7, and NGLY3+8) for binding of autoantibodies and for their activity in the presence and absence of 50 samples derived from patients with iTTP., Results: NGLY variants showed greatly reduced antibody binding, down to 27% of wild-type (wt) ADAMTS-13 binding. Moreover, NGLY variants of ADAMTS-13 remained more active in FRETS-VWF73 assay in the presence of the plasma samples from these 50 patients with acute phase iTTP when compared with wtADAMTS-13. On average, wtADAMTS-13 activity was reduced to 37% of regular levels in the presence of plasma, while NGLY3 and NGLY3+7 remained 69% and 81% active, respectively., Conclusion: These results reinforce our previous findings that NGLYs shield ADAMTS-13 from antibody binding and hence restore ADAMTS-13 activity in the presence of autoantibodies., Competing Interests: Declaration of competing interests N.A.G.G., B.E., and J.V. are listed as inventors on a patent application for NGLY modified ADAMTS-13. At the time of the study N.A.G.G., J.F.d.S., and B.M.L. were employed by Sanquinnovate, which is fully owned by Sanquin Blood Supply Foundation, a not-for-profit organisation. K.V. is a member of the advisory board of Takeda. P.C. is a member of the clinical advisory board for Alexion, Sanofi, Shire, Takeda, and Janssen. A.V. is a member of the advisory boards for Sanofi, Takeda, and LFB biomedicaments. The other authors have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
49. Cattle-FRETS71, a novel fluorogenic substrate with broad applicability for characterizing ADAMTS13 properties and function.
- Author
-
Barton JC, Anderson C, Miranda FZ, Kelley R, Kremer Hovinga JA, Terrell D, Vesely SK, George JN, and Muia J
- Subjects
- Humans, Cattle, Animals, Fluorescent Dyes chemistry, ADAM Proteins metabolism, ADAMTS13 Protein, Fluorescence Resonance Energy Transfer methods, von Willebrand Factor chemistry, Citric Acid, Purpura, Thrombotic Thrombocytopenic diagnosis
- Abstract
Background: Current ADAMTS13 activity assays are important for diagnosing thrombotic thrombocytopenic purpura (TTP) but are unreliable to assay ADAMTS13 activity in animal models. The Cattle-FRETS71 assay is capable of detecting ADAMTS13 activity in plasma from multiple animal species, making it a potentially useful reagent at all stages of clinical research. The performance of Cattle-FRETS71 in TTP diagnosis is not yet known., Objectives: We evaluated the performance of the Cattle-FRETS71 substrate against the human FRETS-rVWF71 and the FRETS-VWF73 commercial substrates in human plasma and serum samples to validate its utility in diagnosing TTP in patients., Methods: Internal validation was performed using heparinized plasma samples (n = 81). External validation was a blinded study using serum samples from the Oklahoma TTP Registry (n = 118, collected 2004-2014) that had been initially assayed by FRETS-VWF73 within 1 year of collection. Additional validation was performed with citrated plasma samples with variable ADAMTS13 activities (n = 32) that were analyzed by FRETS-VWF73., Results: There was an excellent correlation (r = 0.94) between Cattle-FRETS71 and FRETS-rVWF71 for assayed heparinized plasma samples (n = 81). Assay results between Cattle-FRETS71 and FRETS-VWF73 of Oklahoma TTP Registry serum samples (n = 118) and citrated plasma samples (n = 32) were comparably good (r = 0.81 and r = 0.85, respectively)., Conclusion: The Cattle-FRETS71 assay is comparable with other assays in quantifying ADAMTS13 activity in human plasma collected from patients with documented or suspected TTP. The versatility of Cattle-FRETS71, combined with its specificity and sensitivity, makes it a useful tool for the standardization of ADAMTS13 activity across basic and clinical research paradigms., Competing Interests: Declaration of competing interests J.M. holds the patent, “Fluorogenic substrate for ADAMTS13,” US 8663912, issued to Washington University. J.C.B., C.A., F.Z.M., R.K., J.A.K.H., D.T., S.K.V., and J.G. have no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
50. VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion.
- Author
-
Fogarty H, Ahmad A, Atiq F, Doherty D, Ward S, Karampini E, Rehill A, Leon G, Byrne C, Geoghegan R, Conroy H, Byrne M, Budde U, Schneppenheim S, Sheehan C, Ngwenya N, Baker RI, Preston RJS, Tuohy E, McMahon C, and O'Donnell JS
- Subjects
- Humans, Child, von Willebrand Factor metabolism, Hemolysis, Hydroxyurea therapeutic use, Blood Transfusion, ADAMTS13 Protein, Anemia, Sickle Cell drug therapy, Vascular Diseases, Hemostatics
- Abstract
Previous studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF-ADAMTS13 axis dysfunction. In total, 180 children with a confirmed diagnosis of SCD (hemoglobin SS) on hydroxycarbamide (n = 96) or blood transfusion (n = 84) were included. Despite disease-modifying treatment, plasma VWF and VWF propeptide were elevated in a significant proportion of children with SCD (33% and 47%, respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared with the blood transfusion cohort (P < .05). Additionally, increased levels of other Weibel-Palade body-stored proteins, including factor VIII (FVIII), angiopoietin-2, and osteoprotegerin were observed, indicated ongoing endothelial cell activation. Children treated with hydroxycarbamide also had higher FVIII activity and enhanced thrombin generation compared with those in the blood transfusion cohort (P < .001). Finally, hemolysis markers strongly correlated with VWF levels (P < .001) and were significantly reduced in the blood transfusion cohort (P < .001). Cumulatively, to our knowledge, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF-ADAMTS13 axis is present in a significant subgroup of pediatric patients with SCD, especially those treated with hydroxycarbamide., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.