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Mubarak M, Raza A, Rashid R, Sapna F, Shakeel S. Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra. World J Transplant 2024; 14:90277. [PMID: 38576763 PMCID: PMC10989473 DOI: 10.5500/wjt.v14.i1.90277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/28/2024] [Accepted: 03/04/2024] [Indexed: 03/15/2024] Open
Abstract
Thrombotic microangiopathy (TMA) is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys. This review is specifically focused on post-transplant TMA (PT-TMA) involving kidney transplant recipients. Its reported prevalence in the latter population varies from 0.8% to 14% with adverse impacts on both graft and patient survival. It has many causes and associations, and the list of etiologic agents and associations is growing constantly. The pathogenesis is equally varied and a variety of patho genetic pathways lead to the development of microvascular injury as the final common pathway. PT-TMA is categorized in many ways in order to facilitate its management. Ironically, more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case. Pathologically, the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature. Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists. The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase. Management of the condition is also challenging and still largely empirical. It varies from simple maneuvers, such as plasmapheresis, drug withdrawal or modification, or dose reduction, to lifelong complement blockade, which is very expensive. A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective. This review aims to increase the awareness of relevant stakeholders regarding this important, potentially treatable but under-recognized cause of kidney allograft dysfunction.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Amber Raza
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Rahma Rashid
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Fnu Sapna
- Department of Pathology, Montefiore Medical Center, The University Hospital for Albert Einstein School of Medicine, Bronx, NY 10461, United States
| | - Shaheera Shakeel
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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de Boisriou I, Ellouze S, Kassasseya C, Feral-Pierssens AL, Gerlier C, Chauvin A, Beaune S, Dubreucq E, Pereira L, Chocron R, Khellaf M, Mariotte É, Zafrani L, Peyrony O. Misdiagnosis of thrombotic microangiopathy in the emergency department: a multicenter retrospective study. Intern Emerg Med 2024; 19:115-124. [PMID: 37914919 DOI: 10.1007/s11739-023-03457-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/08/2023] [Indexed: 11/03/2023]
Abstract
To estimate the rate of inappropriate diagnosis in patients who visited the ED with thrombotic microangiopathy (TMA) and to assess the factors and outcomes associated with emergency department (ED) misdiagnosis. Retrospective multicenter study of adult patients admitted to the intensive care unit (ICU) for TMA from 2012 to 2021 who had previously attended the ED for a reason related to TMA. Patient characteristics and outcomes were compared in a univariate analysis based on whether a TMA diagnosis was mentioned in the ED or not. Forty patients were included. The diagnosis of TMA was not mentioned in the ED in 16 patients (40%). Patients for whom the diagnosis was mentioned in the ED had more frequently a request for schistocytes research, and therefore had more often objectified schistocytes. They also had more frequently a troponin dosage in the ED (even if the difference was not significant), an ECG performed or interpreted, and were admitted more quickly in the ICU (0 [0-0] vs 2 [0-2] days; P = 0.002). Hemoglobin levels decreased significantly in both groups, and creatinine levels increased significantly in the misdiagnosis group between ED arrival and ICU admission. In patients with a final diagnosis of TTP, the time to platelets durable recovery was shorter for those in whom the diagnosis was mentioned in the ED without reaching statistical significance (7 [5-11] vs 14 [5-21] days; P = 0.3).
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Affiliation(s)
| | - Sami Ellouze
- Emergency Department, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - Christian Kassasseya
- Emergency Department, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Camille Gerlier
- Emergency Department, Groupe Hospitalier Paris-Saint-Joseph, Paris, France
| | - Anthony Chauvin
- Emergency Department, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sebastien Beaune
- Emergency Department, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Paris, France
- Université Versailles St Quentin- UFR Simone Veil santé, Montigny-le-Bretonneux, France
| | - Evelyne Dubreucq
- Emergency Department, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Laurent Pereira
- Emergency Department, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Richard Chocron
- Emergency Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
- INSERM, UMR-S970, Paris Cardiovascular Research Center, Team "Integrative Epidemiology of Cardiovascular Diseases", Université Paris Cité, Paris, France
| | - Mehdi Khellaf
- Emergency Department, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Éric Mariotte
- Intensive Care Unit, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Lara Zafrani
- Intensive Care Unit, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Olivier Peyrony
- Emergency Department, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010, Paris, France.
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Pereira MCB, Ruschel B, Schneider B, de Melgar VSGM, Rech TH. COVID-19-Induced Fatal Thrombotic Thrombocytopenic Purpura in a Healthy Young Patient. Case Rep Crit Care 2022; 2022:2934171. [PMID: 36523352 PMCID: PMC9747321 DOI: 10.1155/2022/2934171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 11/09/2022] [Accepted: 11/19/2022] [Indexed: 02/23/2025] Open
Abstract
Since the global coronavirus disease 2019 (COVID-19) pandemic began, findings indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might induce autoimmune disorders. Thrombotic thrombocytopenic purpura (TTP) is a devastating disease if not emergently treated. It presents with severe thrombocytopenia, microangiopathic hemolytic anemia, and neurologic findings with or without renal insufficiency. The antibody-mediated reduced activity of the disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) induces the accumulation of ultrahigh-molecular-weight multimers of von Willebrand factor, leading to platelet aggregation and thrombosis. TTP can be an unusual presentation of COVID-19 disease mediated by the virus-induced immune response. We report a case of a healthy young patient presenting with the classic TTP pentad a few days after a diagnosis of COVID-19 confirmed by a positive SARS-CoV-2 RT-PCR test. The patient was initially treated with high-dose methylprednisolone and fresh frozen plasma until she was transferred to a tertiary care facility and plasma exchange was available. She evolved with a malignant ischemic vascular accident and was declared brain-dead 24 hours after the first plasma exchange section.
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Affiliation(s)
| | - Bruna Ruschel
- School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Bruna Schneider
- Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | | | - Tatiana Helena Rech
- School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Chung CH, Tsai IJ, Tseng MH, Chou HH, Tain YL, Tsai JD, Chiou YY, Chiou YH, Lin CY. Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan. Medicine (Baltimore) 2021; 100:e25986. [PMID: 34011089 PMCID: PMC8137071 DOI: 10.1097/md.0000000000025986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/28/2021] [Indexed: 01/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.
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Affiliation(s)
- Ching-Hu Chung
- Department of Medicine, Mackay Medical College, New Taipei City
| | - I-Jung Tsai
- Division of Nephrology, Department of Pediatrics, National Taiwan University Children Hospital, Taipei
| | - Min-Hua Tseng
- Division of Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Pediatrics, Xiamen Chang Gung Hospital, Ximen, China
| | - Hsin-Hsu Chou
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi
- Department of Bioinformatics and Medical Engineering, College of Information and Electrical Engineering, Asia University, Taichung
| | - You-Lin Tain
- Division of Pediatric Nephrology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung
| | - Jeng-Daw Tsai
- Division of Nephrology, Department of Pediatrics, MacKay Children's Hospital, Taipei
| | - Yuan-Yow Chiou
- Departments of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University Medical College and Hospital, Tainan 704
| | - Yee-Hsuan Chiou
- Department of Pediatrics, Kaohsiung Veterans General Hospital
- Department of Medical Technology, Fooyin University, Kaohsiung 831
| | - Ching-Yuang Lin
- Clinical Immunological Center, Children's Hospital, China Medical University, Taichung, Taiwan
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Schmidt J, Zafrani L, Lemiale V, Stepanian A, Joly B, Azoulay E, Mariotte E. The clinical picture of thrombotic microangiopathy in patients older than 60 years of age. Br J Haematol 2020; 192:e25-e28. [PMID: 33216950 DOI: 10.1111/bjh.17176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Julien Schmidt
- Medical Intensive Care Unit, Saint-Louis Hospital, APHP, Paris, France
| | - Lara Zafrani
- Medical Intensive Care Unit, Saint-Louis Hospital, APHP, Paris, France
| | - Virginie Lemiale
- Medical Intensive Care Unit, Saint-Louis Hospital, APHP, Paris, France
| | - Alain Stepanian
- Hematology and Hemostasis Laboratory, APHP, Lariboisière Hospital, Paris, France
| | - Bérangère Joly
- Hematology and Hemostasis Laboratory, APHP, Lariboisière Hospital, Paris, France
| | - Elie Azoulay
- Medical Intensive Care Unit, Saint-Louis Hospital, APHP, Paris, France
| | - Eric Mariotte
- Medical Intensive Care Unit, Saint-Louis Hospital, APHP, Paris, France
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Pagliari MT, Boscarino M, Cairo A, Mancini I, Martinelli I, Bucciarelli P, Rossi F, Rosendaal FR, Peyvandi F. ADAMTS13 activity, high VWF and FVIII levels in the pathogenesis of deep vein thrombosis. Thromb Res 2020; 197:132-137. [PMID: 33212380 DOI: 10.1016/j.thromres.2020.10.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/02/2020] [Accepted: 10/31/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Deep vein thrombosis (DVT) is a common multi-factorial disease with a partially understood aetiology. Although the roles of high factor (F)VIII and von Willebrand factor (VWF) levels are recognized, that of ADAMTS13 is still unclear. AIM To assess the association between ADAMTS13 activity levels, VWF antigen (VWF:Ag) and FVIII coagulant activity (FVIII:C) levels and DVT. MATERIALS AND METHODS 365 Italian DVT patients and 292 age- and sex-matched controls were considered. Plasma ADAMTS13 activity was measured using FRETS-VWF73 assay. VWF:Ag and FVIII:C were measured using immunoassay and one-stage clotting assay (ACL TOP analyzer), respectively. Quartile analyses were performed to evaluate the individual association between ADAMTS13 activity, VWF:Ag, FVIII:C and DVT. The combined effect of high VWF levels (> 4th quartile) and low ADAMTS13 levels (< 1st quartile) was evaluated using binary variables. All models were age- and sex-adjusted. Estimated risks were reported as Odds ratio (OR) with 95% confidence intervals (CI). RESULTS ADAMTS13 activity was lower in DVT patients (94% vs. 98% of controls). Patients with an ADAMTS13 activity <1st quartile (86%) showed a 1.6-fold increased risk of DVT (95%CI, 1.05-2.55). The combination of low ADAMTS13 activity and high VWF:Ag levels was associated with a 15-fold increased risk (95%CI, 7.80-33.80). VWF:Ag and FVIII:C were associated to DVT with a dose-response relationship. CONCLUSIONS ADAMTS13 activity < 86% was associated with a moderate risk of DVT. The co-presence of low ADAMTS13 activity and high VWF levels resulted in a strong synergistic effect on DVT risk. The association of VWF:Ag and FVIII:C with DVT was confirmed.
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Affiliation(s)
- Maria Teresa Pagliari
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Marco Boscarino
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Andrea Cairo
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Ilaria Mancini
- Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy
| | - Ida Martinelli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Paolo Bucciarelli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Federica Rossi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Flora Peyvandi
- Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
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Sapet M, Fouillet L, Daguenet E, Laurent B, Guyotat D, Le Jeune C. [Proteinuria in multiple myeloma: Be careful to iatrogeny]. Bull Cancer 2020; 107:519-520. [PMID: 32178835 DOI: 10.1016/j.bulcan.2020.01.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/30/2020] [Accepted: 01/30/2020] [Indexed: 11/25/2022]
Affiliation(s)
- Manon Sapet
- Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42270 Saint-Priest-en-Jarez, France
| | - Ludovic Fouillet
- Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42270 Saint-Priest-en-Jarez, France
| | - Elisabeth Daguenet
- Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42270 Saint-Priest-en-Jarez, France
| | - Blandine Laurent
- Laboratoire d'histologie rénale, CHU de St.-Etienne, 42055 St.-Etienne cedex 02, France
| | - Denis Guyotat
- Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42270 Saint-Priest-en-Jarez, France
| | - Caroline Le Jeune
- Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42270 Saint-Priest-en-Jarez, France.
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Shanmugam SG, Priyathersini N, Muralikrishnan S, Balasubramanian A. Thrombotic thrombocytopenic purpura presenting as recurrent thrombocytopenia in a young female - A case report. Hematol Transfus Cell Ther 2020; 42:376-380. [PMID: 31956090 PMCID: PMC7599268 DOI: 10.1016/j.htct.2019.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/27/2019] [Accepted: 10/17/2019] [Indexed: 11/16/2022] Open
Affiliation(s)
- Sri Gayathri Shanmugam
- Sri Ramachandra Institute of Higher Education and Research SRIHER [DU], Porur, Chennai, India.
| | - Nagarajan Priyathersini
- Sri Ramachandra Institute of Higher Education and Research SRIHER [DU], Porur, Chennai, India
| | - Srikanth Muralikrishnan
- Sri Ramachandra Institute of Higher Education and Research SRIHER [DU], Porur, Chennai, India
| | - Archana Balasubramanian
- Sri Ramachandra Institute of Higher Education and Research SRIHER [DU], Porur, Chennai, India
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le Besnerais M, Veyradier A, Benhamou Y, Coppo P. Caplacizumab: a change in the paradigm of thrombotic thrombocytopenic purpura treatment. Expert Opin Biol Ther 2019; 19:1127-1134. [PMID: 31359806 DOI: 10.1080/14712598.2019.1650908] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is an immune-mediated deficiency in von Willebrand factor-cleaving protease ADAMTS13 allowing unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis. Caplacizumab, an anti-von Willebrand factor humanized, bivalent single-domain nanobody preventing its binding to the platelet has been investigated and approved for use in the treatment of iTTP. Areas covered: The purpose of this article is to summarize the available clinical data on the efficacy and safety of caplacizumab in iTTP and to provide our opinion on the place of caplacizumab in current treatment regimens. Expert opinion: Caplacizumab is a new drug with a complementary mechanism of action with respect to the standard available therapeutics. It demonstrated efficacy in clinical trials through a faster platelet count normalization and protection of patients from exacerbations and refractoriness. Caplacizumab is well tolerated with minor bleeds as the most important side effect. The efficacy of caplacizumab now needs to be assessed in real-life but definitely, this drug opens hope for a significant improvement in iTTP prognosis at the very early, critical step of the disease.
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Affiliation(s)
- Maëlle le Besnerais
- Département de Médecine Interne, CHU Charles Nicolle , Rouen , France.,Normandie Univ, UNIROUEN, INSERM U1096 EnVI , Rouen , France
| | - Agnès Veyradier
- Service d'Hématologie biologique and EA3518 Université Paris Diderot, Groupe Hospitalier Saint Louis - Lariboisière, Assistance Publique, Hôpitaux de Paris , Paris , France.,French Reference Center for Thrombotic Microangiopathies, Hôpital Saint Antoine, Assistance Publique -Hôpitaux de Paris , Paris , France
| | - Ygal Benhamou
- Département de Médecine Interne, CHU Charles Nicolle , Rouen , France.,Normandie Univ, UNIROUEN, INSERM U1096 EnVI , Rouen , France
| | - Paul Coppo
- French Reference Center for Thrombotic Microangiopathies, Hôpital Saint Antoine, Assistance Publique -Hôpitaux de Paris , Paris , France.,Département d'Hématologie clinique , Paris , France
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Bayer G, von Tokarski F, Thoreau B, Bauvois A, Barbet C, Cloarec S, Mérieau E, Lachot S, Garot D, Bernard L, Gyan E, Perrotin F, Pouplard C, Maillot F, Gatault P, Sautenet B, Rusch E, Buchler M, Vigneau C, Fakhouri F, Halimi JM. Etiology and Outcomes of Thrombotic Microangiopathies. Clin J Am Soc Nephrol 2019; 14:557-566. [PMID: 30862697 PMCID: PMC6450353 DOI: 10.2215/cjn.11470918] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 02/04/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVES Thrombotic microangiopathies constitute a diagnostic and therapeutic challenge. Secondary thrombotic microangiopathies are less characterized than primary thrombotic microangiopathies (thrombotic thrombocytopenic purpura and atypical hemolytic and uremic syndrome). The relative frequencies and outcomes of secondary and primary thrombotic microangiopathies are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a retrospective study in a four-hospital institution in 564 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period. We estimated the incidence of primary and secondary thrombotic microangiopathies, thrombotic microangiopathy causes, and major outcomes during hospitalization (death, dialysis, major cardiovascular events [acute coronary syndrome and/or acute heart failure], and neurologic complications [stroke, cognitive impairment, or epilepsy]). RESULTS We identified primary thrombotic microangiopathies in 33 of 564 patients (6%; thrombotic thrombocytopenic purpura: 18 of 564 [3%]; atypical hemolytic and uremic syndrome: 18 of 564 [3%]). Secondary thrombotic microangiopathies were found in 531 of 564 patients (94%). A cause was identified in 500 of 564 (94%): pregnancy (35%; 11 of 1000 pregnancies), malignancies (19%), infections (33%), drugs (26%), transplantations (17%), autoimmune diseases (9%), shiga toxin due to Escherichia coli (6%), and malignant hypertension (4%). In the 31 of 531 patients (6%) with other secondary thrombotic microangiopathies, 23% of patients had sickle cell disease, 10% had glucose-6-phosphate dehydrogenase deficiency, and 44% had folate deficiency. Multiple causes of thrombotic microangiopathies were more frequent in secondary than primary thrombotic microangiopathies (57% versus 19%; P<0.001), and they were mostly infections, drugs, transplantation, and malignancies. Significant differences in clinical and biologic differences were observed among thrombotic microangiopathy causes. During the hospitalization, 84 of 564 patients (15%) were treated with dialysis, 64 of 564 patients (11%) experienced major cardiovascular events, and 25 of 564 patients (4%) had neurologic complications; 58 of 564 patients (10%) died, but the rates of complications and death varied widely by the cause of thrombotic microangiopathies. CONCLUSIONS Secondary thrombotic microangiopathies represent the majority of thrombotic microangiopathies. Multiple thrombotic microangiopathies causes are present in one half of secondary thrombotic microangiopathies. The risks of dialysis, neurologic and cardiac complications, and death vary by the cause of thrombotic microangiopathies.
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Affiliation(s)
- Guillaume Bayer
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Florent von Tokarski
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Benjamin Thoreau
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Adeline Bauvois
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Christelle Barbet
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Sylvie Cloarec
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | - Elodie Mérieau
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
| | | | - Denis Garot
- Service de Médecine Intensive Réanimation, Hôpital Bretonneau
| | - Louis Bernard
- Service de Maladies Infectieuses, Hôpital Bretonneau
| | - Emmanuel Gyan
- Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau
- Équipe de Recherche Labellisée Centre National de la Recherche Scientifique 7001, Université de Tours, Tours, France
| | | | - Claire Pouplard
- Laboratoire d’Hématologie-Hémostase, Hôpital Trousseau
- Équipe d'accueil7501 and
| | | | - Philippe Gatault
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
- Équipe d'accueil4245, François Rabelais University, Tours, France
| | - Bénédicte Sautenet
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
- Institut National de la Santé et de la Recherche Médicale U1246, Hôpital Bretonneau, and
| | - Emmanuel Rusch
- Laboratoire de Santé Publique, Hôpital Bretonneau, Centre Hospitalier Universitaire Tours, Tours, France
| | - Matthias Buchler
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
- Équipe d'accueil4245, François Rabelais University, Tours, France
| | - Cécile Vigneau
- Centre Hospitalier Universitaire Pontchaillou, Service de Néphrologie, Rennes, France
- Université Rennes 1, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1085, Rennes, France; and
| | - Fadi Fakhouri
- Centre de recherche en Transplantation et immunologie, Unité Mixte de Recherche 1064, Institut National de la Santé et de la Recherche Médicale, Université de Nantes et département de Néphrologie et Immunologie, Centre Hospitalier Universitaire Nantes, Nantes, France
| | - Jean-Michel Halimi
- Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville
- Équipe d'accueil4245, François Rabelais University, Tours, France
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11
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Falter T, Herold S, Weyer-Elberich V, Scheiner C, Schmitt V, von Auer C, Messmer X, Wild P, Lackner KJ, Lämmle B, Scharrer I. Relapse Rate in Survivors of Acute Autoimmune Thrombotic Thrombocytopenic Purpura Treated with or without Rituximab. Thromb Haemost 2018; 118:1743-1751. [PMID: 30235478 PMCID: PMC6202932 DOI: 10.1055/s-0038-1668545] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Autoimmune thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated severe a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) deficiency leading to micro-angiopathic haemolytic anaemia (MAHA) and thrombocytopenia with organ damage. Patients survive with plasma exchange (PEX), fresh frozen plasma replacement and corticosteroid treatment. Anti-CD20 monoclonal antibody rituximab is increasingly used in patients resistant to conventional PEX or relapsing after an acute bout. OBJECTIVE This retrospective observational study focused on the relapse rate and possible influencing factors including treatment with rituximab first introduced in 2003. PATIENTS AND METHODS Seventy patients treated between January 2003 and November 2014 were evaluated. Number, duration, clinical manifestations, laboratory data and treatment of acute episodes were documented. Diagnostic criteria of acute iTTP were thrombocytopenia, MAHA, increased lactate dehydrogenase and severe ADAMTS13 deficiency. RESULTS Fifty-four female and 16 male patients had a total of 224 acute episodes over a median observation period of 8.3 years. The relapse rate was 2.6% per month, for women 2.4% and for men 3.5% per month. Since 2003, 17 patients with a first iTTP episode were treated with rituximab, whereas 28 were not. There was a trend towards lower relapse rates after rituximab treatment over the ensuing years. However, this was statistically not significant. CONCLUSION This analysis does not show a significant reduction of acute iTTP relapses by rituximab given during an acute bout. Initial episodes are characterized by more severe clinical signs compared with the less severe relapses. Furthermore, men suffer significantly more frequent and considerably more serious acute relapses.
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Affiliation(s)
- Tanja Falter
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Stephanie Herold
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Veronika Weyer-Elberich
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Carina Scheiner
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Veronique Schmitt
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Charis von Auer
- Department of Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Xavier Messmer
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany.,Department of Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Philipp Wild
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Karl J Lackner
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
| | - Bernhard Lämmle
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany.,University Clinic of Hematology & Central Hematology Laboratory, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Inge Scharrer
- Department of Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany
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12
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Dahal S, Ghimire DKC, Sapkota S, Dahal S, Kafle P, Bhandari M. Myocardial Infarction as an Early Presentation in Thrombotic Thrombocytopenic Purpura: A Rare Case Series. J Investig Med High Impact Case Rep 2018; 6:2324709618773789. [PMID: 29761111 PMCID: PMC5946356 DOI: 10.1177/2324709618773789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 03/28/2018] [Accepted: 04/08/2018] [Indexed: 12/22/2022] Open
Abstract
Renal and neurological involvements are frequently seen in thrombotic thrombocytopenic purpura (TTP). Cardiac involvement, however, has been rarely reported. In this article, we present 2 cases of myocardial infarction in patients with TTP. In the first case, a young man presented with non-ST-segment elevation myocardial infarction that resolved promptly with plasmapheresis. The second patient developed ST-segment elevation myocardial infarction early in the course of the disease and died before plasmapheresis could be initiated. Hence, a high degree of suspicion with prompt diagnosis and treatment is needed to prevent mortality associated with cardiac involvement in TTP.
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Affiliation(s)
- Sumit Dahal
- Interfaith Medical Center, Brooklyn, NY, USA
| | | | | | - Suyash Dahal
- KIST Medical College and Teaching Hospital, Lalitpur, Nepal
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13
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Yıldız S, Demirkan F. What is the evidence for the role of therapeutic apheresis in the management of complement-associated thrombotic microangiopathies? Transfus Apher Sci 2018; 57:31-34. [PMID: 29506907 DOI: 10.1016/j.transci.2018.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Thrombotic microangiopathies (TMAs) are disorders characterized by endothelial cell activation, microangiopathic hemolytic anemia, thrombocytopenia and organ failure of variable intensity. The pathophysiology of various types of TMAs have become an interesting field of study. Alternative complement system activation plays an important role in several pathophysiological conditions. Complement activation is also described in an increasing number of TMAs. Inherited defects in complement regulatory genes and acquired autoantibodies against complement regulatory proteins have been described. Atypical hemolytic uremic synrome (HUS) is caused by uncontrolled activation of the alternative complement system, now called complement-mediated TMAs. Recently, application of a monoclonal antibody that specifically binds to C5 became available to treat patients with complement-mediated TMAs. Eculizumab is a humanized monoclonal antibody that blocks complement C5 activation. Empiric therapeutic apheresis is also recommended in all forms of complement-mediated TMAs. The justification for therapeutic apheresis use in all forms of complement-mediated TMAs is that it can effectively remove the autoantibodies or mutated circulating complement regulators while replacing absent or defective complement regulators. Currently, therapeutic apheresis and eculizumab are the available treatment options for complement-mediated TMAs. In this paper, we review the evidence for the role of therapeutic apheresis in the management of complement-associated TMAs.
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Affiliation(s)
- Serkan Yıldız
- Dokuz Eylul University, Division of Nephrology, Department of Internal Medicine, Izmir, Turkey
| | - Fatih Demirkan
- Dokuz Eylul University, Division of Hematology, Department of Internal Medicine, 35340, Inciralti, Izmir, Turkey.
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14
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Sharma S, Lang IM. Current understanding of the pathophysiology of chronic thromboembolic pulmonary hypertension. Thromb Res 2017. [PMID: 28624155 DOI: 10.1016/j.thromres.2017.06.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension arising from fibrotic obliteration of major pulmonary arteries. Pro-thrombotic states, large clot burden and impaired dissolution are believed to contribute to the occurrence and progression of thrombosis after an acute pulmonary embolic event. Recent data utilizing several models have facilitated the understanding of clot resolution. This review summarizes current knowledge on pathophysiological mechanisms of major vessel occlusion in CTEPH.
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Affiliation(s)
- Smriti Sharma
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Irene M Lang
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
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15
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Renal Thrombotic Microangiopathy in Proliferative Lupus Nephritis: Risk Factors and Clinical Outcomes: A Case-Control Study. J Clin Rheumatol 2017; 22:235-40. [PMID: 27464767 DOI: 10.1097/rhu.0000000000000425] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Renal thrombotic microangiopathy (TMA) may be associated with lupus nephritis. Its relationship to other disease factors and its specific effect on prognosis are not precisely known. Evidence regarding these aspects is controversial, and information focusing on kidney-limited TMA in systemic lupus erythematosus (SLE) patients is scarce. OBJECTIVES The aims of this study were to identify risk factors for renal TMA in patients with lupus nephritis and to determine its impact on clinical outcomes. METHODS A case-control study was performed. We studied 245 renal biopsies from SLE patients. We included patients with renal TMA, as well as control subjects adjusted for glomerulonephritis class, estimated glomerular filtration rate, activity and chronicity indices, and follow-up time. Serological and clinical features were measured at the time of the biopsy and during follow-up. RESULTS Twenty-three patients with renal TMA and 21 control subjects were included. There were no differences in Systemic Lupus Erythematosus Disease Activity Index score, end-stage renal disease, or mortality between groups during follow-up. After multivariate analysis, lymphopenia (odds ratio, 10.69; 95% CI, 1.35-84.74) and anti-Ro antibody positivity (odds ratio, 8.96; 95% CI, 1.49-53.57) remained significantly associated with renal TMA. CONCLUSIONS Lymphopenia and anti-Ro positivity are independent risk factors for renal TMA in SLE patients. This increased risk could be a consequence of the potential role of these factors in endothelial dysfunction and damage. Outcomes were similar for patients with the same estimated glomerular filtration rate and biopsy characteristics, regardless of the presence of TMA.
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16
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Jamme M, Raimbourg Q, Chauveau D, Seguin A, Presne C, Perez P, Gobert P, Wynckel A, Provôt F, Delmas Y, Mousson C, Servais A, Vrigneaud L, Veyradier A, Rondeau E, Coppo P, French Thrombotic Microangiopathies Reference Centre. Predictive features of chronic kidney disease in atypical haemolytic uremic syndrome. PLoS One 2017; 12:e0177894. [PMID: 28542627 PMCID: PMC5436831 DOI: 10.1371/journal.pone.0177894] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 05/04/2017] [Indexed: 11/18/2022] Open
Abstract
Chronic kidney disease (CKD) is a frequent and serious complication of atypical haemolytic uremic syndrome (aHUS). We aimed to develop a simple accurate model to predict the risk of renal dysfunction in aHUS based on clinical and biological features available at hospital admission. Renal function at 1-year follow-up, based on an estimated glomerular filtration rate < 60mL/min/1.73m2 as assessed by the Modification of Diet in Renal Disease equation, was used as an indicator of significant CKD. Prospectively collected data from a cohort of 156 aHUS patients who did not receive eculizumab were used to identify predictors of CKD. Covariates associated with renal impairment were identified by multivariate analysis. The model performance was assessed and a scoring system for clinical practice was constructed from the regression coefficient. Multivariate analyses identified three predictors of CKD: a high serum creatinine level, a high mean arterial pressure and a mildly decreased platelet count. The prognostic model had a good discriminative ability (area under the curve = .84). The scoring system ranged from 0 to 5, with corresponding risks of CKD ranging from 18% to 100%. This model accurately predicts development of 1-year CKD in patients with aHUS using clinical and biological features available on admission. After further validation, this model may assist in clinical decision making.
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Affiliation(s)
- Matthieu Jamme
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, AP-HP, Paris, France
| | | | - Dominique Chauveau
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie-immunologie clinique, Hôpital Rangueil, Toulouse, France
| | - Amélie Seguin
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Réanimation Médicale, Centre Hospitalier Universitaire de Caen, Normandy, France
| | - Claire Presne
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie - Médecine Interne, Hôpital Sud, Amiens, France
| | - Pierre Perez
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie-Immunologie, Service de Réanimation, CHU Brabois, Nancy, France
| | - Pierre Gobert
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Médecine Interne et Néphrologie, Hôpital Général Henri Duffaut, Avignon, France
| | - Alain Wynckel
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie, Hôpital Maison Blanche, Reims, France
| | - François Provôt
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie, Hôpital Albert Calmette, Lille, France
| | - Yahsou Delmas
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie-Transplantation-Dialyse, CHU de Bordeaux, Bordeaux, France
| | - Christiane Mousson
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie, Dijon, France
| | - Aude Servais
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Néphrologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Laurence Vrigneaud
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service de Médecine interne, Néphrologie et Médecine vasculaire, Centre hospitalier de Valenciennes, Valenciennes, France
| | - Agnès Veyradier
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service d'Hématologie Biologique, Hôpital Lariboisière, AP-HP, Paris, France
| | - Eric Rondeau
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, AP-HP, Paris, France
| | - Paul Coppo
- Centre de Reference des Microangiopathies Thrombotiques, Hôpital Saint Antoine, AP-HP, Paris, France
- Service d’Hématologie, Hôpital Saint Antoine, AP-HP, Paris, France
- * E-mail:
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17
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Clark WF, Patriquin C, Licht C, Huang SH, Rock G. Simple diagnosis and treatment algorithm for adult thrombotic microangiopathy. Transfus Apher Sci 2017; 56:50-51. [PMID: 28139433 DOI: 10.1016/j.transci.2016.12.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- W F Clark
- University of Western Ontario, London Health Sciences Centre, London, Canada.
| | | | - C Licht
- Sick Kids Hospital, University of Toronto, Toronto, Canada
| | - S H Huang
- University of Western Ontario, London Health Sciences Centre, London, Canada
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18
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Le Besnerais M, Favre J, Denis CV, Mulder P, Martinet J, Nicol L, Levesque H, Veyradier A, Kopić A, Motto DG, Coppo P, Richard V, Benhamou Y. Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura. J Thromb Haemost 2016; 14:1917-1930. [PMID: 27501520 DOI: 10.1111/jth.13439] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 07/18/2016] [Indexed: 01/01/2023]
Abstract
Essentials Endothelial injury is thought to be a key event in thrombotic thrombocytopenic purpura (TTP). Endothelial and cardiac damages were assessed in a model of TTP using ADAMTS-13 knockout mice. Damages of cardiac perfusion and function were associated with nitric oxide pathway alteration. Endothelial dysfunction constitutes a critical event in TTP development and cardiac injury. SUMMARY Background Cardiac alterations represent a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). Endothelial injury remains poorly defined, but seems to be a key initiating event leading to the formation of platelet-rich thrombi in TTP patients. Objectives To assess the changes in endothelial function and the induced cardiac damage in a mouse model of TTP. Patients/methods We used an animal model in which TTP-like symptoms are triggered by injection of 2000 units kg-1 of recombinant von Willebrand factor in ADAMTS-13 knockout mice. Results These mice developed TTP-like symptoms, i.e. severe thrombocytopenia, schistocytosis, and anemia. On day 2, magnetic resonance imaging demonstrated a decrease in left ventricular perfusion associated with alteration of left ventricular ejection fraction, fractional shortening, and cardiac output, suggesting early systolic dysfunction. This was associated with decrease in endothelium-mediated relaxation responses to acetylcholine in mesenteric and coronary arteries, demonstrating severe early endothelial dysfunction. In parallel, we showed decreased cardiac expression of endothelial nitric oxide (NO) synthase and increased expression of antioxidant enzymes, suggesting alteration of the NO pathway. At this time, cardiac immunohistochemistry revealed an increase in the expression of VCAM-1 and E-selectin. Conclusion This study provides evidence that the heart is a sensitive target organ in TTP, and shows, for the first time, strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. The mechanisms incriminated are the occurrence of a pro-oxidant state, and proadhesive and proinflammatory phenotypes. This previously largely unrecognized vascular dysfunction may represent an important contributor to the systemic organ failure occurring in TTP.
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Affiliation(s)
- M Le Besnerais
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
- Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - J Favre
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - C V Denis
- INSERM UMR S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - P Mulder
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - J Martinet
- INSERM U905, UFR médecine pharmacie Rouen, Rouen, France
| | - L Nicol
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - H Levesque
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - A Veyradier
- Service d'hématologie biologique, Hôpital Lariboisière, AP-HP, Paris, France
- EA3518, IUH Saint Louis, Université Paris-Diderot, Paris, France
| | - A Kopić
- Baxalta Innovations GmbH, Vienna, Austria
| | - D G Motto
- Bloodworks Northwest Research Institute, Seattle, WA, USA
| | - P Coppo
- Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France
- Service d'Hématologie, Hôpital Saint-Antoine, AP-HP, Paris, France
- Institut Gustave Roussy, INSERM U1170, Villejuif, France
| | - V Richard
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - Y Benhamou
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France.
- INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
- Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France.
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19
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Engert A, Balduini C, Brand A, Coiffier B, Cordonnier C, Döhner H, de Wit TD, Eichinger S, Fibbe W, Green T, de Haas F, Iolascon A, Jaffredo T, Rodeghiero F, Salles G, Schuringa JJ. The European Hematology Association Roadmap for European Hematology Research: a consensus document. Haematologica 2016; 101:115-208. [PMID: 26819058 PMCID: PMC4938336 DOI: 10.3324/haematol.2015.136739] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/27/2016] [Indexed: 01/28/2023] Open
Abstract
The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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Affiliation(s)
| | | | - Anneke Brand
- Leids Universitair Medisch Centrum, Leiden, the Netherlands
| | | | | | | | | | | | - Willem Fibbe
- Leids Universitair Medisch Centrum, Leiden, the Netherlands
| | - Tony Green
- Cambridge Institute for Medical Research, United Kingdom
| | - Fleur de Haas
- European Hematology Association, The Hague, the Netherlands
| | | | | | | | - Gilles Salles
- Hospices Civils de Lyon/Université de Lyon, Pierre-Bénite, France
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20
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Pépin M, Kleinjan A, Hajage D, Büller HR, Di Nisio M, Kamphuisen PW, Salomon L, Veyradier A, Stepanian A, Mahé I. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. J Thromb Haemost 2016; 14:306-15. [PMID: 26589836 DOI: 10.1111/jth.13205] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 10/16/2015] [Indexed: 12/11/2022]
Abstract
UNLABELLED ESSENTIALS: Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are associated with the occurrence of VTE in cancer. BACKGROUND Patients with cancer are at high risk of venous thromboembolism (VTE). ADAMTS-13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE. OBJECTIVES The aim of this study was to search for an association between the levels of VWF and ADAMTS-13 and VTE in patients with cancer and to compare current scoring systems for prediction of VTE before and after addition of these parameters. PATIENTS/METHODS In a case-control study, in which patients with recently diagnosed cancer were followed-up for 6 months, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, and type and stage of cancer. We measured VWF, ADAMTS-13 (activity and antigen), P-selectin, D-dimer and F1 + 2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P-selectin and D-dimer levels. RESULTS VWF levels were significantly higher in cases when compared with controls (326 ± 185% vs. 242 ± 158%) and correlated with advanced stage of cancer: localized, 185 [142; 222]; locally advanced, 240 [146; 257]; metastatic, 267 [153; 324] (mean [interquartile range]). The addition of two biomarkers, ADAMTS-13 activity and F1 + 2 levels, to the Khorana score improved receiver operating curves. CONCLUSIONS von Willebrand factor and ADAMTS-13 are associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS-13 and F1 + 2 levels to the Khorana score considerably increases the predictive value for VTE.
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Affiliation(s)
- M Pépin
- Service de Médecine Interne, Hôpital Louis Mourier (AP-HP), Colombes, France
- Unité 1176, INSERM, Le Kremlin-Bicêtre, France
| | - A Kleinjan
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - D Hajage
- Département d'Epidémiologie et Recherche Clinique, URC Paris-Nord, Hôpital Bichat-Claude Bernard (AP-HP), Paris, France
- INSERM, CIC 1425-EC, UMR1123, Paris, France
| | - H R Büller
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - M Di Nisio
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
- Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio, Chieti, Italy
| | - P W Kamphuisen
- Department of Vascular Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - L Salomon
- Département de Recherche, Centre Ophtalmologique Rothschild, Paris, France
| | - A Veyradier
- Service d'Hématologie biologique, Hôpital Lariboisière (AP-HP), Paris, France
- Universitaire Paris Diderot, EA 7334 REMES Sorbonne Paris Cité, Paris, France
- Université Paris Diderot, Institut Universitaire d'Hématologie, EA3518, Paris, France
| | - A Stepanian
- Service d'Hématologie biologique, Hôpital Lariboisière (AP-HP), Paris, France
- Université Paris Diderot, Institut Universitaire d'Hématologie, EA3518, Paris, France
| | - I Mahé
- Service de Médecine Interne, Hôpital Louis Mourier (AP-HP), Colombes, France
- Universitaire Paris Diderot, EA 7334 REMES Sorbonne Paris Cité, Paris, France
- Université Paris Diderot, Institut Universitaire d'Hématologie, EA3518, Paris, France
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Benhamou Y, Baudel JL, Wynckel A, Galicier L, Azoulay E, Provôt F, Pène F, Mira JP, Presne C, Poullin P, Halimi JM, Rivière E, Kanouni T, Seguin A, Mousson C, Servais A, Bordessoule D, Perez P, Hamidou M, Chauveau D, Veyradier A, Coppo P. Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center. Am J Hematol 2015; 90:E127-9. [PMID: 25740210 DOI: 10.1002/ajh.23997] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 02/27/2015] [Indexed: 11/06/2022]
Affiliation(s)
- Ygal Benhamou
- Service de Médecine Interne; CHU Charles Nicolle; Rouen France
- Inserm U1096; Rouen France
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
| | - Jean-Luc Baudel
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Sorbonne Université, UPMC Univ Paris 06; Paris France
- Service De Réanimation Médicale, CHU Saint-Antoine, AP-HP; Paris France
| | - Alain Wynckel
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Néphrologie, Hôpital Maison Blanche; Reims France
| | - Lionel Galicier
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service D'immunologie Clinique; Hôpital Saint-Louis, AP-HP; Paris France
- Univ. Paris Diderot, Sorbonne Paris Cité; Paris France
| | - Elie Azoulay
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Univ. Paris Diderot, Sorbonne Paris Cité; Paris France
- Service De Réanimation Médicale, Hôpital Saint-Louis, AP-HP; Paris France
| | - François Provôt
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Néphrologie, Hôpital Albert Calmette; Lille France
| | - Frédéric Pène
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Réanimation Polyvalente, Hôpital Cochin, AP-HP; Paris France
- Université Paris 5; Paris France
| | - Jean-Paul Mira
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Réanimation Polyvalente, Hôpital Cochin, AP-HP; Paris France
- Université Paris 5; Paris France
| | - Claire Presne
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Néphrologie, Médecine Interne, Hôpital Sud; Amiens France
| | - Pascale Poullin
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service D'hémaphérèse, Hôpital De Marseille Conception; Marseille France
| | - Jean-Michel Halimi
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De néphrologie-Immunologie Clinique, Hôpital Bretonneau; Tours France
- EA 4245, Université François-Rabelais; Tours France
| | - Etienne Rivière
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Médecine Interne/Réanimation Médicale, Université Bordeaux Segalen; Bordeaux France
- Inserm U1034; Centre Hospitalier Universitaire; Bordeaux France
| | - Tarik Kanouni
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Unité D'hémaphérèse Thérapeutique; CHU De Montpellier; Montpellier France
| | - Amélie Seguin
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Réanimation Médicale; Centre Hospitalier Universitaire De Caen; Caen France
| | - Christiane Mousson
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Néphrologie; Dijon France
| | - Aude Servais
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Néphrologie; Hôpital Necker-Enfants Malades; AP-HP; Paris France
| | - Dominique Bordessoule
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service D'hématologie Clinique Et De Thérapie Cellulaire; CHU Dupuytren; Limoges France
| | - Pierre Perez
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service De Réanimation; CHU Brabois; Nancy France
| | - Mohamed Hamidou
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service Médecine Interne a; Hôpital Hôtel-Dieu; Nantes France
| | - Dominique Chauveau
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Département De Néphrologie Et Transplantation D'organes; Hôpital Rangueil; Toulouse France
| | - Agnès Veyradier
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Service D'hématologie Biologique, Hôpital Lariboisière; AP-HP; Paris France
- Université Paris-Sud 11; Le Kremlin-Bicêtre France
| | - Paul Coppo
- Centre De Référence Des Microangiopathies Thrombotiques; Hôpital Saint-Antoine, AP-HP; Paris France
- Inserm U1009; Institut Gustave Roussy; Villejuif France
- Service D'hématologie, Hôpital Saint-Antoine; AP-HP; Paris France
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Yoshida Y, Miyata T, Matsumoto M, Shirotani-Ikejima H, Uchida Y, Ohyama Y, Kokubo T, Fujimura Y. A novel quantitative hemolytic assay coupled with restriction fragment length polymorphisms analysis enabled early diagnosis of atypical hemolytic uremic syndrome and identified unique predisposing mutations in Japan. PLoS One 2015; 10:e0124655. [PMID: 25951460 PMCID: PMC4423893 DOI: 10.1371/journal.pone.0124655] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 03/17/2015] [Indexed: 01/19/2023] Open
Abstract
For thrombotic microangiopathies (TMAs), the diagnosis of atypical hemolytic uremic syndrome (aHUS) is made by ruling out Shiga toxin-producing Escherichia coli (STEC)-associated HUS and ADAMTS13 activity-deficient thrombotic thrombocytopenic purpura (TTP), often using the exclusion criteria for secondary TMAs. Nowadays, assays for ADAMTS13 activity and evaluation for STEC infection can be performed within a few hours. However, a confident diagnosis of aHUS often requires comprehensive gene analysis of the alternative complement activation pathway, which usually takes at least several weeks. However, predisposing genetic abnormalities are only identified in approximately 70% of aHUS. To facilitate the diagnosis of complement-mediated aHUS, we describe a quantitative hemolytic assay using sheep red blood cells (RBCs) and human citrated plasma, spiked with or without a novel inhibitory anti-complement factor H (CFH) monoclonal antibody. Among 45 aHUS patients in Japan, 24% (11/45) had moderate-to-severe (≥50%) hemolysis, whereas the remaining 76% (34/45) patients had mild or no hemolysis (<50%). The former group is largely attributed to CFH-related abnormalities, and the latter group has C3-p.I1157T mutations (16/34), which were identified by restriction fragment length polymorphism (RFLP) analysis. Thus, a quantitative hemolytic assay coupled with RFLP analysis enabled the early diagnosis of complement-mediated aHUS in 60% (27/45) of patients in Japan within a week of presentation. We hypothesize that this novel quantitative hemolytic assay would be more useful in a Caucasian population, who may have a higher proportion of CFH mutations than Japanese patients.
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Affiliation(s)
- Yoko Yoshida
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | - Toshiyuki Miyata
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | | | - Yumiko Uchida
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yoshifumi Ohyama
- Molecular and Cellular Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
| | - Tetsuro Kokubo
- Molecular and Cellular Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
| | - Yoshihiro Fujimura
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
- * E-mail:
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24
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How I treat refractory thrombotic thrombocytopenic purpura. Blood 2015; 125:3860-7. [PMID: 25784681 DOI: 10.1182/blood-2014-11-551580] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 03/07/2015] [Indexed: 01/01/2023] Open
Abstract
Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.
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25
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Benhamou Y, Boelle PY, Baudin B, Ederhy S, Gras J, Galicier L, Azoulay E, Provôt F, Maury E, Pène F, Mira JP, Wynckel A, Presne C, Poullin P, Halimi JM, Delmas Y, Kanouni T, Seguin A, Mousson C, Servais A, Bordessoule D, Perez P, Hamidou M, Cohen A, Veyradier A, Coppo P. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center. J Thromb Haemost 2015; 13:293-302. [PMID: 25403270 DOI: 10.1111/jth.12790] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Indexed: 08/31/2023]
Abstract
BACKGROUND Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. OBJECTIVES To assess the predictive value of cTnI in patients with TTP for death or refractoriness. PATIENTS/METHODS The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. RESULTS Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 μg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 μg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). CONCLUSIONS A CTnI level of > 0.25 μg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.
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Affiliation(s)
- Y Benhamou
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France; Inserm U1096, Rouen, France; Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France
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27
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Ojeda-Uribe M, Merieau S, Guillon M, Aujoulat O, Hinschberger O, Eisenmann JC, Kenizou D, Debliquis A, Veyradier A, Chantrel F. Secondary thrombotic microangiopathy in two patients with Philadelphia-positive hematological malignancies treated with imatinib mesylate. J Oncol Pharm Pract 2015; 22:361-70. [PMID: 25591869 DOI: 10.1177/1078155214568580] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Drug-mediated thrombotic microangiopathy may cause life-threatening medical emergencies. Novel targeted therapies have dramatically changed the prognosis of a number of oncological diseases. Tyrosine kinase inhibitors of the Breakpoint Cluster Region-Abelson (BCR-ABL) oncoprotein are used in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Imatinib mesylate, which was the first anti-BCR-ABL tyrosine kinase inhibitor, has demonstrated a high tolerance profile and efficacy in these patients for many years. Good results have also been observed in patients with gastrointestinal stromal tumors. In this study, we describe two patients with Philadelphia chromosome-positive hematological malignancies who presented with secondary thrombotic microangiopathy that was most likely linked to the use of imatinib. Other potential causes of thrombotic microangiopathy were discarded, and the predisposing role of some comorbidities and potential short or long-term drug-drug interactions was assessed. The clinical and biological data were more indicative of atypical secondary hemolytic uremic syndrome in one of the cases and of secondary thrombotic microangiopathy with renal and cardiac impairment in the other, which is also categorized as secondary hemolytic uremic syndrome. The outcome was favorable after imatinib discontinuation and the treatment of severe cardiac and renal failures.
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Affiliation(s)
- Mario Ojeda-Uribe
- Department of Hematology and Cellular Therapy Unit, Hôpital Emile Muller, Mulhouse, France Centre de Competences on Thrombotic Microangiopathies, Region Alsace, France
| | - Sylvain Merieau
- Laboratory of Hematology, Hôpital Emile Muller, Mulhouse, France
| | - Marie Guillon
- Laboratory of Hematology, Hôpital Emile Muller, Mulhouse, France
| | | | - Olivier Hinschberger
- Centre de Competences on Thrombotic Microangiopathies, Region Alsace, France Department of Internal Medicine, Hôpital Emile Muller, Mulhouse, France
| | - Jean-Claude Eisenmann
- Department of Hematology and Cellular Therapy Unit, Hôpital Emile Muller, Mulhouse, France
| | - David Kenizou
- Department of Cardiology, Hôpital Emile Muller, Mulhouse, France
| | - Agathe Debliquis
- Centre de Competences on Thrombotic Microangiopathies, Region Alsace, France Laboratory of Hematology, Hôpital Emile Muller, Mulhouse, France
| | - Agnès Veyradier
- Department of Biological Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Université Paris, Clamart, France
| | - François Chantrel
- Centre de Competences on Thrombotic Microangiopathies, Region Alsace, France Department of Nephrology, Hôpital Emile Muller, Mulhouse, France
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Kraus E, Kraus K, Obser T, Oyen F, Klemm U, Schneppenheim R, Brehm MA. Platelet-free shear flow assay facilitates analysis of shear-dependent functions of VWF and ADAMTS13. Thromb Res 2014; 134:1285-91. [DOI: 10.1016/j.thromres.2014.08.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 08/01/2014] [Accepted: 08/19/2014] [Indexed: 11/16/2022]
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Affiliation(s)
- Larry A Greenbaum
- Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, 2015 Uppergate Drive NE, Atlanta, GA 30322, USA.
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30
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Valavi E, Ahmadzadeh A, Amoori P, Daneshgar A. High frequency of acquired ADAMTS13 deficiency after hemolysis in Hemiscorpius Lepturus (scorpion) stung children. Indian J Pediatr 2014; 81:665-9. [PMID: 23893367 DOI: 10.1007/s12098-013-1089-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 05/15/2013] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To estimate the frequency of acquired ADAMTS13 deficiency in severe cases of Hemiscorpius lepturus stung patients and the frequency of acute kidney injury (AKI) in these patients. METHODS Sixty scorpion stung children who were referred with severe hemolysis and hemoglobinuria were studied. None of them had received blood products and no one had a past medical history of renal failure. RESULTS Plasma levels of ADAMTS13 and ADAMTS13 antibody (IgG) were measured using ELISA. ADAMTS13 was decreased in 91.7 % of patients and the anti-ADAMTS13 antibody (Ab) was increased in 98.3 %. ADAMTS13 decreased in all of the patients with acute kidney injury and none of those with normal levels of ADAMTS13 developed renal failure; all patients with AKI had also increased levels of ADAMTS13Ab. Acute kidney injury was found in 23.3 % and had significant association with severe anemia, thrombocytopenia, pyuria, hematuria and considerable proteinuria (p < 0.001). Disseminated intravascular coagulation (DIC) and Hemolytic uremic syndrome (HUS) developed in 6.7 % and 10 % respectively. CONCLUSIONS The index findings demonstrate that Hemiscorpius lepturus sting is usually associated with ADAMTS13 deficiency, and increased ADAMTS13 autoantibody. These combined mechanisms may contribute to scorpion sting-induced coagulopathies and may predispose patients to develop DIC and HUS.
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Affiliation(s)
- Ehsan Valavi
- Division of Pediatric Nephrology, Abuzar Children's Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 6163933874, Iran,
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Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD. The glomerulus: the sphere of influence. Clin J Am Soc Nephrol 2014; 9:1461-9. [PMID: 24875196 DOI: 10.2215/cjn.09400913] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The glomerulus, the filtering unit of the kidney, is a unique bundle of capillaries lined by delicate fenestrated endothelia, a complex mesh of proteins that serve as the glomerular basement membrane and specialized visceral epithelial cells that form the slit diaphragms between interdigitating foot processes. Taken together, this arrangement allows continuous filtration of the plasma volume. The dynamic physical forces that determine the single nephron glomerular filtration are considered. In addition, new insights into the cellular and molecular components of the glomerular tuft and their contribution to glomerular disorders are explored.
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Affiliation(s)
- Martin R Pollak
- Beth Israel Deaconess Medical Center, Boston, Massachusetts;
| | - Susan E Quaggin
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and
| | | | - Lance D Dworkin
- Brown Medical School, Brown University, Providence, Rhode Island
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32
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Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood 2014; 124:204-10. [PMID: 24869941 DOI: 10.1182/blood-2014-01-550244] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In acquired thrombotic thrombocytopenic purpura (TTP), the persistence of severe ADAMTS13 deficiency (<10%) during remission is associated with more relapse. Preemptive (ie, after remission) administration of rituximab in these patients to prevent relapses remains controversial. We performed a cross-sectional analysis of 12-year follow-up data to compare the relapse incidence with or without preemptive rituximab infusion. Among 48 patients who experienced at least one episode of acquired TTP followed by severe ADAMTS13 deficiency during remission, 30 received preemptive rituximab (group 1); the other 18 did not (group 2). After a median of 17 months (interquartile range [IQR], 11-29) following rituximab, the relapse incidence decreased from 0.57 episodes/year (IQR, 0.46-0.7) to 0 episodes/year (IQR, 0-0.81) (P < .01) in group 1. ADAMTS13 activity 3 months after the first rituximab infusion increased to 46% (IQR, 30%-68%). Nine patients required additional courses of rituximab. In 5 patients, ADAMTS13 activity failed to increase durably. Four patients experienced manageable adverse effects. In group 2, the relapse incidence was higher (0.5 relapses/year; IQR, 0.12-0.5; P < .01). Relapse-free survival was longer in group 1 (P = .049). A persistent severe ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses.
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Gastaud L, Ambrosetti D, Otto J, Marquette CH, Coutts M, Hofman P, Esnault V, Favre G. Acute kidney injury following crizotinib administration for non-small-cell lung carcinoma. Lung Cancer 2013; 82:362-4. [DOI: 10.1016/j.lungcan.2013.08.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 08/03/2013] [Accepted: 08/07/2013] [Indexed: 10/26/2022]
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Falter T, Alber KJ, Scharrer I. Long term outcome and sequelae in patients after acute thrombotic thrombocytopenic purpura episodes. Hamostaseologie 2013; 33:113-20. [PMID: 23599034 DOI: 10.5482/hamo-12-11-0019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 04/10/2013] [Indexed: 11/05/2022] Open
Abstract
UNLABELLED We report on 21 patients with idiopathic thrombotic thrombocytopenic purpura (TTP) whose courses of disease have been followed from the respective diagnosis until now. They had a documented ADAMTS13 activity below 5%, a high autoantibody titer and detectable ultralarge von Willebrand factor (VWF) multimers during their episodes. The initial diagnosis was based on clinical symptoms and on laboratory parameters: thrombocytopenia, haemolytic anaemia, schistocytes and an increased LDH level. 103 acute clinical episodes of 21 TTP-patients during a time period of 30 years are described. Case histories, comorbidities and sequelae were retrospectively documented. RESULTS, CONCLUSION Although patients are consistently in a prothrombotic status, clinical acute manifestations only occur after triggering. Most common trigger factors are gastrointestinal infections and pregnancy. The relapse risk per month is 0.026; men have a higher risk for relapses (0.044) than women (0.021). Patients recover physically well, except for renal insufficiency in four cases. Nevertheless, major portion of patients suffers persistently from depression, anxiety disorders and persistent neurocognitive impairments.
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Affiliation(s)
- T Falter
- III. Medizinische Klinik, Universitätsmedizin Mainz, Langenbeckstraße 1, Mainz, Germany
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35
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Bilateral serous detachment of retina: an unusual mode of revelation of thrombotic thrombocytopenic purpura of favorable outcome with plasma exchange. Graefes Arch Clin Exp Ophthalmol 2013; 252:181-3. [PMID: 23529795 DOI: 10.1007/s00417-013-2306-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 03/04/2013] [Indexed: 10/27/2022] Open
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36
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Kiss JE, Uhl L. Telltale signs of progress in the management of thrombotic thrombocytopenic purpura. Transfusion 2013; 52:2498-501. [PMID: 23231672 DOI: 10.1111/j.1537-2995.2012.03946.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Purpura thrombotique thrombocytopénique et autres syndromes de microangiopathie thrombotique au cours de l’infection par le virus de l’immunodéficience humaine. Rev Med Interne 2012; 33:259-64. [DOI: 10.1016/j.revmed.2011.11.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 11/04/2011] [Accepted: 11/22/2011] [Indexed: 11/23/2022]
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Hodgkins KS, Bobrowski AE, Lane JC, Langman CB. Clinical grand rounds: atypical hemolytic uremic syndrome. Am J Nephrol 2012; 35:394-400. [PMID: 22517061 DOI: 10.1159/000337954] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.
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Affiliation(s)
- Kavita S Hodgkins
- Division of Kidney Diseases, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, and Children's Memorial Hospital, Chicago, IL, USA
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39
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Yagi H, Matsumoto M, Fujimura Y. Paradigm shift of childhood thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency. Presse Med 2012; 41:e137-55. [PMID: 22264931 DOI: 10.1016/j.lpm.2011.10.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 10/20/2011] [Indexed: 10/14/2022] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological conditions termed thrombotic microangiopathy (TMA). TTP is thought to predominantly affect adults and to rarely occur in children. Currently, TTP is defined by a severe deficiency in the activity of ADAMTS13, a metalloprotease that specifically cleaves unusually large von Willebrand factor multimers under high shear stress. Genetic mutations in and acquired autoantibodies to ADAMTS13 cause congenital TTP (termed Upshaw-Schulman syndrome [USS]) and acquired TTP, respectively. Because of very few overt clinical signs for TTP, USS is often misdiagnosed as chronic idiopathic thrombocytopenic purpura or overlooked during childhood. However, in women with USS, pregnancy can induce thrombocytopenia followed by the development of TTP. Furthermore, early childhood cases of acquired idiopathic TTP have not been characterized. From 1998 to 2008, our institution at Nara Medical University functioned as a TMA referral center in Japan and collected a large dataset on 919 TMA patients (Intern Med 2010;49:7-15). This registry contains 324 patients with a severe deficiency in ADAMTS13 activity, including 41 patients with USS and 283 patients with acquired TTP. Of note, the latter population contains 17 patients who were enrolled as children (≤ 15years old), including 14 children with idiopathic TTP and three with connective tissue disease-associated TTP. Of the 14 patients with idiopathic TTP, five were very young children (under 2 years old). This study focused on these 58 patients (41 USS and 17 acquired TTP) who were diagnosed with a severe deficiency in ADAMTS13 activity during childhood, causing a paradigm shift in our concept of TTP.
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Affiliation(s)
- Hideo Yagi
- Nara Medical University, Department of Blood Transfusion Medicine, Nara 634-8522, Japan
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40
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Postendoscopic retrograde cholangiopancreatography pancreatitis: a rare cause of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Eur J Gastroenterol Hepatol 2011; 23:825-7. [PMID: 21716116 DOI: 10.1097/meg.0b013e328348e73a] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Endothelial injury is perhaps the inciting factor leading to the microangiopathic process that initiates thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). TTP-HUS after postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is extremely rare, but potentially is life threatening. Here, we describe a case of a 23-year-old man with a history of choledocholithiasis, who developed TTP-HUS, 2 days after the onset of post-ERCP pancreatitis. It is important that physicians recognize TTP-HUS as one of the potential causes of acute kidney injury in cases of acute pancreatitis and post-ERCP pancreatitis for adult patients, especially when there is concomitant thrombocytopenia and hemolytic anemia. The early initiation of plasma exchange has a major impact on the survival and preservation of renal function. Exchange transfusion of fresh frozen plasma remains the cornerstone treatment of TTP-HUS.
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41
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Thomas JG, Sethi S, Norby SM. Chronic Thrombotic Microangiopathy Secondary to Chemotherapy for Urothelial Carcinoma in a Patient With a History of Wegener Granulomatosis. Am J Kidney Dis 2011; 57:799-802. [DOI: 10.1053/j.ajkd.2011.01.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Accepted: 01/02/2011] [Indexed: 12/21/2022]
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42
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Stepanian A, Cohen-Moatti M, Sanglier T, Legendre P, Ameziane N, Tsatsaris V, Mandelbrot L, de Prost D, Veyradier A. Von Willebrand factor and ADAMTS13: a candidate couple for preeclampsia pathophysiology. Arterioscler Thromb Vasc Biol 2011; 31:1703-9. [PMID: 21512165 DOI: 10.1161/atvbaha.111.223610] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE The goal of this study was to search for an association between a desintegrin-like and metalloprotease thrombospondin type 1 motif, member 13 (ADAMTS13) levels and the occurrence of preeclampsia, its characteristics (time-onset and severity), and its consequences (occurrence of fetal growth restriction or preterm delivery). METHODS AND RESULTS We studied 140 pairs of women in a case-control study with 3 matching criteria: maternal age, gestational age, and ethnic origin. We measured ADAMTS13 activity using a fluorescence resonance energy transfer assay with the fluorescence resonance energy transfer-VWF73 peptide. ELISA was used to assess protein antigen levels: ADAMTS13, von Willebrand Factor (VWF), interleukin-6, C-reactive protein, P-selectin, and thrombospondin-1. The lowest levels of ADAMTS13 (activity ≤ 70% or antigen ≤ 592 ng/mL) were significantly associated with preeclampsia (odds ratios [OR] [95% confidence interval] of 4.2 [1.1 to 15] and 14.3 [1.7 to 123], respectively). This association was independent of VWF levels and preeclampsia risk factors but dependent on interleukin-6 and C-reactive protein levels for ADAMTS13 activity. Levels of ADAMTS13 activity (≤ 57%) were significantly associated with early-onset preeclampsia (OR = 2.5 [1.1 to 5.8]). Severe preeclampsia was associated with the highest levels of P-selectin (>57 ng/mL) (OR = 3.4 [1.2 to 9.7]). CONCLUSIONS Preeclampsia is associated with decreased levels of ADAMTS13, independently of VWF. This decrease is quantitative, occurs early, and seems to be dependent on inflammation. Our results suggest that ADAMTS13 could participate in the pathophysiology of preeclampsia.
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Affiliation(s)
- Alain Stepanian
- AP-HP Hôpital Antoine Béclère, Service d'Hématologie biologique, 157 rue de la Porte de Trivaux, 92141 Clamart cedex, France.
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Abstract
Thrombotic-thrombocytopenic purpura (TTP) is a microangiopathic disorder characterized by multiple von Willebrand-Factor (vWF) rich microthrombi affecting the arterioles and capillary vessels of several organs. Ultra large von Willebrand multimers cause the blood clotting process by linking to platelets due to a lack of a plasma metalloprotease named ADAMTS13. Deficiency of this vWF-cleaving enzyme is caused by an inborn mutation in the gene coding or, more often, by acquired autoantibodies that inhibit ADAMTS13. TTP is a life-threatening disease which requires urgent admission to a hematological centre. Plasmapheresis therapy should be started immediately when diagnosis of primary TTP is likely. Patients typically present with schistozytes, hemolysis, thrombocytopenia and neurological abnormalities such as headache, focal deficits or coma. The monoclonal CD20 antibody rituximab targets ADAMTS13 antibody production and has the potential to be an effective therapy for relapsed TTP or initial treatment to shorten duration of plasma exchange.
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Affiliation(s)
- M Hellmann
- Klinik I für Innere Medizin, Universitätsklinikum Köln, Kerpener Straße 62, 50937 Köln, Deutschland.
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Coppo P, Centre de référence des Microangiopathies thrombotiques. Microangiopathie thrombotique en réanimation — Vers une classification physiopathologique pour des thérapeutiques ciblées. MEDECINE INTENSIVE REANIMATION 2011. [DOI: 10.1007/s13546-010-0110-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Thrombotic microangiopathy in haematopoietic cell transplantation: an update. Mediterr J Hematol Infect Dis 2010; 2:e2010033. [PMID: 21776339 PMCID: PMC3134219 DOI: 10.4084/mjhid.2010.033] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 10/29/2010] [Indexed: 12/17/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) represents a vital procedure for patients with various hematologic conditions. Despite advances in the field, HCT carries significant morbidity and mortality. A rare but potentially devastating complication is transplantation-associated thrombotic microangiopathy (TA-TMA). In contrast to idiopathic TTP, whose etiology is attributed to deficient activity of ADAMTS13, (a member of the A Disintegrin And Metalloprotease with Thrombospondin 1 repeats family of metalloproteases), patients with TA-TMA have > 5% ADAMTS13 activity. Pathophysiologic mechanisms associated with TA-TMA, include loss of endothelial cell integrity induced by intensive conditioning regimens, immunosuppressive therapy, irradiation, infections and graft-versus-host (GVHD) disease. The reported incidence of TA-TMA ranges from 0.5% to 75%, reflecting the difficulty of accurate diagnosis in these patients. Two different groups have proposed consensus definitions for TA-TMA, yet they fail to distinguish the primary syndrome from secondary causes such as infections or medication exposure. Despite treatment, mortality rate in TA-TMA ranges between 60% to 90%. The treatment strategies for TA-TMA remain challenging. Calcineurin inhibitors should be discontinued and replaced with alternative immunosuppressive agents. Daclizumab, a humanized monoclonal anti-CD25 antibody, has shown promising results in the treatment of TA-TMA. Rituximab or the addition of defibrotide, have been reported to induce remission in this patient population. In general, plasma exchange is not recommended.
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Abstract
PURPOSE OF REVIEW In the following study new aspects and insights into the epidemiology, pathogenesis and typical morphology of kidney involvement in thrombotic microangiopathy (TMA) are discussed. TMA comprises a spectrum of microvascular thrombosis syndromes associated with multiple pathogenetic factors, that is, typical and atypical haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), malignant hypertension, drugs or systemic autoimmune diseases or antibody-mediated rejection. RECENT FINDINGS The present article will put particular emphasis on new pathophysiological insights into the development of TMA in the various settings. In addition, new options in the therapeutic management of TMA in atypical HUS are discussed. The pathogenesis of TMA in atypical HUS primarily involves hereditary or acquired deficiencies and disturbances of the complement system. Eculizumab is a promising new therapeutic option that has been discovered recently. SUMMARY In HUS/TTP the kidney shows characteristic vascular changes due to endothelial damage, that is, TMA, which should be clinically and morphologically differentiated from other diseases. Recent genetic and molecular studies have shed more light on the pathogenesis of TMA in atypical HUS, that is, disturbances of various aspects of the complement system, and in TTP, that is, von Willebrand factor regulation by ADAMTS13, which are also helpful in the differential diagnosis.
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47
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Kiss JE. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol 2010; 91:36-45. [DOI: 10.1007/s12185-009-0478-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 12/16/2009] [Indexed: 01/01/2023]
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Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998-2008. Intern Med 2010; 49:7-15. [PMID: 20045995 DOI: 10.2169/internalmedicine.49.2706] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Thrombotic microangiopathies (TMAs) are pathological conditions characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. Two typical phenotypes of TMAs are hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Severe deficiency of plasma ADAMTS13 activity (ADAMTS13: AC) is more specific for TTP, but not for HUS. Since 1998, our laboratory has functioned as a nationwide referral center for TMAs by analyzing ADAMTS13. METHODS Of 1,564 patients tested from 426 hospitals, 919 were positive for TMA. Levels of ADAMTS13: AC and the ADAMTS13 neutralizing autoantibody (ADAMTS13: INH) were determined by chromogenic act-ELISA and/or by classic von Willebrand factor multimer assay. RESULTS TMA patients consisted of two groups: severe (less than 3% of normal control) and non-severe deficiency of ADAMTS13: AC. Both groups were divided into congenital (n=65) and acquired (n=854) TMA. Of the former, 41 had congenital deficiency of ADAMTS13: AC, while the remaining 24 had disease of unknown etiology. The 854 patients with acquired TMA could be largely grouped into three categories: idiopathic TTP (n=284), idiopathic HUS (n=106), and secondary TMAs (n=464). The secondary TMAs were observed in heterogeneous patient groups and were associated with drugs, connective tissue diseases, malignancies, transplantation, pregnancy, E. coli O157: H7 infection, and other factors. All of the patients with acquired severe ADAMTS13: AC deficiency were positive for ADAMTS13: INH. CONCLUSION Although TMAs are highly heterogeneous pathological conditions, one-third of TMA patients have severe deficiency of ADAMTS13: AC. Platelet transfusions to such patients are contraindicated. Rapid ADAMTS13: AC assays are therefore prerequisite to appropriately treat TMA patients.
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Affiliation(s)
- Yoshihiro Fujimura
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
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Nascimento EJM, Silva AM, Cordeiro MT, Brito CA, Gil LHVG, Braga-Neto U, Marques ETA. Alternative complement pathway deregulation is correlated with dengue severity. PLoS One 2009; 4:e6782. [PMID: 19707565 PMCID: PMC2728508 DOI: 10.1371/journal.pone.0006782] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Accepted: 07/15/2009] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The complement system, a key component that links the innate and adaptive immune responses, has three pathways: the classical, lectin, and alternative pathways. In the present study, we have analyzed the levels of various complement components in blood samples from dengue fever (DF) and dengue hemorrhagic fever (DHF) patients and found that the level of complement activation is associated with disease severity. METHODS AND RESULTS Patients with DHF had lower levels of complement factor 3 (C3; p = 0.002) and increased levels of C3a, C4a and C5a (p<0.0001) when compared to those with the less severe form, DF. There were no significant differences between DF and DHF patients in the levels of C1q, immunocomplexes (CIC-CIq) and CRP. However, small but statistically significant differences were detected in the levels of MBL. In contrast, the levels of two regulatory proteins of the alternative pathway varied widely between DF and DHF patients: DHF patients had higher levels of factor D (p = 0.01), which cleaves factor B to yield the active (C3bBb) C3 convertase, and lower levels of factor H (p = 0.03), which inactivates the (C3bBb) C3 convertase, than did DF patients. When we considered the levels of factors D and H together as an indicator of (C3bBb) C3 convertase regulation, we found that the plasma levels of these regulatory proteins in DHF patients favored the formation of the (C3bBb) C3 convertase, whereas its formation was inhibited in DF patients (p<0.0001). CONCLUSION The data suggest that an imbalance in the levels of regulatory factors D and H is associated with an abnormal regulation of complement activity in DHF patients.
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Affiliation(s)
- Eduardo J. M. Nascimento
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Ana M. Silva
- Virology and Experimental Therapy Laboratory, Aggeu Magalhães Research Center-CPqAM/FIOCRUZ, Recife, Pernambuco, Brazil
| | - Marli T. Cordeiro
- Virology and Experimental Therapy Laboratory, Aggeu Magalhães Research Center-CPqAM/FIOCRUZ, Recife, Pernambuco, Brazil
| | - Carlos A. Brito
- Virology and Experimental Therapy Laboratory, Aggeu Magalhães Research Center-CPqAM/FIOCRUZ, Recife, Pernambuco, Brazil
| | - Laura H. V. G. Gil
- Virology and Experimental Therapy Laboratory, Aggeu Magalhães Research Center-CPqAM/FIOCRUZ, Recife, Pernambuco, Brazil
| | - Ulisses Braga-Neto
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas, United States of America
| | - Ernesto T. A. Marques
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Virology and Experimental Therapy Laboratory, Aggeu Magalhães Research Center-CPqAM/FIOCRUZ, Recife, Pernambuco, Brazil
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
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